Building a Culture of Pharmaceutical QualityImproving 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

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

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

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, 13:17336 % 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.

West meets East: Clash of Cultures?

Adulterated

Central drug controller unveils

‘world’s biggest’ quality check!

Communication Style

Meets Specs

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

A simple framework for CoQ

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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

Score-card; Key Areas of Improvement and Recommendations

Illustrative Score Card: For a company currently in cGMP remediation.

Stars & color codes

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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

Good progress, continue efforts already initiated

Blind-spots, current efforts need additional considerations

Blind-spot + new targeted projects/efforts needed

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

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

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

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

More U.S. Marines contract MalariaWednesday, 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.

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DPA/CDER/FDA Memo B. J. Westenberger, 17 October 2003

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

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….

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 million2σ: 308,537 dpm

(Noncompetitive companies)3σ: 66,807 dpm?Cost of Quality?

3σ: 25-40% of sales4σ: 15-25% of sales5σ: 5 -15% of sales6σ: 1% of sales

Impact of “failure” on

human behavior?

Do , or how do, we deliver

6 sigma products?

Who is responsible for “failure”?

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

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

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