The document discusses the challenges and complexities in ensuring pharmaceutical quality, emphasizing the need for a more integrated and efficient regulatory approach. It outlines the FDA's creation of a 'super-office' to enhance oversight and promote better quality assurance practices, while addressing past failures and current challenges faced by the pharmaceutical industry. The presentation also highlights the importance of collaboration and innovative strategies to prevent quality issues and enhance drug availability.

1. Pharmaceutical Quality:
The Office of
Ajaz S. Hussain, Ph.D.
Executive Director
The National Institute for Pharmaceutical Technology & Education
Duquesne University
Illinois Institute of Technology
Purdue University
Rutgers University
Universidad de Puerto Rico
University of Connecticut
University of Iowa
University of Kansas
University of Kentucky
University of Maryland
University of Michigan
University of Minnesota
University of Wisconsin
10/27/2014 Ajaz@NIPTE.ORG 1

2. CDER Creates
"Super-Office"
to Keep Closer
Eye on Drug
Quality
 “The restructuring will improve the way we
deal with global challenges and increasing
product complexity, and assure that
quality medicines are available to the
American public,” Dr. Woodcock added.
Genetic Engineering & Biotechnology News, Oct 16, 2014.
http://www.genengnews.com/gen-news-highlights/cder-creates-super-office-to-keep-closer-eye-on-drug-quality/81250478/
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3. Assurance of
pharmaceutical
quality poses a
challenge
Pharmaceuticals exhibit market failures that can have
devastating consequences
Devastating consequence → intention to change behavior
and improve approaches for assuring pharmaceutical quality
Lacking effective means to objectively assess & mitigate
risks, we accumulate layers of procedures
Which increases complexity – it , in and of itself, poses
challenges & leads to inefficiencies
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4. If you change the
way you look at
things, the things
you look at change.
Wayne Dyer
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)
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality
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5. it only provides
unnecessary
complexity, since a
manufacturing facility’s
performance is only as
good as the last
inspector’s opinion of
the GMPs
http://www.pharmaceuticalonline.com/doc/cder-s-janet-woodcock-nobody-can-really-tell-me-if-fda-inspections-are-effective-0001
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6. Presentation
Outline:
Questions
• Assurance of pharmaceutical quality poses
a challenge? Why
• Complexities?
• Global challenges?
• Structure of OPQ?
What
• Improve assurance of quality?
• CPPR, NIPTE and other similar
collaborative efforts can help?
How
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7. Preconditions to
malice or
disregard
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality
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8. Human behavior is
predictably irrational
In trying to understand
how best to regulate
“market failure” –
Behavioral economics
or morality based
policies?
We ship! When no one is looking!
http://www.dilbert.com/
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9. Root-cause may
be upstream!
Satisfy reviewer
requirements
Throw-over the wall
Then just do it …
Prone to ‘process entropy’ without FDA Inspections!
Commercial
Operations
Development
& Application
Pharmacovigilance
Inspections – 483,
WL,…
Marketing,….
Manufacturing
Marketing
Authorization
Pre-Approval
Inspection
Review
Application
Development
http://www.nike.com/us/en_us/c/justdoit
“Throw-over the wall”
“Satisfy Reviewer Requirements”
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality
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10. Chemometric, Pharmacometrics & Econometrics: Three Dimensions of QbD.
Ajaz S. Hussain. Swiss Pharma (2012).
Business Decisions:
Commercial operations,
profitability & availability.
Periodic Regulatory Inspections
Review & Approval
Chemometrics
Econometrics
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 Kahneman
Science. 211, pp. 453-458 (1981)
The End of Rational Economics. Dan Ariely.
Harvard Business Review, July 2009.
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality
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11. Complexities &
Global Challenges
Devastating
Consequences
Heparin Disaster
2007-2008
Compounding
Contamination …2011 and
Current Issues
Drug Shortages
2007-2012… Currently.
Therapeutic In-equivalence
Current Issues
Data Integrity and Quality
Assurance – India, China,..
Current Issue
Prophylactic medicine:
Poor Adherence or Quality
2003
Six illustrative examples
See slide 32 for references.
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12. Recap
• Assurance of pharmaceutical quality poses
a challenge? Why
• Complexities?
• Global challenges?
• Structure of OPQ?
What
• Improve assurance of quality?
• CPPR, NIPTE and other similar
collaborative efforts can help?
How
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13. Drivers for
OPQ:
Past Success (?) &
Current Challenges
FDA’s Pharmaceutical Quality
for 21st Century Initiative:
Successes
 ‘Enabling’ of modern technology
(e.g., PAT)
 Updates to GMP regulations; revised
GMP guidance
 Multiple ICH documents:
 Pharmaceutical Development and
Quality by Design
 Quality Risk Management;
 Quality Systems
 Question-based review
 Formation of Pharmaceutical
Inspectorate
 Risk-based selection of facilities for
inspection
Current Challenges
(Not All-Inclusive or In Order of
Priority)
 Drug Shortages
 State of Quality?
 GDUFA Backlog
 Internal Process Improvements
Needed
 Multiple Systems / Databases
 Risk Based Quality Assessment Not
Fully Realized
 Knowledge & Lifecycle Management
 Communication / Silos
 Innovation is Not Increasing
http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf
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14. OPQ Structure
OPQ
Immediate
Office
Office of Programs & Regulatory Operations
Office of Policy
Office of New Drug Products
Office of Lifecycle Drug Products
Office of Process and Facilities
Office of Surveillance
Office of Testing & Research
Office of Biotechnology Products
http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf
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15. Highlights
Quality intelligence, risk
analysis & modeling
Organizational excellence,
training and development
Process & facility (quality & risk)
Dosage forms & life-cycle
http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf
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16. Integrative
thinking, actions,
and tools
http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf
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17. Centralize quality drug review —creating one quality voice by integrating quality
review, quality evaluation, and inspection across the product lifecycle
Consistent quality standards and risk -based approaches
OPQ will establish consistent quality standards and clear expectations for industry
Product standards should be captured in clinical quality attributes and clinically -
relevant specifications
Identifying quality problems, requiring corrective actions where standards are not
met, and making enforcement decisions will require close interaction between OC,
OPQ, and ORA
OPQ will anticipate quality problems before they develop and help prevent drug
shortages
With better knowledge of product and facility quality, we can help assure better
quality drugs that are consistently available
http://www.fda.gov/downloads/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/UCM409544.pdf
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18. Recap &
Summary
• Assurance of pharmaceutical quality poses
a challenge? Why
• Complexities?
• Global challenges?
• Structure of OPQ?
What
• Improve assurance of quality?
• CPPR, NIPTE and other similar
collaborative efforts help?
How
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19. Past successes??
Why the slow
progress?
http://www.slideshare.net/a2zpharmsci/us-fdas-pat-guidance-10-years-and-now-final
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20. Some reasons for
the slow progress
per McKinsey
Report (2011)
How will OPQ
overcome this?
http://www.slideshare.net/a2zpharmsci/us-fdas-pat-guidance-10-years-and-now-final
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21. Reflecting back
10+ years:
Integrated , systems,
thinking essential – it
is like learning to
dance together!
What efforts are
planned to ensure
OPQ will learn to build
effective teams..
http://www.slideshare.net/a2zpharmsci/us-fdas-pat-guidance-10-years-and-now-final
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22. Blind-spots
(cognitive biases)
Data Integrity and Quality
Assurance – India, China,.. Current
Issue
Prophylactic medicine: Poor
Adherence or Quality 2003
More that than a decade
ago to the current
situation…..
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23. More U.S. Marines
contract Malaria
Wednesday, 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.
More than a decade ago…….
 We faced significant challenges in our analysis: Unexpected
inter-laboratory differences that highlighted limitation of the
current calibration procedure
 “We are at a loss to explain the difference between DPA’s and PHI-DO’s
initial results. ………………..
 We further contend that the Helium sparging does not remove
dissolved air as well as the vacuum procedures and therefore could
account for the additional 5 or 6% increase in the dissolution results.
And finally, for this formulation basket wobble can significantly
increase the dissolution values.”
DPA/CDER/FDA Memo B. J. Westenberger, 17 October 2003
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24. Today a better
understanding;
Testing into
compliance –why?
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….
“Throw-over the wall
What I am learning via surveys and interviews…
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality
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25. Process Validation
(2011), Statistical
Confidence,
Continued Process
Verification…
Quality Metrics,….
Will need us to
confront our ‘blind
spots’!
http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004
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26. If we are to
anticipate quality
problems before
they develop – it is
essential to learn
how not to create
problems in the
first place!
http://www.slideshare.net/a2zpharmsci/performance-testing-pharmaceutical-quality-2004
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27. Recap &
Summary
• Assurance of pharmaceutical quality poses
a challenge? Why
• Complexities?
• Global challenges?
• Structure of OPQ?
What
• Improve assurance of quality?
• CPPR, NIPTE and other similar
collaborative efforts can help?
How
10/27/2014 Ajaz@NIPTE.ORG 27

28. Environment that facilitates individuals
to guide their behavior to work
consciously in the interest of patients
and to continually improve this ability.
Culture of Quality
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality
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29. Scientific
methodology
Engineering
Design
Plan-Do-
Check-Act
Consciously
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)
Subconsciously
Consciously ask the right questions in the interest of the patients,
describe the accepted assumptions and set the level of precision
needed for the answers to the questions posed. Be a good scientist –
in the interest of the patients.
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
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30. A useful tool
http://www-2.rotman.utoronto.ca/integrativethinking/definition.htm
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31. A major step
taken by FDA –
we all must work
together to help.
We all are
regulators!
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32. Six illustrative
examples –
references
(additional reading)
 HOUSE HEARING, 110th CONGRESS -THE HEPARIN DISASTER: CHINESE
COUNTERFEITS AND AMERICAN FAILURES. http://www.gpo.gov/fdsys/pkg/CHRG-
110hhrg53183/content-detail.html
 Fungal Meningitis Outbreak.
http://www.fda.gov/Safety/MedWatch/SafetyInformation/SafetyAlertsforHumanMedicalP
roducts/ucm323946.htm
 Seeking solutions to “incredibly complex issue” of drug shortages - See more at:
http://www.wdde.org/22573-rx-shortages-update#sthash.1Htx532R.dpuf
 Drug Shortages. http://www.fda.gov/drugs/drugsafety/drugshortages/
 Update: Bupropion Hydrochloride Extended-Release 300 mg Bioequivalence Studies.
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/uc
m153270.htm
 In quality crackdown, US drug regulator finds Indian companies critically ill. US FDA
turning stricter to ensure compliance levels and quality of medicines. Sushmi Dey. Business
Standard. New Delhi , September 24, 2013. http://www.business-standard.
com/article/companies/in-quality-crackdown-us-drug-regulator-finds-indian-companies-
critically-ill-113092300890_1.html
 More Malaria For Liberia Marines, CBS News September 8, 2003.
http://www.cbsnews.com/news/more-malaria-for-liberia-marines/
 FDA’s ACPS Meeting October 2005. Achieving and demonstrating “Quality by Design” with respect to drug
release/dissolution performance for conventional or immediate release solid oral dosage forms .
http://www.fda.gov/ohrms/dockets/ac/05/briefing/2005-4187B1_01_03-Achieve-Demo-QbD.pdf
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