educating the next generation pharmacist for industry. the panjab university pharmaceutical science...

Educating the Next Generation Pharmacist for Industry

Ajaz S. Hussain, Ph.D.

Insight, Advice & Solutions LLCMaryland, USA

Executive Director, the National Institute for Pharmaceutical Technology & Education

12/12/2014 [email protected] 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 SciencesHendrik 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 (SouthKorea),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 conceptTranslated into the concept of Biowaivers / Biopharmaceutics Classification System (BCS)

Generic Drug ProductsEffective treatment of diseases at a greatly reduced cost. Strong stimulus for the continual innovation that brings new drugs to market

Drug Utilization ReviewsMaximizing the therapeutic benefit while minimizing adverse effects at the lowest overall cost

BiotechnologyNew way of treating diseases through complex molecules (vaccines, antibodies, therapeutic proteins, gene therapy)

Novel Dosage FormsImprove 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


http://www.goodreads.com/author/show/72401.Daniel_Kahneman

http://www.goodreads.com/work/quotes/16402639

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

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)

http://www.cbsnews.com/news/more-malaria-for-liberia-marines/

http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004

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

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(accessed 6 December 2014)

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 controlQuality by

DesignQuality 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 modeCompounding standard applied to modern mass production



Rationalization & Attitude

Pressure & Incentive

Opportunity –‘holes in the QMS”

Individual & TeamBlind-Spots

Latent Conditions

Focus of GMP Remediation – SOP’s

Two products; better than placeboHealing 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(accessed 6 December 2014)


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

PharmacovigilanceInspections – 483, WL,…

Marketing,….Manufacturing

Marketing Authorization

Pre-Approval InspectionReview

ApplicationDevelopment

“Prone to Process Entropy” In ControlContinued Process VerificationEffective CAPAContinual Improvement

“Throw-over the wall”Knowledge & Technology TransferBio – Exhibit – PQ: Life Cycle

“Satisfy Reviewer Requirements”First: Define & Satisfy Requirements based on your expertise; Effective regulatory communication

First: Define & Satisfy Your Own RequirementsRegulator 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?

TestableHypothesis

(accessed 6 December 2014)

http://www.slideshare.net/a2zpharmsci/eca-continuous-manufactruing-ajaz-hussain

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

IntentionFuture

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.

PastBehavior

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


Integrated Framework: Culture of Quality


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

http://www.slideshare.net/a2zpharmsci/

Same shade of gray!




Oration memories….
