Quality by Design, recalls, warning letters, pragmatic, make science visible, OOS investigations

1. 8th World Meeting on Pharmaceutics, Biopharmaceutics, and Pharmaceutical Technology
19th to 22nd March 2012, Istanbul, Turkey
Pharmaceutical Quality by Design:
A Personal Review of Progress and Challenges
Ajaz S. Hussain, Ph.D.
Current Affiliation: Chief Scientific Officer
Philip Morris International R&D, Neuchatel, Switzerland
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2. Reflections, a decade ago at FDA
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3. Reflections, a decade ago at FDA
OVERALL CYCLE TIMES:
QC TESTING TIMES ARE SIGNIFICANT
Overall Cycle Time Components
25
20
TIME 1 5
(D ays) 1 0 Pro ce s s Time s
QC Te stin g Time s
5
0
A B C D E F
PR OC ESS CASE STUD Y
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
•[PPT] Final Report on Process Analytical Technology and ... - FDA
•www.fda.gov/ohrms/dockets/ac/04/.../2004-4080s1_09_Hussain.ppt
•(Source: G. K. Raju, M.I.T. FDA Science Board Meeting, November 16, 2001).
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4. Reflections, a decade ago at FDA
Pharmaceutical Manufacturing:
Impact of Exceptions
(Detailed Analysis of 2 Products)
PERFORMANCE MEASURE VALUE
• Average Cycle time 95 days
• Std dev(Cycle time) > 100 days
• Exceptions increase cycle time by > 50 %
• Exceptions increase variability by > 100%
• Capacity Utilization of “System” LOW
NEED FOR FUNDAMENTAL TECHNOLOGY
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
•[PPT] Final Report on Process Analytical Technology and ... - FDA
•www.fda.gov/ohrms/dockets/ac/04/.../2004-4080s1_09_Hussain.ppt
•(Source: G. K. Raju, M.I.T. FDA Science Board Meeting, November 16, 2001).
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5. Reflections, a decade ago at FDA
Pharma Manufacturing - Unmet Performance Expectations
 Utilisation levels - 15% or less
(but low levels masked).
 Scrap and rework - we plan for 5-10%
(accepted as necessary).
 Time to effectiveness - takes years
(not challenged).
 Costs of quality - in excess of 20%
(that's the way it is).
9
•[PPT] Final Report on Process Analytical Technology and ... - FDA
•www.fda.gov/ohrms/dockets/ac/04/.../2004-4080s1_09_Hussain.ppt
•(Source: FDA Science Board Meeting, November 16, 2001).
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6. Shared vision for the 21st Century
Product quality and performance are achieved and
assured by design of effective and efficient
manufacturing processes
Product specifications are based on a mechanistic
understanding of how formulation and process
factors impact product performance
Manufacturers are able to effect continuous
improvement and continuous "real time"
assurance of quality
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7. Observing the current trends
Recent industry comments suggest an ongoing
struggle; for example, “QbD is in its infancy” or “not
focused on QbD”
State of QbD Implementation: Adoption, Success and
Challenges (McKinsey Report, 2011)
Negative perceptions - quality related recalls, warning
letters, consent decrees, drug shortages, etc.
How should we measure progress of this
initiative?
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharma
ceuticalScienceandClinicalPharmacology/UCM263468.pdf 3/19/2012 Ajaz S. Hussain, Ph.D. 7

8. How should we measure progress
of this initiative?
Number of guidance documents and the numerous
conferences on the topic?
Industry comments (‘QbD is in its infancy’) or
regulatory plans for implementing QbD by 2013?
Number of recalls, unresolved OOS investigations,
warning letters and the resulting erosion of public trust?
QbD has always been the foundation – are there
gaps in the initiative that needs to be filled
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9. Gaps that needs to be filled
Precise vocabulary & communication
• QbD is the foundation
• Objective is to make science visible
‘Initiatives’ and ‘on the ground’ quality
• Enhance efforts on effective root-cause investigations
• Risk management
Pragmatic approach to design-space
• Continual improvement
• Supporting innovation
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10. Precise vocabulary &
communication
The phrase “quality cannot be tested into products,
it has to be built in by design” describes the
foundation for Process Validation in the
pharmaceutical industry
In early 2000 an additional focus was placed on this
foundational element and the phrase ‘quality by
design’ was used for emphasis
The objective was to overcome ‘art’ vs. ‘science’
debate and to ‘make science more visible’ and
effectively utilized for risk-based decisions
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11. Design: Art or science?
A decade ago, at FDA, we debated the utility of
pharmaceutical development information in regulatory
decisions; “art (practice) vs. science’
The natural sciences are concerned with how things
are...design on the other hand is concerned with how
things ought to be
Scientific design is based on scientific knowledge but
utilizes a mix of both intuitive and non-intuitive design
methods
Through the application of scientific knowledge in
practical tasks, design ‘makes science visible’
Cross, Nigel (2001). Designerly ways of knowing: design discipline versus design science. Design Issues, 17(3), pp. 49–
55.
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12. Make science visible
Why? To provide assurance of quality, for demonstrating
effective risk reduction, and justifying options for
efficiency improvements
How? Recognizing that ‘uncertainty = risk +
opportunity’ and that regulators are open to science-
based risk reduction and to create flexibility to facilitate
efficiency improvements
What? Science and practice of assuring effective
quality risk management and efficiency
improvement
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13. Science and practice of
Quality risk reduction Efficiency improvement
• Risks such as in 483 • Reducing development,
observations & Warning production and regulatory
letters, and multiple review cycle times & costs
cycles • Timely implementation of
• Improving assurance of post-approval changes needed
identity, purity, strength, to improve the business
potency ‘bottom line’
• Justifying acceptable variability • Reducing stress and
of critical quality attributes uncertainty associated with
• Capability for rapid root-cause regulatory inspections
investigations
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14. Initiative's and ‘on the ground
quality’
Currently there are a large number of high profile
‘quality issues’ such as product recalls and warning
letters that have attracted publics’ attention
While at the same time several companies have
significant initiatives related to QbD
Is there not a need to balance efforts to also
improve assurance of effective quality risk
management for current products?
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15. Enhance the focus on effective quality
risk management for current products
Risks such as in 483 observations & warning letters, and
multiple review cycles
Justifying acceptable variability of critical quality attributes
Capability for rapid and effective problem root-cause
investigations
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16. Capability for effective problem
root-cause investigations
Root-cause investigations often conclude with ‘root
cause unknown’
How we set specifications can contribute to OOS
simply because of inherent variability ( often ‘common
cause variability)
Discussions in Nov 2001 at the FDA Science Board
highlithed a potential weakens in how we currently
set specifications
Resolution of OOS is often difficult, a reason for
warning letter - escalating to a consent decree
OOS: Out of specification Ajaz S. Hussain, Ph.D. 16
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17. Conflicts in risk management
Cognitive: Lack of agreement on causal links
Evaluative: Lack of agreement on trade-offs
Normative: Lack of agreement on values and fairness
Manifest depending on complexity, uncertainty and
ambiguity in the problem to be solved
Risk Analysis (2002) 3/19/2012 Ajaz S. Hussain, Ph.D.

18. Risk management: Simple to
ambiguous problems Risk tradeoff
analysis and
Risk balancing deliberations
necessary necessary
Scientific risk- • Risk assessment • Risk assessment
assessment necessary and balancing
necessary necessary
Routine operation • Conflict:
Cognitive and • Conflict:
• Agency staff • Conflict: Cognitive,
Cognitive Evaluative
• Discourse: Evaluative,
• Agency staff & • Agency staff, Normative
Internal external
external experts • Agency staff,
• Simple experts,
• Discourse: external
Cognitive stakeholders
experts,
• Complex • Discourse: stakeholders,
Reflective public
• Uncertain representatives
• Discourse:
Causal links identified & Low confidence in causal Participatory
quantified links • Ambiguous
Difficult to identify and Variable interpretation of
quantify causal links identical data
Risk Analysis (2002)
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19. Resolving conflicts for effective risk
management
Cognitive conflict: Improving understanding and
acceptance of causal links
Evaluative conflict: Improving understanding of
uncertainty inherent in the current approach and/or
agreement on acceptable level of uncertainty
Ideally done by ‘making science visible’ when in
good compliance status; after a warning letter
focus on options that minimize evaluative
conflict
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20. Making science visible during
review phase
A decade ago, in the US, pharmaceutical development
information was not considered useful for CMC review
Currently ICH Q8 has been implemented in the NDA
review process and by 2013 will be implemented for
ANDAs
ICH Q8 introduced the concept of ‘design space’ to
facilitate continual improvement; an option to reduce
uncertainty and post-approval supplements
Pragmatic implementation of ICH Q8 (including
design space) is necessary
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/HowDrugsareDevelopedandApproved/ApprovalApplications/Abbrevi
atedNewDrugApplicationANDAGenerics/ucm292533.htm?source=govdelivery
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21. Pragmatic implementation of
ICHQ8
Objective: scientific understanding to identify
critical to quality attributes, variability in these
attributes; to set controls and specifications
Specific information to improve decisions (e.g., risk-
based)
Design space development – a focus on anticipated
or planned efficiency improvements in the post
approval phase can be a useful guide
Scientific design is based on scientific
knowledge but utilizes a mix of both intuitive
and non-intuitive design methods
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22. Regulatory submissions: Pharmaceutics
& Pharmaceutical Technology
Design thinking (often implicit)
Reasoning about uncertainty (blind spot?)
Making estimates (implicit)
Need to explicitly state the underlying theories
and generate testable predictions
http://www.unusualleading.com/wp-content/uploads/2009/12/HBR-on-Design-Thinking.pdf
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23. What is scientific and what is not?
The U.S. Supreme Court: An Evolved Theory of Science (2000)
The theoretical underpinnings of the methods
Francis Bacon’s
Scientific Method must yield testable predictions by means of
which the theory could be falsified
Karl Popper’s
Falsification Theory
Thomas Kuhn’s
Paradigm Shifts
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
http://www.fjc.gov/public/pdf.nsf/lookup/sciman00.pdf/$file/sciman00.pdf
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24. Quality: Testable predictions?
(illustrative)
For the selected formulation, plus established raw-material
acceptance criteria and control of process equipment, variability in
content uniformity is expected to be within X% regardless of
manufacturing site (e.g., Chicago vs. Louisiana)
Change in the supplier of excipients, using the established
acceptance criteria, is expected to have an insignificant impact on
shelf-life.
The established SOP and training procedures will result in X%
deviations in first 1Q 2012 and the rate of deviations will reduce to
Y% by end of 4Q 2012.
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25. Pharmacokinetic/
pharmacodynamics modeling
• Utilizes theories and methods from
physics, mathematics and engineering
• Examples
• Transform theory from mathematics
Pharmacometics • Transport phenomena from
(a multidisciplinary field) engineering and physics
• Linear systems analysis from
engineering systems theory
• Control theory from electrical
engineering
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26. Impact of Pharmacometrics on
drug approval decisions
Pharmacometric analyses are an increasingly
important component NDA and BLA submissions to
the US FDA (End of Phase II Meetings)
During 2000–2008 the number of reviews with an
impact on approval and labeling increased
significantly
Selection of pediatric dosing regimens, approval of
regimens that had not been directly studied in
clinical trials and provision of evidence of
effectiveness to support a single pivotal trial.
Clinical Pharmacokinetics (October 2011)
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27. Concluding remarks
A decade ago, at FDA, we debated the utility of
pharmaceutical development information in regulatory
decisions; “art (practice) vs. science’
Through the application of scientific knowledge in
practical tasks, design ‘makes science visible’’
A pragmatic approach based on explicit description of
‘theory’ underpinning assurance of product quality is
essential
“Without theory, there is no learning.”
- William E Deming
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