On FDA’s Guidance on Pharmaceutical Process Validation (2011)l

On FDA’s Guidance on Pharmaceutical Process Validation (2011)

CONNECTORS BETWEEN CULTURE – METRICS – CPV OF

PROCESS VALIDATION?

Ajaz S. Hussain | Insight Advice & Solutions LLC

1

2/29/2016

Confidence is a critical quality attribute

• CGMP violations erode confidence and increase nocebo effects

• Currently – “breaches in assurance of data integrity” is a global concern

• Exposed the prevailing ‘regulator heterogeneity’

• Re-building ‘epistemic trust” is difficult generally; more so with US FDA


2

2/29/2016

Re-building ‘epistemic trust” is difficult generally; more so with US FDA

For US FDA

• A comprehensive investigation into the extent of the inaccuracies in data records and reporting

• A detailed investigation protocol and methodology; 3rd party ….

• A comprehensive retrospective evaluation

• Interviews of current and former employees to identify the nature, scope, and root cause of data inaccuracies

• Number of OOS failures , out of trend or unexpected results obtained and that were not investigated at the time of occurrence

• Several other requirements…


3

2/29/2016

Culture – Metrics – Process Validations CPV?

Root cause of “breaches”

Human errors

Malicious

•Individual

•System wide (cheating by design)

Human factors and/or

process/method factors??


4

2/29/2016


5

Pre- OPS OPS Post-OPS → OPQ

2015Generic Drug Scandal OGDONDCOCPBOTR

OGDONDCOBPOTR

OGDONDQOBPOTR

ICH Q8…ICH Q6a… PAT

PAT then 21st Century Initiative

Development Report – QbD MethodologyFocus on what is ‘Critical’Risk-based decisions

1987 Process Validation: Quality can not be tested into products, It has to be built in by design (QbD)

US FDA CDER: Office of Pharmaceutical Science

2/29/2016

Vision 2020

Quality by Design Vs

Cheating by Design


6

2/29/2016

https://www.linkedin.com/pulse/schr%C3%B6dingers-cat-my-journey-from-2015-2020-ajaz-s-hussain-ph-d-

21st Century: Strengthen scientific foundation to facilitate risk-based orientation

From “Art” to “Science” of

pharmaceutical product and

process development


7

2/29/2016

2005 -2012: German/Swiss experience

QbD Methodology… ICH

Q8…CTD-P2


8

More than a new paradigm –A potential revolution?

My favorite words – why?• Design space• Procrustean• Epistemology

2/29/2016


9

Recall started in 2008: “…recalled more than 6 million bottles in 2008 when it was discovered the product might not meet certain specifications”

And have continued….

October 21, 2014: “…Another drugmaker is having to recall metoprolol succinate extended release tablets…..

June 30, 2015: “..recalled ..metoprolol succinate extended-release tablets.. because it had failed dissolution testing..

Are the SUPAC-MR research findings “generalizable” – to inform policy?

For example to metoprolol succinate extended-release tablets?

Development, Validation, Review & Inspection of complex (generic) products in need for improvement -protect patients, prevent erosion of confidence and nocebo effects…

SUPAC to Design Space

2/29/2016

http://www.bloomberg.com/news/articles/2014-05-06/thousands-of-complaints-on-blood-pressure-drugs-spur-test

http://www.fiercepharmamanufacturing.com/story/mylan-recalls-blood-pressure-med-following-recalls-generic-two-other-drugma/2014-10-21

http://www.fiercepharmamanufacturing.com/story/indias-dr-reddys-recalls-10-lots-two-drugs-failed-specifications/2015-06-30

http://www.fiercepharmamanufacturing.com/story/indias-dr-reddys-recalls-10-lots-two-drugs-failed-specifications/2015-06-30


10

Chemometrics

Eco

no

met

rics

Review & Approval

Business Decisions:Commercial operations,

profitability & availability.Periodic Regulatory Inspections

Three Econometric Papers on Quality

Decay, Shock, and Renewal: Operational Routines and Process Entropy in the Pharmaceutical Industry. Gopesh Anand, John Gray, and Enno Siemsen. Organization Science. 23:1700-1716 (2012)

Regulator Heterogeneity and Endogenous Efforts to Close the Information Asymmetry Gap: Evidence from FDA regulation. Jeffrey T. Macher, John W. Mayo and Jack A. Nickerson. Journal of Law and Economics. 54: 25 – 54 (2011)

Quality Risk in Offshore Manufacturing: Evidence from the Pharmaceutical Industry. John Gray, Aleda Roth, and Michael Leiblein. Journal of Operations Management. 29: 737–752 (2011)

How do people really make decisions?

Prospect Theory: An Analysis of Decision under Risk. Daniel Kahneman and Amos Tversky Econometrica. 47: 263-291 (1979)

The Framing of Decisions and the Psychology of Choice. Amos Tversky and Daniel KahnemanScience. 211, pp. 453-458 (1981)

The End of Rational Economics. Dan Ariely. Harvard Business Review, July 2009.

Chemometric, Pharmacometrics & Econometrics: Three Dimensions of QbD. Ajaz S. Hussain. Swiss Pharma (2012).

2/29/2016


11

Professor Kahneman’s System 1 and System 2 of human cognition conceptualized

Working consciously, when no one is looking. Questions -

Why some are better than others?

What are the mechanisms for developing consciousness?

How can we facilitate transformation to higher order of consciousness?

2/29/2016

2/29/2016Ajaz S. Hussain | Insight Advice & Solutions LLC

12 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….


13

http://www.pharmamanufacturing.com/assets/Media/MediaManager/Hussein_Pharma_Quality_By_Design.pdf

QbD link to cGMP

Internal FDA Training

2/29/2016



14


QbD link to cGMP

“Approved” & “Validated”

483’s & WL’s link to ‘design’

Learning opportunities

Continuous improvement

2/29/2016



15


QbD link to cGMP

“....well rehearsed demonstration that manufacturing formula can work three successive times.”

“..followed by many hours (possibly days or weeks) of troubleshooting and experimental work after a batch or two of product fails to meet specifications. This becomes a never ending task.”

2/29/2016



16

DATA DERIVED FROMTRIAL-N-ERROR EXPERIMENTATION

WITHOUR A THEORETICAL FOUNDATION

DECISIONS BASED ONUNIVARIATE APPROACH

CAUSAL LINKSPREDICT PERFORMANCE

MECHANISTICUNDERSTANDING

1st Principles

Ajaz S. Hussain. The Nation Needs a Comprehensive Pharmaceutical Engineering

Education and Research System. Pharmaceutical Technology. September 2005

Significant gaps prevail – company logo suggest a path forward!

2/29/2016


17

Epistemic TrustCulture of Quality

2/29/2016


18

Holes not filled or filled after FDA InspectionBreaches

Reasons to rationalize irrational behaviors ‘Framing” effects & irrational decisions

Opportunity & “not harming anybody”

Namesake QMS(A folder of papers – often written by consultants)

Ineffective training & inadequate supervision

Inability to say NO or toexplain what is required

Push for results!Assumption: ‘Quality is Good”;“FDA approved, validated, past inspections okay”

2/29/2016


19

Culture of

Quality

Normal

Easy

Rewarding

QMS

System

Knowledge

Variation

Behavior

Behavior - GXPs

Fear Removed

Awareness

Mastery

EnvironmentLeadership Emphasis

Message Credibility Peer InvolvementEmployee

Empowerment

Connect to CoQConnect to GXPs

http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality

Integrated Framework: Culture of Quality

QbD

2/29/2016

http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality

Subject- Object; Orders of Consciousness

Mechanism of Transformation

• Five stages or orders of human development

• Increasing complexity of our consciousness

• “We have object; we are subject”;

• Objects are elements of our knowing or organizing that we can reflect on

• Transformation is about changing the way we make-meaning; “Subject” becomes the “Object”

• Occurs when we can step back and reflect on something and make decisions about it

Transformative learning

• Occurs when we change the way we behave, the way we feel, what we know, and the way we know it !

Epistemology and

transformative

learning


20

Kegan, R. (1994). In over our heads: The mental demands of modern life. Cambridge, MA. Harvard University Press.

2/29/2016


21

Making-sense of Pharmaceutical Quality in

the 21st Century (Org.) Object

Impulses & desires

Opinions of others

Self-identity, authorship

Subject

Opinions of others

Self-identity (ego) – (need

Dil Se)

Dialectic between

ideologies

Sensemaking

In category- to across

categories

Systematic

System of systems

4th

5th

Check-Box approach. USP/FDA responsible for quality.

Quality; above and beyond USP/FDA. Taking responsibility.

Leaders with maturity to shape industry standards

Kegan, R. (1994). In over our heads: The mental demands of modern life. Cambridge, MA: Harvard University Press.

A scientist is a person engaging in a systematic activity to acquire knowledge.

3rd

2/29/2016

“Market failure”Critical mass of 4th Order Consciousness + Dil Se Necessary

• Regulatory frameworks such a licensing, and “Qualified Person” [self-identity] or the FDA’s emphasis on ‘systems’ approach to Quality[‘systemic’] point towards 4th Order of Consciousness

• Only at this level can we expect a sustained level of a systems approach to quality & culture of quality!

• A critical mass of ‘4th order consciousness’ coupled with effective systems based polices and procedures is a measure of an organization’s trustworthiness


22

Elephant in the Dark or Six Blind Men

2/29/2016

https://www.linkedin.com/pulse/pharmaceutical-quality-elephant-dark-six-blind-men-hussain-ph-d-


23

Epistemic TrustCulture of Quality

Summary: Connectors between Culture – Metrics – CPV of Process Validation?

2/29/2016

Small Business & Entrepreneurship

On FDA’s Guidance on Pharmaceutical Process Validation (2011)l