Culture of Quality Bagladesh AAPS 8 August 2015 Final

04/17/2023 1

Culture of Pharmaceutical Quality: What, Why, How?

AABPS Convention 2015 Philadelphia Marriott Downtown, Philadelphia, Pennsylvania

Saturday, August 8, 2015

[email protected]

© Ajaz S. Hussain Insight Advice & Solutions LLC

mailto:[email protected]

04/17/2023 © Ajaz S. Hussain Insight Advice & Solutions LLC 2

Thanks for this kind invitation to share some thoughts about Culture of Quality

EnvironmentOrganizationsCulturesSystems

FDA AABPS

NovartisGSK

Merck Others

Today @ Philadelphia Marriott Downtown

USA

BangladeshIndiaChina


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 _ EvidenceBetter 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.

http://www.sciencedirect.com/science/article/pii/S0140673609617062

http://www.nature.com/nrd/journal/v12/n3/abs/nrd3923.html

http://www.economist.com/node/21528593

http://www.economist.com/node/21528593

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

http://www.fda.gov/Drugs/NewsEvents/ucm428298.htm


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 2014FDA Bans Drugs Made by Indian Manufacturer Over GMP Problems January 2015Data Integrity: The Whole Story

http://www.pharmtech.com/data-integrity-key-gmp-compliance-0

http://www.pharmtech.com/data-integrity-key-gmp-compliance-0

http://www.raps.org/Regulatory-Focus/News/2015/01/23/21159/FDA-Bans-Drugs-Made-by-Indian-Manufacturer-Over-GMP-Problems/



http://blog.fdazilla.com/2015/04/data-integrity-the-whole-story/

http://blog.fdazilla.com/2015/04/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

http://www.slideshare.net/a2zpharmsci/excipient-knowledge-management-mumbai-12-march-part-1-2

http://www.slideshare.net/a2zpharmsci/excipient-knowledge-management-mumbai-12-march-part-1-2

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

performing 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

http://www.slideshare.net/a2zpharmsci/product-quality-patient-safety-usp-workshop-mumbai-12-june-2015

http://www.slideshare.net/a2zpharmsci/product-quality-patient-safety-usp-workshop-mumbai-12-june-2015


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

http://www.goodreads.com/author/show/72401.Daniel_Kahneman


http://www.goodreads.com/work/quotes/16402639





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

PracticePracticePractice

Develop Good HabitsOvershadow Bad Habits

Awarenessof Biases

2Slow

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, LogicTraining, Assessment,Scientific methodologyPlan-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.

Emphasis on OutcomeEmphasis on

PeopleTeamworkInnovationStabilityAggressiveness

http://study.com/academy/lesson/what-is-organizational-culture-definition-characteristics.html

http://study.com/academy/lesson/what-is-organizational-culture-definition-characteristics.html


Causal chain:From Antecedents to Culture through to Outcomes

AntecedentsStructureSystem

TechnologySkills

Constructive norms

Passive/Defensive

norms

Aggressive/Defensive

norms

Individual OutcomesRole clarity

Communication Quality“Fit” in organizationBehavior conformity

Job satisfaction

Organizational OutcomesQuality of products/services

Commitment- customer satisfactionAdaptability

TurnoverQuality 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’

http://www.researchgate.net/profile/Robert_Cooke5/publication/235295839_Dysfunctional_culture_dysfunctional_organization_Capturing_the_behavioral_norms_that_form_organizational_culture_and_drive_performance/links/5434a4960cf2bf1f1f27cb89.pdf


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 asupervisor’s order even when they know forsure that the supervisor’s order is not in theinterest of patients.

I disagree with this statement

I completely agree with this statement

N=263Skipped = 0


How would you respond to this statement?

I think management should urgently work towards making error/mistakereporting Normal, Easy and Rewarding.

5.86.6

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=259Skipped =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

EnvironmentLeadership 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

Mastery

EmotionalMastery Technical

Awar

enes

sConfidenceAppr

ecia

te

the

Syst

em

Theory of

Knowledge

Knowledge of Variation

Psychology

Hum

an factorsQua

lity

is

Norm

al

Quality is Easy

Quality is

Rewarding


Going beyond rules pays..

Creating a Culture of Quality: Financial incentives don’t reduce errors. Employees must be passionate about eliminating mistakes. Ashwin Srinivasan and Bryan Kurey. Harvard Business Review, April 2014.

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,…

80’s

90’s

00’s

10’s20’s

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 ..

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