The document discusses the need for a culture of quality in the pharmaceutical industry to improve the effectiveness and confidence in medicines. It highlights issues related to the perceptions of generic medications, emphasizing mistrust among patients and healthcare professionals, and suggests that cognitive biases may contribute to these perceptions. Additionally, it proposes a framework for fostering a culture of quality that prioritizes compliance and effective quality management systems in the pharmaceutical sector.

1. Building a Culture of Pharmaceutical Quality
Improving Confidence in Quality of Medicines
Ajaz S. Hussain, Ph.D.
Insight Advice and Solutions LLC
National Institute of Pharmaceutical Technology & Education
ajaz@ajazhussain.com or ajaz@nipte.org

2. My Viewpoints
• 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%)
• About –the National Institute of
Pharmaceutical Technology &
Education http://www.nipte.org/
• Not-for-profit organization, 14 US
Universities, primarily funded by US FDA
• Research to inform FDA regulatory
policies, QbD training for FDA reviewers
• Improving Quality & Confidence and
Lowering Costs

3. Predictably irrational
• ~40 % US medicines imported
• Breaches in data integrity
• 19 FDA Investigators in India
• Culture of Quality, Metrics, Risk
• Negative media coverage
• Placebo & nocebo increased
• Pricier placebo more effective
• Shape & color of generics

4. generics are for minor but
not serious illnesses;… and
poor people are forced to
‘settle’ for generics.
What do people really think of generic medicines? A systematic review and
critical appraisal of literature on stakeholder perceptions of generic drugs. BMC Medicine 2015, 13:173
36 % of the patients reported negative
experiences after medication substitution
89 % of pharmacists reported receiving
patient complaints regarding use of generic
medicine, although 64 % suggested that this
was due to a nocebo effect
Only 50.2 % of the surveyed pharmacists
agreed that all products that were
approved as generic equivalents can be
considered therapeutically equivalent.
Just 6 % of pharmacists considered
that dry powder inhalers were
interchangeable.
While acceptance of generic medications is improving, substantial mistrust and lack of confidence remains,
particularly within the patient and, to a lesser extent, physician groups.
Nearly half the patients stated they would
refuse generic substitution when it became
available if this was just to save the health
authority money.
Generic medicines were
considered to be poor quality and
treated with suspicion.

5. West meets East: Clash of Cultures?
Adulterated
Central drug controller unveils
‘world’s biggest’ quality check!
Communication
Style
Meets Specs

6. Culture of Quality Training Program
Provide a basis to be confident in improving compliance with cGMPs at facilities in India
and globally
Find ways to ensure efforts are not encumbered by difficult to correct human factors
that may be keeping some companies under a protracted cGMP remediation state
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)
Specifically to appreciate the value of systems approach to quality, identify behaviors
that strengthen it and behaviors that need to change

7. A simple framework for CoQ
7
Culture
of
Quality
Quality is
Normal
Easy
Rewarding
QMS
System
Knowledge
Variation
Behavior
Behavior
- GXPs
Fear
Removed
Mastery
Awareness
Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment
Deming’s Profound Knowledge
& James Reasons – Human Factors
Metrics

8. Score-card; Key Areas
of Improvement and
Recommendations
Illustrative Score Card: For a company
currently in cGMP remediation.
Stars & color codes
8
• 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
Good progress, continue efforts already
initiated
Blind-spots, current efforts need additional
considerations
Blind-spot + new targeted projects/efforts
needed

9. An illustrative impact assessment
One month after completion of training (anonymous survey via Survey Monkey).

10. Areas for added emphasis
• From namesake QMS (a folder of papers) to Systems thinking - a
product of interacting parts. Improving the parts taken separately will
not improve the system
• Non-existing knowledge management to effective theory based CAPA
and Plan-Do-Check-Act (thinking consciously)
• Knowledge of variations – common and special causes
• Behaviors – irrational (system 1 & cognitive biases) to rational – pride
of workmanship
• Culture of error management and QbD
• Training effectiveness – focus on why and not 21 CFR

11. Good practices incompatible with complex processes
• GMPs - complicated process; predictable outcomes from a set starting conditions
• Complex processes do not produce predictable outcomes from a set starting
conditions; small changes can have big impact
• We assume our current process validation justifies this assumption; this is a blind
spot
• FDA’s 2011 Process Validation Guidance addresses this gap; it needs to be fully
implemented

12. An example of a stubborn blind-spot:
Dissolution Testing
• 1995 Testing into Compliance – Remaining cases Generic Scandal
• 2000 USP 1 to 2 – 40 year old product had to be redesigned
• 2001 FDA Science Board – current approach untenable
• 2003 Dissolution becomes a National Security issue
• 2004 FDA Advisory Committee votes 11/0 Calibrator
• ….. Issues continue
• 2015 Testing into Compliance - Breaches in data integrity

13. More U.S. Marines contract
Malaria
Wednesday, September 10, 2003
Posted: 9:25 AM EDT (1325 GMT)
WASHINGTON (CNN) -- Ten more U.S.
military personnel serving as part of the
peacekeeping mission in Liberia are showing
signs of having contracted malaria.
13
DPA/CDER/FDA Memo B. J. Westenberger, 17 October 2003

14. November 2001: FDA Science Board Meeting
G.K.Raju, Ph.D. Executive Director, Pharmaceutical Manufacturing Initiative (PHARMI),
Massachusetts Institute of Technology

15. Anatomy of Testing into Compliance (dissolution)
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….

16. Irrationality in Pharmaceutical Quality
Cognitive biases and attitudes: Enemies of Good Practices
 The pharmaceutical industry’s over-reliance on quality by
inspection is a very ineffective way to do business and most
other industries, …. moved away from this way of working
many years ago (Gerry Migliaccio, former head of global quality at Pfizer)
 A large facility produces 1 billion dosage units per annum
(in 1000 batches) with a 3 sigma process
 How may batches will exhibit OOS, how many will be rejected?
 CEO’s Big & a [small] pharma company
— Senior VP’s of R&D, Operations, Quality,…HR
— Directors, …, Supervisors
— Staff on the ‘front-line’
“We produce
six sigma
products with
three sigma
processes”
Defects per million
2σ: 308,537 dpm
(Noncompetitive companies)
3σ: 66,807 dpm?
Cost of Quality?
3σ: 25-40% of sales
4σ: 15-25% of sales
5σ: 5 -15% of sales
6σ: 1% of sales
Impact of
“failure” on
human
behavior?
Do , or how do,
we deliver
6 sigma
products?
Who is
responsible
for “failure”?

17. Where do we go form here?
• We make two products – medicine and evidence (documents) but
many forget this and do not pay attention to documentation
• Level of attention to documentation is a “canary in a coal mine”
• Breaches are irrational –”System 1 thinking” and cognitive biases
• Culture of Quality is familiar to all of us – a framework proposed
• Quality Metrics – great idea – very much needed; but we are not yet
ready for an FDA Guidance
• We must first address our collective blind spots; be confident that
process validation truly ensures complexity is sufficiently reduced
and that outcomes are predictable

18. Notes and references
• CoQ Framework and Blind-spots - for more detail and references see
• 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
• FDA’s Pharmaceutical CGMPs for the 21st Century. Innovation and Continuous
Improvement in Pharmaceutical Manufacturing (2004)
• http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4080b1_01_manufSciWP.pdf

19. Placebo – nocebo related references
• Dunne, Suzanne S., and Colum P. Dunne. "What do people really think of generic
medicines? A systematic review and critical appraisal of literature on stakeholder
perceptions of generic drugs." BMC medicine 13, no. 1 (2015): 173.
• Espay, A. J., Norris, M. M., Eliassen, J. C., et. al.. Placebo effect of medication cost
in Parkinson disease: A randomized double-blind study. Neurology, 84(8), 794-
802 (2015)
• Peter A. LeWitt, P A., and Kim, S. The pharmacodynamics of placebo: Expectation
effects of price as a proxy for efficacy Neurology, ;84:766–767 (2015)
• Kesselheim, A. S., Misono, A. S., Shrank, W. H., Greene, J. A., Doherty, M., Avorn,
J., & Choudhry, N. K. Variations in pill appearance of antiepileptic drugs and the
risk of nonadherence. JAMA internal medicine, 173(3), 202-208. (2013).
• US FDA Guidance for Industry: Size, Shape, and Other Physical Attributes of
Generic Tablets and Capsules. June 2015