Educating the Next Generation Pharmacist for Industry. The Panjab University Pharmaceutical Science Oration 2014

Educating the Next Generation
Pharmacist for Industry
Ajaz S. Hussain, Ph.D.
Insight, Advice & Solutions LLC
Maryland, USA
Executive Director, the National Institute for
Pharmaceutical Technology & Education
12/12/2014 Ajaz@ajazhussain.com 1
The Panjab University Pharmaceutical Science Oration 2014

“The dream begins with a teacher who believes in you,
who tugs and pushes and leads you to the next
plateau, sometimes poking you with a sharp stick
called ‘truth’.“
Plato, the Republic

Pharmacist
• B.Pharm., M. Pharm., Pharm. D., Ph.D.,…
• License to practice,..
• Retail, Hospital, Academia, Industry, Government,…..
• Many permutations and combinations….
• Significant differences

Pharmaceutical Scientist
• B.Pharm., M. Pharm., Pharm. D., Ph.D.,…
• Other Disciplines
• Academia, Industry, Government,…

Three questions
• What are the most influential ideas, concepts, and developments
introduced by ‘pharmaceutical scientists’ over the last 50 years?
• How have these ideas/concepts introduced into practice?
• How can we improve?

FIP Survey (2010), Five Groups &
Coordinators
• Drug Discovery (Prof. Christian Noe)
• Pharmacokinetics and Pharmacodynamics
(Prof. Geoffrey Tucker)
• Formulation Sciences (Prof. Daan Crommelin)
• Drug Regulation (Dr Carl Peck)
• Drug Utilisation (Dr Mario Rocci)
Impact of the Pharmaceutical Sciences
Hendrik de Jong, FIP secrétaire scientifique, Correspondant Européen, Académie Nationale de, Pharmacie

Who responded to the survey?
Greg Amidon (USA)
Larry Augsburger (USA)
Klaus Peter Bogeso
(Denmark),
Alasdair Breckenridge (UK),
Douwe Breimer
(Netherlands),
Bill Charman (Australia),
Patrick Couvreur (France),
Daan Crommelin
(Netherlands),
Hendrik De Jong
(Netherlands),
Hartmut Derendorf (USA),
Jürgen Engel (Germany),
Alexander Florence (UK),
Leung Fung (USA)
Johan Gabriellson (Sweden),
Giovanni Gaviraghi (Italy),
Anders Grahnen (Sweden),
Theo Guentert (Switzerland),
Richard Guy (UK),
Hideoyshi Harashima
(Japan),
Mitsuru Hashida (Japan),
Keith Jones (UK),
Bill Jusko (USA),
Thomas Kissel (Germany),
Axel Kleemann (Germany),
Larry Lesko (USA)
Panos Macheras (Greece)
Henri Manasse Jr. (USA),
Kamal K. Midha (Canada),
Peter Milligan (UK),
Klaus Mueller (Switzerland),
Ernst Mutschler (Germany),
Tsuneji Nagai (Japan),
Christian Noe (Austria),
Sandy Pang (Canada),
Carl Peck (USA),
Roberto Pelliciari (Italy),
Malcolm Rowland (UK),
Tomas Salmonson (Sweden),
Shigeki Sasaki (Japan),
Hitoshi Sasaki (Japan),
Walter Schunack (Germany),
Vinod Shah (USA),
Chang-Koo Shim (South
Korea),
Juergen Siepmann (France),
Phil Smith (USA),
Don Stanski (Switzerland),
Kjell Strandberg (Sweden),
Yusuke Tanigawara (Japan),
Henk Timmermann
(Netherlands),
Vladimir Torchilin (USA),
Geoffrey Tucker (UK),
Mitsuru Uchiyama (Japan),
Albert Wertheimer (USA)

Drug Discovery
• Molecular drug targets
• Classification of pharmacological receptors including their subtypes for better insight into drug-target interaction of
increasingly complex systems
• Computation in drug design
• Calculation of physical-chemical parameters (QSAR), pharmacophore modelling and high throughput docking
• Molecular Biology – Tools and Drugs
• Biopharmaceuticals, new tools in discovery and development, new imaging techniques, stratification of patients (trials
and therapy)
• Automated screening
• Increased efficiency in hit identification
• Biochemistry, signaling pathways and metabolic networks
• Better mapping of disease biology and design of new drugs with “individualised” therapeutic properties

Pharmacokinetics and
Pharmacodynamics
• The linkage of PK and PD in combined models
• Enhanced interpretation of drug response and the design of optimal dosage regimens
• The Clearance concept
• Allowed understanding of the impact of physiological and pathological changes on the elimination of drugs from the body
• Whole Body Physiologically-Based PK modelling
• Improved prediction of human (and animal) PK and drug-drug interactions, and associated variability
• The concepts of Bioavailability / Bioequivalence
• Provided a scientific basis for improved design of oral (and other) drug products and evaluation of the therapeutic equivalence
of innovator and generic products
• Nonlinear Mixed Effect modelling (“Population PK”)
• Improved insight into population variability in response to drugs (both PK and PD) based on sparse data from individuals.

Formulation Sciences
• Development and implementation of more and more advanced equipment for the production of
high quality “classical” pharmaceutical formulations
• Computational pharmaceutics
• Improved process design and development (ANN, QbD, PAT...)
• Bioavailability concept
• Translated into the concept of Biowaivers / Biopharmaceutics Classification System (BCS)
• Modified release dosage forms (oral and parenteral delivery)
• Improved PK characteristics of medicines and new relevant excipients
• Drug targeting concept with carrier systems
• Temporal and spatial release of medicines, targeted actions of medicines (efficacy, toxicity...)
• New routes of administration apart from oral and parenteral routes
• Improved bioavailability features for transdermal and pulmonary (systemic) delivery

Drug Regulation
• ADME/PK-PD modeling concepts, pharmacometric analyses, and simulation
techniques, leading to:
• Regulatory guidance/ standards for safer, more effective individualized dosing regimens. Facilitated development and
regulatory decisions.
• BioAvailability / BioEquivalence
• Efficient bridging of candidate drug formulations and abbreviated regulatory pathway for generic products
• Pharmacogenomics
• Regulatory acceptance of genetic biomarkers associated with PK-PD variability and disease states
• Risk-benefit evaluation methods
• PKPD, drug metabolism and simulation methods for identification, evaluation and guidance on drug-related Risks
• Formulation optimization / drug delivery systems
• Reduction of regulatory burden via regulatory guidance and evaluation of drug products, including the
Biopharmaceutical Classification System (BCS)

Drug Utilisation
• Generic Drug Products
• Effective treatment of diseases at a greatly reduced cost. Strong stimulus for the continual innovation that brings new
drugs to market
• Drug Utilization Reviews
• Maximizing the therapeutic benefit while minimizing adverse effects at the lowest overall cost
• Biotechnology
• New way of treating diseases through complex molecules (vaccines, antibodies, therapeutic proteins, gene therapy)
• Novel Dosage Forms
• Improve patient’s adherence and effectiveness of drug therapy; reduce the frequency of adverse effects
• Personalized Medicine
• Disease are heterogeneous in nature. Highly target approach to the development of drugs based on patient attributes.
In its infancy, will happen – strong societal and scientific forces at play

Their conclusions
• Along with scientists from other fields, ‘pharmaceutical scientists’
have contributed significantly to the discovery and development of
new drugs and drug preparations, and to improving the efficacy and
safety of existing drugs and drug preparations.
• In particular, pharmaceutical scientists have been key players in
facilitating the translation of these discoveries and developments
into better healthcare
Impact of the pharmaceutical sciences on health care: A reflection over the past 50 years. Malcolm Rowland, Christian R. Noe, Dennis A. Smith, G. T.
Tucker, Daan J. A. Crommelin, Carl C. Peck, Mario L. Rocci Jr., Luc Besançon and Vinod P. Shah. J.Pharm Sci 2012 Aug 21

Formulation Sciences - Drug Utilization -
Drug Regulation
Computational
pharmaceutics
Improved process design
and development (ANN,
QbD, PAT...)
Bioavailability concept
Translated into the concept
of Biowaivers /
Biopharmaceutics
Classification System (BCS)
Generic Drug Products
Effective treatment of diseases at a greatly
reduced cost. Strong stimulus for the
continual innovation that brings new drugs
to market
Drug Utilization Reviews
Maximizing the therapeutic benefit while
minimizing adverse effects at the lowest
overall cost
Biotechnology
New way of treating diseases through
complex molecules (vaccines, antibodies,
therapeutic proteins, gene therapy)
Novel Dosage Forms
Improve patient’s adherence and
effectiveness of drug therapy; reduce the
frequency of adverse effects
ADME/PK-PD modeling
concepts, pharmacometric
analyses, and simulation
techniques, leading to:
Regulatory guidance/ standards for safer,
more effective individualized dosing
regimens. Facilitated development and
regulatory decisions.
BioAvailability /
BioEquivalence
Efficient bridging of candidate drug
formulations and abbreviated regulatory
pathway for generic products
Formulation optimization /
drug delivery systems
Reduction of regulatory burden via
regulatory guidance and evaluation of
drug products, including the
Biopharmaceutical Classification System
(BCS)

Next 50 years?
Formulation Sciences - Drug Utilization - Drug Regulation
Don’t limit a child to your own learning, for he was born in another time.
Rabindranath Tagore

Providing a healing touch – a higher
standard than ‘do no harm’
• “Work is love made visible” ~
Kahlil Gibran
• “Your task is not to seek for love,
but merely to seek and find all
the barriers within yourself that
you have built against it.”
~Rumi

By Design: Intention to act consciously
• In the interest of patients, and to continually improve this ability
• To provide a healing touch – one life at a time, in what we do, and how we
do it.
Consciously
Scientific methodology
Engineering Design
Plan-Do-Check-Act
Subconsciously
Habits (work to get rid of bad ones)
Habits (work to cultivate good one)
Keystone habits (Safety @ Alcoa;
A.L.C.O.A. of data integrity)
The Power of Habit: Why We Do What We Do in Life and Business. Charles Duhigg (2012)
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality

“we can be blind to the obvious, and we are also
blind to our blindness.”
Daniel Kahneman, Thinking, Fast and Slow

We like to think we're rational human
beings; few examples of our 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:
http://www.businessinsider.com/cognitive-biases-2014-6?op=1#ixzz3L8GdJOVe

The squares marked A and B
http://web.mit.edu/persci/people/adelson/checkershadow_proof.html
Same or
different
shade of
gray?

Reflections
• Art
• Compounding
•Science
•Mass Production
•Individualized

By Design is the foundation of Culture of
Quality
It is hard to foster a Culture of Quality!
also @ FDA

Quality & Security
What was the root cause?
• Both pure and applied science have
gradually pushed further and further
the requirements for accuracy and
precision. However, applied science,
particularly in the mass production
of interchangeable parts, is even
more exacting than pure science in
certain matters of accuracy and
precision. Walter A. Shewhart
http://www.cbsnews.com/news/more-malaria-for-liberia-marines/ http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004
(accessed 6 December 2014) (accessed 6 December 2014)

Do no harm → Providing a healing touch
First few days @
FDA
• Learning about death of a child; Fentanyl Patch Transfer
when the child slept in a bed used by grandmother
Working hard to
change minds and
policies
• Hitting a brick wall
Last couple of
months @ FDA
• Death of a young lady following a visit to a dentist; again
poor adhesion a contributing factor
Day 1 to Last
couple of months
@ FDA, and
Currently
• Quality impacts one life at a time, and it manifests in what
we do, and how we do it!
http://www.slideshare.net/a2zpharmsci/good-regulators-of-pharmaceuticals-grp-22-october-2014

We need to learn how not to create
problems in the first place!
http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004
(accessed 6 December 2014)

In order to conform to in-process blend uniformity test specifications, powder blends
were either enriched with additional drug (fentanyl) or diluted with other
ingredients! FDA response ‘there are no validation studies to assure that there is no
adverse product impact throughout shelf life.
http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4080b1_01_manufSciWP.pdf

Practice, Control, Process: Maturity
Initial
• Unpredictable
Managed
• Characterized,
but reactive
Defined
• Characterized;
proactive
Measured &
Controlled
• In control
Optimizing
• Focus on
improvement
Capability Maturity Model Integration; Carnegie Mellon University
A validated process?

Maturity Level & Assurance of Quality
Managed Characterized,
but reactive
High risk of
‘Cheating by
Design’
“Trial
Injections”
“Testing in to
Compliance”
Defined Characterized;
proactive
Lower level of
assurance
Stopping &
Correcting
Batch
Rejection
Measured &
Controlled
In control
Quality by
Design
Quality
Assured
Improvement
Opportunities

At the individual level, in QC function– how
often does this occur?
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
Indian
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….

Compendial standards and manufacturing

Constraints that keep the system in a
corrective action mode
Compounding standard applied to modern mass production

Rationalization &
Attitude
Pressure &
Incentive
Opportunity –
‘holes in the QMS”
Individual & Team
Blind-Spots
Latent Conditions
Focus of GMP
Remediation – SOP’s
Two products; better than placebo
Healing touch for body and mind
Quality & Confidence

Modern, mass production environment
• “The scientific challenges facing pharmaceutical manufacturing go
well beyond the problem of the clinical readout. Despite the slogan
building quality in, most quality assessment today relies on end-
product testing. This is a problem in and of itself. In addition, many
of the tests methods currently being used have severe limitations in
the modern, mass production environment.“
• Woodcock, J. The Concept of Pharmaceutical Quality. American
Pharmaceutical Review. Nov/Dec 2004

Measurement System Analysis
• From ‘calibration’ to ‘Gauge R&R’
Particularly for physical
attributes; destructive analysis
• Many (including regulators) have not yet
understood its importance
Gauge R&R well established
but not commonly practiced
• Measurement system in a state of control;
effective CAPA, quality metrics, Culture of Quality
With the move towards
Statistical Process Control
• Demonstrate equivalent in vitro performance;
more exacting criteria
Development of complex
generic products (ER,
Injectable, Inhalation, etc.)

Process Validation (2011), Statistical
Confidence, Continued Process Verification…
http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004

Critically important attributes may not be
identified, measured and controlled
• “..the limits on quality attributes are often chosen empirically to
ensure production of batches that resemble the batches tested in the
clinic. However, this approach will only ensure consistent clinical
performance if the relationship between those limits and the clinical
outcome is understood. Without this understanding, the limits could
be overly wide, unnecessarily tight, or completely irrelevant to
clinical performance. Even worse, other, critically important
attributes may not be identified, measured and controlled.”
• Woodcock, J. The Concept of Pharmaceutical Quality. American
Pharmaceutical Review. Nov/Dec 2004

Development
& Application
Commercial
Operations
Pharmacovigilance
Inspections – 483, WL,…
Marketing,….
Manufacturing
Marketing Authorization
Pre-Approval Inspection
Review
Application
Development
“Prone to Process Entropy”
In Control
Continued Process Verification
Effective CAPA
Continual Improvement
“Throw-over the wall”
Knowledge & Technology Transfer
Bio – Exhibit – PQ: Life Cycle
“Satisfy Reviewer Requirements”
First: Define & Satisfy Requirements based
on your expertise; Effective regulatory
communication
First: Define & Satisfy Your Own Requirements
Regulator may not always know what is best for the patients

Novartis-MIT
Center for CM
(2007)
8/12/2008,
11/18/2011,……
FDA WLs
GMP Problems
300 Jobs
Chopped At
Novartis Plant
After Mfg.
Gaffes, Worried
Novartis CEO
Insists 'Quality
Matters’
Novartis CEO -
company plans
to build
commercial-
scale
continuous mfg.
facility by 2015
“This will
change the way
medicine is
made around
the world”
Creating a different mass production
environment: Novartis’s 10 year journey …..
http://www.slideshare.net/a2zpharmsci/eca-continuous-manufactruing-ajaz-hussain
Disclosure: I am an advisor & shareholder @
Why GMP problems occur & difficult to remediate? Will this change anything?
Testable
Hypothesis

From academia
to FDA – to
Industry …
added emphasis
needed on
human behavior
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’

Attitude
towards the
behavior
Subjective
norm
Perceived
behavioral
control
Intention
Future
Behavior
usually found to predict
behavioral intentions with a
high degree of accuracy
Intentions, in combination
with perceived behavioral
control, can account for a
considerable proportion of
variance in behavior.
Past
Behavior
Ajen, I. The theory of planned behavior. ORGANIZATIONAL
BEHAVIOR AND HUMAN DECISION PROCESSES 50, 179-211
(1991)
Intention to Behavior: Predictably rational or irrational

Seek and find all the barriers within yourself
that you have built against it
Consciously asking the right questions in the interest of the patients
Describing the accepted assumptions, and
Pre-defining the level of precision needed in the answers to the
questions we have posed
Keep practicing to make it a habit to consciously ask the right
questions,……

Culture
of
Quality
Normal
Rewarding
Easy
QMS
System
Knowledge
Variation
Behavior
Behavior
- GXPs
Fear
Removed
Mastery
Awareness
Environment Leadership Emphasis Message Credibility Peer Involvement Employee Empowerment
Connect to CoQConnect to GXPs
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality
Integrated Framework: Culture of Quality

Providing a healing touch – one life at a
time, in what we do, and how we do it
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!

For additional information:
http://www.slideshare.net/a2zpharmsci/

Same shade of gray!
http://web.mit.edu/persci/people/adelson/checkershadow_proof.html

Oration memories….

Educating the Next Generation Pharmacist for Industry. The Panjab University Pharmaceutical Science Oration 2014

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Educating the Next Generation Pharmacist for Industry. The Panjab University Pharmaceutical Science Oration 2014