25 May 2012 Basel, Switzerland. A philosophical exploration - Scientific understanding and risk-based regulatory decisions on Quality by Design. How good are the scientific explanations in regulatory submissions? Scientific explanations yield understanding; quality of explanations differ.What role can Chemometrics, Pharmacometics and Econometrics play? Understanding multidisciplinary (cGMP, CMC, Clin. Pharm., Tox., Clinical, Public Health) perspectives on risk is important. Opportunities; only when the disciplinary divides are bridged. Within the regulatory realm how we set specifications and assess risk have progressed incrementally; at this rate the Vision 2020 may be expected to be visible broadly over time, by 2020?

1. Ajaz S. Hussain, Ph.D.
Fellow, Swiss Society for Pharmaceutical
Sciences
New Affiliation:
Chief Scientific Officer & President
Biotechnology
Wockhardt Ltd.
Chemometrics, Pharmacometrics and
Econometrics Dimensions of Quality by
Design
5/25/20121

2. A philosophical exploration
Scientific understanding and risk-based
regulatory decisions on Quality by Design
5/25/20122

3. Motivation
 FDA Initiatives launched a decade ago have had a profound
impact on the global pharmaceutical sector
 Process Analytical Technology
 Quality by Design
 Efforts to conducts risk-based regulatory review and inspections
 Good guidelines and significant regulatory efforts around the world
 Significant industrial programs and efforts
 Academic programs and scholarly contributions
 Yet, the number of „compliance issues‟, „recalls‟, „drug
shortages‟, „warning letters‟, etc., today rival the
situation a decade ago
 Why? What is missing? How can we improve the
situation?
5/25/20123

4. Looking back, briefly
How good are the scientific explanations in
regulatory submissions?
5/25/20124

5. Dr. Woodcock‟s Challenge in 2000
“Will this $ X00 million consent decree improve quality of the real
[physical] product?
How effective is “process validation”? Is it not just a “well-rehearsed
demonstration…. 3 times”?
Is our system truly a “modern quality system”?
Are our “specifications” based on sound science and risk
principles?
How is “c” in cGMP established?
Do current regulations support “continuous improvement”?
How efficient is pharmaceutical manufacturing?
5/25/20125

6. Compliance and noncompliance
are complex behaviors
The product of habits and routines.
Automatic
The intentional pursuit of various goals,
such as to maximize one‟s utility, fulfill a
moral obligation such as duty or trust, or
dispose of one‟s fear of sanctions.
Planned
Can be the result of regulatees‟
incapacity, incompetence, ignorance or
misunderstanding of regulatory
prescriptions.
Other
Brehm and Hamilton (1996)
5/25/20126

7. Framing & conceptualizing
“I can see clearly now”
Vision 2020
“Scientific explanation
yields understanding”
 Perspectives on
Regulation: Law,
Discretion, and
Bureaucratic Behavior
(Kagan and Scholz, May
1980)
 „Good citizens‟ Vs.
{„political citizens,
„incompetent‟, and/or
„amoral‟}
 For FDA to be science and
risk-based it needs
scientific data &http://www.fda.gov/ohrms/dockets/ac/04/briefing/2004-4052B1_09_Hussain-Arden-UK-
Presentation.ppt
5/25/20127

8. Making the case (in the US) for CMC
review of development reports
Creating a common ICH vision (“desired state”)
to develop ICH Q8, Q9 and Q10
5/25/20128

9. How good are the scientific
explanations in regulatory
submissions?
First principles
Mechanistic
understanding
Causal links –
predict
performance
Univariate
methods
Empirical data via
trial-n-error
• Variability in cGMP
compliance?,
• Variability in critical to
quality attributes (e.g.,
within and between lots;
also now individual
units),
• Variability in PK/PD &
outcome (e.g., intra- and
inter- individual
variability),
• Other …….
Humans are
driven to
acquire and
provide
explanations
(but not
necessarily to
regulators).
5/25/20129

10. Three perspectives on improving scientific
understanding through development reports
(2003)
Development
reports still a
stumbling
block in GMP
Initiative
Development reports remain a point of
contention …. manufacturers are skeptical
about how FDA will use the data,…. how
much information to share with the agency
Ajaz Hussain
(FDA, CDER) "What is needed is the knowledge that is
captured within that report, ….." He said
that if companies can share that
knowledge, the agency can …. set more
meaningful specifications to manage those
changes in less burdensome ways”.
http://www.thefreelibrary.com/Development+reports+still+a+stumbling+block+in+GMP+Initiative.+(C
MC).-a0104031269
5/25/201210

11. Three perspectives on improving scientific
understanding through development reports
(2003)
Doug
Ellsworth
(FDA New
Jersey
District
Office)
Currently the agency spends a lot of time looking at
deviations, failure investigations, things that are a
result of a less- than- ideal product or process
knowledge. "We'll know we're getting close when
investigators can spend more time on adequacy of
the quality system and not necessarily how the
product has been adequately validated," he said.
Gerry
Migliaccio
(Global QA
Chief,
Pfizer)
"We will have a victory if I can sit back and set Pfizer
quality standards based on regulations and guidance
documents not based on warning letters and 483s…
will improve our process, ..requirements are
predictable and the process for getting that change
is streamlined, straightforward and very timely. .. a
change that can be done without prior approval,
where we've demonstrated the knowledge of our
process."
5/25/201211
http://www.thefreelibrary.com/Development+reports+still+a+stumbling+block+in+GMP+Initiative.+(C
MC).-a0104031269

12. FDA & ICH Initiatives
PAT Initiative
• Guidance +
Review,
Compliance &
Inspection Team
ICH
Guidelines
• Q8, Q9 and
Q10 (Q11)
Additionally
• Office of
Generic Drug’s
efforts
5/25/201212

13. Scientific explanations yield
understanding; quality of explanations
differ
Making a Case for Regulatory Utility of
Chemometrics, Pharmacometrics and
Econometrics
5/25/201213

14. Although understanding arises from
explanation, a question remains
Explanation could be
subjective -- a feeling of
grasping the connection
between explanandum and
explanans; if so
• Such understanding would be
denied any epistemological status
Therefore, scientific
understanding, in a regulatory
context, best communicated …
• Explanation,
• Prediction, and
• Confirmation
THE EPISTEMOLOGICAL STATUS OF SCIENTIFIC THEORIES: AN INVESTIGATION OF THE
STRUCTURAL REALIST ACCOUNT Ioannis Votsis, LONDON SCHOOL OF ECONOMICS AND
POLITICAL SCIENCE (2004) 5/25/201214
how do you know what you know?

15. What is scientific and what is not?
The U.S. Supreme Court: An Evolved Theory of Science
(2000)
The theoretical underpinnings of the methods
must yield testable predictions by means of
which the theory could be falsified
There should be a known rate of error that
can be used in evaluating the results.
The methods should preferably be published
in a peer-reviewed journal.
The methods should be generally accepted
within the relevant scientific community
Francis Bacon‟s
Scientific Method
Karl Popper‟s
Falsification Theory
Thomas Kuhn‟s
Paradigm Shifts
http://www.fjc.gov/public/pdf.nsf/lookup/sciman00.pdf/$file/sciman00.pdf 5/25/201215

16. Analysis of Knowledge
Truth—and
Falsity…—before beliefs
The Correct Analysis of
Knowledge
S is [internally/externally]
justified in believing that
p.
S believes <that> p.
S is justified in
believing <that> p.
p is true.
S knows p.
Unconscious Knowledge and Epistemic Status. LUÍS M. AUGUSTO. UNIVERSITY OF SUSSEX, June
5/25/201216

17. Prescription for trouble
How flaw in FDA safety net may pose
risk to public with generic drugs
• Tom Abate, Todd Wallack, Chronicle Staff Writers
• San Francisco Chronicle. Sunday, December 22,
2002
The issues
• “[Company X] had tested its generic with chocolate
milk. [Ref.product] was chased with apple juice.”
• “Did that matter?”
http://www.sfgate.com/cgi-bin/article.cgi?f=/c/a/2002/12/22/MN35888.DTL&ao=all
5/25/201217

18. What role can Chemometrics, Pharmacometics
and Econometrics play?
The Correct Analysis of
Knowledge
S believes <that> p.
S is justified in
believing <that> p.
p is true.
S knows p.
Unconscious Knowledge and Epistemic Status. LUÍS M. AUGUSTO. UNIVERSITY OF SUSSEX, June
5/25/201218
Build a case example via
discussion with the audience

19. Epistemological Status of Risk
Understanding multidisciplinary (cGMP, CMC,
Clin. Pharm., Tox., Clinical, Public Health)
perspectives on risk is important
5/25/201219

20. Is risk a metaphysical or an
epistemological category?
the mental state of an individual who experiences
uncertainty or doubt or worry as to the outcome of
a given event.
Subjective
risk:
the variation that occurs when actual losses differ
from expected losses.
Objective
risk:
the combination of probability and negative
consequence that exists in the real world.
Real risk:
the measurement of that combination obtained by
constructing a model of the real world.
Observed
risk:
the rough estimate of real risk made by an
untrained member of the general public.
Perceived
risk:
A disciplinary perspective on the epistemological status of risk. Catherine Althaus. Risk Analysis (2005)
5/25/201220

21. Distinguishing risk from
uncertainty
Risk can be considered as an ordered
application of knowledge to the unknown
Different disciplines have a particular
knowledge approach with which they confront
the unknown so as to order its randomness
and convert it into a risk proposition
A disciplinary perspective on the epistemological status of risk. Catherine Althaus. Risk Analysis (2005)
5/25/201221

22. This concept of risk can act as a
mirror
Reflecting the
preoccupations,
strengths, and
weaknesses of
each discipline
as they grapple
with uncertainty
• Acceptable variance in cGMP compliance,
critical to quality attributes (in the context of
safety and efficacy)?
5/25/201222
A disciplinary perspective on the epistemological status of risk. Catherine Althaus. Risk Analysis (2005)

23. Preoccupations, strengths, and
weaknesses of each discipline
Regulatory utility of pharmacometrics has advanced rapidly in
FDA and EMA; it is having a significant impact on clinical trial
designs and science and risk-based decisions in the clinical
pharmacology disciplines
Regulatory utility of chemometrics is sporadic and with
difficulties; there are lessons to be learned from regulatory
applications of pharmacometrics
cGMP risk classifications remain subjective to a large degree;
utility, within regulatory agencies, of econometric approaches is
worth considering
5/25/201223

24. Opportunities; only when the
disciplinary divides are bridged
• Estimate of variance in PK/PD &
outcomes (e.g., intra- and inter-
individual variability)
Pharmacometrics
• Estimate of variance in critical to quality
attributes (in the context of PK/PD
variability)
Chemometrics
• Estimate of variance in cGMP
compliance (in the context of acceptable
variance in critical to quality attributes)
Econometrics?
5/25/201224

25. Why? What is missing? How can
we improve the situation?
The FDA & ICH initiatives have
provided incentives for a few
companies to progress ahead
significantly, with new technologies
and systems, while others have not
Within the regulatory realm how we
set specifications and assess risk
have progressed incrementally; at
this rate the Vision 2020 may be
expected to be visible broadly over
time, by 2020?
5/25/201225

26. Backup slides
5/25/201226

27. Econometric analysis?
Does offshore production
pose an added quality risk
relative to domestic
production?
“Our findings indicate that
Puerto Rico plants operate
with a significantly higher
quality risk than matching
plants operated by the
same firm located in the
mainland U.S., on
average.”
• If so, what factors
influence the quality risk?
• Quality risk in offshore
manufacturing: Evidence
from the pharmaceutical
industry. Volume 29,
Issues 7–8, November
2011, Pages 737–752,
Journal of Operations
Management
5/25/201227

28. Chemometrics
 The chemical discipline that uses mathematical
and statistical methods, (a) to design or select
optimal measurement procedures and
experiments, and (b) to provide maximum
chemical information by analyzing chemical data.
5/25/201228

29. Other examples
Scale-up factor 10X
“3 batches” in process validation
“Significant body of data” for stability requirments
80 – 125%
How do you know what you know?
5/25/201229

30. Process understanding (PAT
Guidance)
A process is generally considered well understood
when
• (1) all critical sources of variability are identified and explained;
• (2) variability is managed by the process; and,
• (3) product quality attributes can be accurately and reliably
predicted over the design space established for materials used,
process parameters, manufacturing, environmental, and other
conditions.
The ability to predict reflects a high degree of
process understanding.
• Although retrospective process capability data are indicative of
a state of control, these alone may be insufficient to gauge or
communicate process understanding.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformat
ion/Guidances/ucm070305.pdf 5/25/201230