Pharmaceutical Quality Assurance

21st Century Pharmaceutical
Quality Assurance: Suitability &
Capability of Measurement Systems
Ajaz S. Hussain, Ph.D.
President, The National Institute of Pharmaceutical Technology & Education
Insight, Advice & Solutions LLC
3/20/2018 ©Copyright 2017-2018 Ajaz S. Hussain, Ph.D. 1

ExpectedP1 – ObservationP1 = ∆P1
ExpectationP2 – ObservationP2 = ∆P2
Objective is to reduce the ∆
∆P1 - ∆P2 = 0 (Satisfaction)

[ExpectedP1]– ObservationP1 = ∆P1
[ExpectationP2]– ObservationP2 = ∆P2
Remove expectancy-effects
∆P1 - ∆P2 ≠ 0

ObservationP0– ObservationP1 = ∆P1
ObservationP0– ObservationP2 = ∆P2
Double-blinding & Placebo-arm
∆P1 - ∆P2 = 0; 95% CI α =0.05; or
∆𝑃𝑃𝑃
∆𝑃𝑃𝑃
= 1 (0.8 to 1.25)

Chang, R.S. and Lotti, V.J., 1986. Biochemical and
pharmacological characterization of an extremely
potent and selective nonpeptide cholecystokinin
antagonist. Proceedings of the National Academy
of Sciences, 83(13), pp.4923-4926.
Colloca, L. and Benedetti, F., 2005.
Placebos and painkillers: is mind as real as
matter?. Nature Reviews Neuroscience,
6(7), p.545..

Is mind as real as matter?
When words are painful: Unraveling the mechanisms of the nocebo effect. Neuroscience,
147(2), pp.260-271 (2007)
Nocebo hyperalgesia: How anxiety is turned into pain. Current Opinion in Anesthesiology, 20(5),
pp.435-439 (2007)
Getting the pain you expect: Mechanisms of placebo, nocebo and reappraisal effects in humans.
Nature medicine, 16(11), p.1277 (2010).
The pharmacodynamics of placebo: Expectation effects of price as a proxy for efficacy. Editorial.
American Academy of Neurology. February 2015.
Interactions between brain and spinal cord mediate value effects in nocebo hyperalgesia.
Science, 358(6359), pp.105-108 (2017)

Is mind as real as matter?
Nature Reviews Neuroscience (2005)
• When words are painful: Unraveling the mechanisms of
the nocebo effect. Neuroscience, 147(2), pp.260-271
(2007)
• Nocebo hyperalgesia: How anxiety is turned into pain.
Current Opinion in Anesthesiology, 20(5), pp.435-439
(2007)
• Getting the pain you expect: Mechanisms of placebo,
nocebo and reappraisal effects in humans. Nature
medicine, 16(11), p.1277 (2010).
• The pharmacodynamics of placebo: Expectation effects of
price as a proxy for efficacy. Editorial. American Academy
of Neurology. February 2015.
• Interactions between brain and spinal cord mediate value
effects in nocebo hyperalgesia. Science, 358(6359),
pp.105-108 (2017)

Pharmaceuticals in the Experience
Economy: illustrative examples of
changing business models and the
rising need for Assurance

We are experiencing pain and inequality in ways that are unprecedented!
Data is dated!

Experiencing Automatic Substitution
Annals of internal medicine.
161(2), pp.96-103 2014
Burden of Changes in Pill Appearance
for Patients Receiving Generic
Cardiovascular Medications After
Myocardial Infarction.
The Washington Post. 14 July 2014.
If Color or Shape of Generic Pills
Changes, Patients May Stop Taking
Them.
Final Guidance. June 2015
Guidance for Industry. Size, Shape, and
Other Physical Attributes of Generic
Tablets and Capsules. Pharmaceutical
Quality/CMC.
Generics for
Me, but a
Brand for
You! #@*
Research in
Social and
Administrative
Pharmacy, 8(6),
pp.574-578
(2012)

Levothyroxine Experience in France
Aug. 24 2017
Levothyrox: The controversy over one of
France's most commonly prescribed drug
explained (The Local)
Sep. 11 2017
No fraud, no conspiracy, no error: France
and Merck say reformulated Euthyrox is
safe (in-Pharma Technologist.com)
Sep. 16 2017
France to bring back old thyroid drug after
complaints (RFI)
Oct. 4 2017
Police raid Merck pharmaceutical plant
amid mysterious drug crisis. Is something
wrong with hormone therapy or are
patients over-reacting? (arsTECHNICA)

Experience New & Improved Formulation!
Assuring the Quality of
the Most Prescribed
Drug
New formulation
launched in France,
March 2017
Within a few weeks,
the social media
started buzzing.
The backlash
intensified; the media
storm posed political
problem for the
French government!
Just wondering if anyone else is taking the new Levo formula from XYZ. I've been on it about 2 or 3
weeks and so far gained three kilos. 😩😩!
“France brings back a phased-out drug after patients rebel against its
replacement” - Science Magazine. 27 September 2017
Germany, New Zealand,….

A hurricane: BAD-I
• Widespread breaches in the assurance of data
integrity
• Pharmaceuticals
• Automobile
• All over
• Companies Everywhere Copied Japanese
Manufacturing. Now the Model is Cracking:
Concepts celebrated in business publications
worldwide have been tarnished by a sting of
scandals. The Wall Street Journal, 4 February 2018.

Illusions of Quality (Gold Sheet 2014)

Hurricane in our mind matters!

Without the burden of BAD-I: It took Amgen About 10 years to 6 σ *
*Ajaz Hussain. How To Break The Pharmaceutical 2-3 Sigma Barrier (Like Amgen).
Pharmaceutical Online. September 2017.

A short history of
Pharma’s key process
quality methodology by
Ron Snee!
• First is the fact that major changes —
so-called paradigm shifts — take a
long time — sometimes a generation
or more before a new idea becomes
standard practice. The adoption of a
new idea moves forward most rapidly
when a major need has been clearly
identified and agreed upon, a usable
solution has been developed, and
clearly and continuously articulated
by the adopters.

To Err is Human & Pharmaceutical Quality for the 21st Century

Healthcare sectors
• Electronic Medical Records
• Quality improvement programs
• Example – fractal-based quality management
infrastructure, lean six sigma, at Johns Hopkins
• Patient satisfaction, outcome and
sustainability metrics
• Professional Development
• Need to change the current culture of continuing
education to focus on Continuous Professional
Development (IOM, 2010)

Goodbye Gauss, hello Pareto:
Welcome to the Experience
Economy!
• Welcome to the Experience Economy (Harvard
Business Review, 1998)
• The End of Rational Economics (Harvard Business
Review, 2009)
• Average Is Over: Powering America Beyond the Age of
the Great Stagnation. Tyler Cowen, Publisher -
Penguin Group, 2013.
• If color or shape of generic pills changes, patients
may stop taking them. Washington Post. 14 July 2014.
• Why is the Placebo Effect Exploding in the U.S. But
Nowhere Else? Forbes. 7 October 2015.
• Side Effects Skyrocket in France With Levothyroxine
Reformulation. Medscape. 11 October 2017.
Andriani, P. and McKelvey, B., Perspective—From
Gaussian to Paretian thinking: Causes and implications
of power laws in organizations. Organization
Science, 20(6), pp.1053-1071. (2009).

4 A grades we must achieve!

Order of
Consciousness

Standing on shoulder of giants….

To Cause the Desired
Effect: From Gaussian to
Paretian thinking: Design
thinking, to Systems
thinking,… the Power Law
ISO to ICH Q10
Deming's Theory of Profound
Knowledge

Let us
recognize our
expectancy
effects in the
real world!

We can choose to keep our blindfolds, or we
can agree to see an elephant in the dark.
• Our development is reflected at times of
challenge and controversy. The mounting
challenges and controversies today are a
reflection of our current order of
consciousness. We will never solve the
problems tomorrow with the same order of
consciousness we are using to create the
problems of today. We must be the change.
To do so, we must pay attention to a canary
which is already in the coals of our mind. We
must agree to see the elephant in the dark.
Only by our commitment to hold high our
knowledge candles, and to be together strong,
we genuinely are suitable and capable of
confronting risks lurking in our collective
darkness. We are in the dark, our candles held
high, no one but us know how secure or
insecure we feel inside. It doesn’t matter as
long as we remain committed to illuminating
the darkness. In doing so, we raise our order
of consciousness!

Pharmaceutical Quality Assurance

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