To frame the current challenges in (the implementation of) Pharmaceutical QbD in a manner that will provide you an opportunity to: (1) Leverage prior learning about medical device QSR to inform and understand key issues in regulation of pharmaceutical QbD (2) Provide an example of a ‘real world’ uncertainty that you should not hesitate to take-on based on the fundamentals of engineering science and practices you have learned

1. Ajaz S. Hussain, Ph.D.
Ajaz S. Hussain, Ph.D., Chief Scientific Officer & President Biotechnology
Quality By Design in Bio/Pharmaceutical Development
2/21/2013
1
BME/Chief598
QualitySystemsandRegulatory
Innovation

2. Ajaz S. Hussain, Ph.D.
BME/ChE 598: Lecture Topics
2/21/2013
2
 Current Status and Future Trends in Biomedical Regulations
 Overview of Quality System Regulation (QSR) for Medical Devices and In-Vitro Diagnostics
 Design Controls in Biomedical Innovation Process
 Human Factors and Reliability Engineering for Patient Safety
 Corrective and Preventive Action (CAPA) and Root Cause Analysis
 Role of Registries in Ensuring Quality and Safety of Orthopaedic and Other Devices
 Quality By Design in Bio/Pharmaceutical Development
 Establishing Regulatory Roadmaps for Generic Drugs, Follow-On Biologics and 510k Medical Products
 Companion Diagnostics and Personalized Medicine
 FDA Regulation of Mobile Health Devices and other Biomedical ICTs
 Risk and Regulation of Radiation Exposure in Biomedical Imaging
 Problems of Regulating Sophisticated Materials and Complex Biomedical Products
 Global Regulatory Harmonization of Biomedical Products and Services
“..this course is
intended to
prepare
students for a
real world
environment..”

3. Ajaz S. Hussain, Ph.D.
Real World Environment
2/21/2013
3
• Risk and uncertainty
• Uncertainty = Risk + Opportunity
Continual change
• How do you reduce risk?
• How do you maximize opportunity?
Regulatory
uncertainty
• Minimize risk and identify opportunity
• Precise vocabulary and clear communication
Fundamentals

4. Ajaz S. Hussain, Ph.D.
Relevant regulatory guidelines
2/21/2013
4
International Conference on Harmonisation -
Quality
Q8(R2) Pharmaceutical Development (PDF - 402KB) 11/20/09
International Conference on Harmonisation -
Quality
Q9 Quality Risk Management (PDF - 113KB) 06/01/06
International Conference on Harmonisation -
Quality
Q10 Pharmaceutical Quality System (PDF - 274KB) 04/07/09
International Conference on Harmonisation -
Quality
Q8, Q9, and Q10 Questions and Answers (PDF - 185KB) 11/01/11
International Conference on Harmonisation -
Quality
Q8, Q9, & Q10 Questions and Answers -- Appendix: Q&As from
Training Sessions (Q8, Q9, & Q10 Points to Consider)
07/25/12
International Conference on Harmonisation -
Quality
Q11 Development and Manufacture of Drug Substances (PDF -
708KB)
11/19/12

5. Ajaz S. Hussain, Ph.D.
Objective of this lecture
2/21/2013
5
 To frame the current challenges in (the implementation of)
Pharmaceutical QbD in a manner that will provide you an
opportunity to
 Leverage prior learning about medical device QSR to inform and
understand key issues in regulation of pharmaceutical QbD
 Provide an example of a ‘real world’ uncertainty that you should not
hesitate to take-on based on the fundamentals of engineering science
and practices you have learned

6. Ajaz S. Hussain, Ph.D.
Quality by Design
 What is ‘quality’?
 What is ‘design’?
 How does ‘design’
deliver ‘quality’?
 Biologics
 Drugs
 Device
 Combination products
2/21/2013
6
Hint: Medical Device Quality System is designed to “assure that products are safe and
effective for their intended use and consistently meet the specifications as defined by results of
clinical and/or detailed technical design and validation

7. Ajaz S. Hussain, Ph.D.
Biologics, Drugs, Devices & Combinations
2/21/2013
7
• Why?
• How?
• What?
Different but
overlapping
regulatory schema
• 21 CFR 56 (IRB’s)
• 21 CFR 58 (GLP)
• 21CFR 11 (Electronic records)
• 21 CFRR 800-1050 (devices)
• 21 CFR 807 (510(k))
• 21 CFR 812 (IDE)
• 21 CFR 814 (PMA)
• 21 CFR 21 CFR 820 QSR (GMP)
Devices

8. Ajaz S. Hussain, Ph.D.
Design Control for a Biologic or Drug
Product?
• Design Planning
• Design Input
• Design Output
• Design Reviews
• Design Verification
• Design Validation
• Design Transfer
• Design Changes
• Design History File
Elements
of Design
Control
(Device)
 A tablet product
 ?
 ?
 ?
2/21/2013
8

9. Ajaz S. Hussain, Ph.D.
Design: Art or Science
2/21/2013
9
 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.

10. Ajaz S. Hussain, Ph.D.
Rest of this lecture..
2/21/2013
10
 Evolution of QbD for pharmaceuticals
 Current state of progress
 Anticipated changes at FDA to improve implementation of
QbD
 Often underestimated challenge; effective multidisciplinary
communication
 Homework assignment

11. Ajaz S. Hussain, Ph.D.
Assumption
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11
• Science (methodology)
• Risk (management)
• Practices
• Guidelines
• Standards
Regulations are
intended to
facilitate
development of
systems that ensure
‘science based risk
management’

12. Ajaz S. Hussain, Ph.D.
Reflections, a decade ago at FDA
History and evolution of QbD for pharmaceuticals
2/21/2013
12

13. 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?
13
2/21/2013Ajaz S. Hussain, Ph.D.

14. Ajaz S. Hussain, Ph.D.
Quality issues and recalls
14
2/21/2013

15. Ajaz S. Hussain, Ph.D.
Low efficiency
15
MIT PHARMACEUTICAL MANUFACTURING INITIATIVE (PHARMI)
OVERALL CYCLE TIMES:
QC TESTING TIMES ARE SIGNIFICANT
0
5
10
15
20
25
TIME
(D ays)
A B C D E F
PR OC ESS CASE STUD Y
Overall Cycle Time Components
Pro cess Time s
QC Te stin g Time s
•[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).
2/21/2013

16. Ajaz S. Hussain, Ph.D.
Opportunity for improvement
16
9
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).
•[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).
2/21/2013

17. Ajaz S. Hussain, Ph.D.
What was not optimal?
2/21/2013
17
CMC review cycles, prior-
approval supplements,
specifications,…
Warning Letters, Consent
Decree, Root-cause
unknown, “c” in
GMP,……..
‘Validation’
with
suboptimal
understanding

18. Ajaz S. Hussain, Ph.D.
Quality has to built-in or be by Design
From 1987: FDA Guidance: General principles of process
validation, May 1987
To 2004: “The goal of PAT is to enhance understanding and
control the manufacturing process, which is consistent with …
quality cannot be tested into products; it should be built-in or
should be by design.” (FDA’s PAT Guidance, 2004)
2/21/2013
18
QbD

19. Ajaz S. Hussain, Ph.D.
Effective risk-assessment
2/21/2013
19
Can occur when both CMC and cGMP functions have a common understanding, and
confidence in, the scientific understanding communicated (in development reports) and
established at a manufacturing facility where a new product will be manufactured
• Acceptable product variability over the intended shelf-life; prior-knowledge,
development data and characterization of clinical trial lots - including process
capability (Cpk) assessment
• CMC to cGMP knowledge sharing meeting - specific considerations relevant to a
novel product and its implications for technology transfer
• Multi-functional FMEA; considering manufacturing facility data (Cpk of similar
products, reject rate, effectiveness of root-cause investigations); also can serve as a
structured approach to guide definition of “c” in GMP

20. Ajaz S. Hussain, Ph.D.
Seamless alignment across functions
2/21/2013
20
• Necessary for common understanding & confidence
• Would allow for an aligned and logical Pharma QbD process
• Facilitate prioritization of critical factors that would be
addressed over the development process
• Improve scientific communication within FDA and with sponsors
• Build confidence in risk-based decisions and to identify
opportunities for ‘less burdensome approaches for continuous
improvement’
CMC review, cGMP compliance
and investigations team approach
(e.g., the previous FDA’s PAT Team)
PicturesfromPATTeam-buildingeventinearly2000

21. Ajaz S. Hussain, Ph.D.
Process Analytical Technology
2/21/2013
21
• Understanding & controlling
variability
• Removing fear of large
samples & new analytics on
old processes
• Opening the door to real-time
release & ‘Design for Six
Sigma’
Process
understanding
• Validation of new methods
based on mechanistic
understanding
• Improvements without “prior-
approval supplement”
• Opening the door to ‘Lean’;
improvements managed within
quality system
Continuous
improvement
• Understanding technologies,
functions & each other
• Finding lean solutions to
facilitate improvement
• Ensuring quality in real-time
from review, compliance and
inspections perspectives
Review-
Compliance-
Investigator Team

22. Ajaz S. Hussain, Ph.D.
Understanding via development reports?
2/21/2013
22
• a point of contention
…. manufacturers
are skeptical about
how FDA will use the
data,…. how much
information to share
with the agency
• "What is needed is the
knowledge .. captured
within that report, ….. if
companies can share that
knowledge, the agency
can …. set more
meaningful specifications
to manage those changes
in less burdensome
ways”.
• “….spends a lot of time
looking at deviations,
failure investigations,
things that are a result of
a less- than- ideal
product or process
knowledge. …..how the
product has been
adequately validated,"
• … will improve our
process, ..requirements
are predictable and the
process …streamlined,
..and very timely. .. a
change …done without
prior approval, where
we've demonstrated the
knowledge of our
process."
ValidationTimes1May2003

23. Ajaz S. Hussain, Ph.D.
Regulatory efforts (2000 – present)
2/21/2013
23

24. Ajaz S. Hussain, Ph.D.
Now, a option to submit …
2/21/2013
24
•Is a option
•With the anticipation it will
not delay approval process
•Not add new requirements
Development
Reports for
CMC review
•Demonstrate science-based
development so that
regulators can make risk-
based decisions
•Reviewer to gain confidence
to support continuous
improvement without prior-
approval supplements
Why?
•Guidance per ICH Q8-10
•Design space?
•Review process?
•Role of compliance &
investigators?
•Less burdensome approach
to improvements?
How?
• Risk-based
specifications?
• Less burdensome
approaches for
improvement?
What?

25. Ajaz S. Hussain, Ph.D.
High level of uncertainty
Current state of progress
2/21/2013
25

26. Ajaz S. Hussain, Ph.D.
An ongoing struggle
2/21/2013
26
 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.
http://www.fda.gov/downloads/AdvisoryCommittees/CommitteesMeetingMaterials/Drugs/AdvisoryCommitteeforPharmac
euticalScienceandClinicalPharmacology/UCM263468.pdf

27. Ajaz S. Hussain, Ph.D.
Functional alignment, improved collaborations
Changes at FDA to improve implementation of QbD?27
2/21/2013

28. Ajaz S. Hussain, Ph.D.
Proposed changes in CDER, FDA
2/21/2013
28

29. Ajaz S. Hussain, Ph.D.
Outside Pharma sector (in the 1990’s)?
2/21/2013
29
LEAN SIX SIGMA ISO to QS-9000 Baldridge Award,
Deming Prize, etc.
Measure, analyze,
and reduce
• wait time
• inventory
• batch size
• process time
• rework
• Use specific
metrics
• Collect data
• Analyze data
• Collect control
data
Monitor and
measure process
performance
Continuous
Improvement
Measure and
improve
• processes
• business results
• overall
organizational
performance
An important area of focus: Statistical analysis and Continuous Improvement (not just CAPA)

30. Ajaz S. Hussain, Ph.D.
Non-pharmaceutical Design for Six Sigma*
2/21/2013
30
Identify
Critical to Customer
(internal and
external) Factors.
Critical to Quality
Factors
Prioritization
Design
Critical to Product
Factors.
Validated Selection
(Analytical) Criteria
Key Process Input &
Output Variables
Optimize
Critical to Process
Tolerances
Optimize inputs
Sensitivity (Risk)
Analysis
Demonstrate
Capability
Validate
Scale-up
Equipment
Qualification
Mistake-proofing &
SOPs
Customer approval,
review & reflection
*Norm Kuchar at General Electric Corporate Research and Development.
Other approaches - Define, Measure, Analyze, Design, Verify (parallel to the
DMAIC process and is advocated by American Society for Quality)

31. Ajaz S. Hussain, Ph.D.
Design for Six Sigma & Pharma QbD
2/21/2013
31
Identify Design Optimize Validate
QTPP CQA Risk
assessment Design space Control
strategy
Continuous
improvement
Design for Six Sigma
Pharma QbD as currently implemented: Advisory Committee for Pharmaceutical Science and Clinical
Pharmacology July 27, 2011

32. Ajaz S. Hussain, Ph.D.
Some observations
 Seamless alignment across functions
that are compartmentalized in
pharmaceutical regulatory review,
compliance & inspection
 Prioritization of critical factors over the
development process
 Optimization includes considerations
for ‘process capability’
 Validation includes a notion of ‘design’
of SOP’s
 Outlined to reflect CMC review; possibly
carving out compliance & inspection
functions
 Conceptual compartmentalization of QTPP,
CQA’s, etc.
 Design space substituted for “optimization”?;
if so, this was not the original intent
 Validation not considered; possibly carving
out compliance & inspection functions
2/21/2013
32
Design for Six Sigma Current Pharma QbD

33. Ajaz S. Hussain, Ph.D.
Design-space substituted for “optimization”?
2/21/2013
33
• Too narrow in scope to be an effective
means for realizing ‘less burdensome
approaches for continuous improvement’
• Focuses review staff to seek large amount
of empirical data which previously was not
submitted
Would make
optimization based on
‘response surface’
methodologies a “new
review requirement”

34. Ajaz S. Hussain, Ph.D.
Get the fundamentals ‘right’
Clear communication
(Planned compliance)
Effective multi-disciplinary communication
2/21/2013
34

35. Ajaz S. Hussain, Ph.D.
Reducing Uncertainty in the Real World
2/21/2013
35
Get the
fundamentals
‘right’
Effective
communication
Planned
compliance

36. Ajaz S. Hussain, Ph.D.
Communication challenge
2/21/2013
36
Causal links
identified &
quantified
Difficult to
identify and
quantify
causal links
Low
confidence in
causal links
Variable
interpretation
of identical
data

37. Disciplinary perspectives on risk
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)?
37
A disciplinary perspective on the epistemological status of risk. Catherine Althaus. Risk Analysis (2005)
2/21/2013Ajaz S. Hussain, Ph.D.

38. Ajaz S. Hussain, Ph.D.
Simple to ambiguous problems
Routine operation
• Agency staff
• Discourse: Internal
• Simple
Scientific risk-
assessment necessary
• Conflict: Cognitive
• Agency staff &
external experts
• Discourse: Cognitive
• Complex
Risk balancing
necessary
• Risk assessment
necessary
• Conflict: Cognitive
and Evaluative
• Agency staff,
external experts,
stakeholders
• Discourse: Reflective
• Uncertain
Risk tradeoff analysis
and deliberations
necessary
• Risk assessment and
balancing necessary
• Conflict: Cognitive,
Evaluative,
Normative
• Agency staff,
external experts,
stakeholders, public
representatives
• Discourse:
Participatory
• AmbiguousRisk Analysis (2002)
38
2/21/2013

39. Ajaz S. Hussain, Ph.D.
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
2/21/2013
39

40. Scientific explanations yield understanding;
quality of explanations differ
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)
40
how do you know what you know?
2/21/2013Ajaz S. Hussain, Ph.D.

41. Ajaz S. Hussain, Ph.D.
Compare and contrast the role of design control
in the development of Medical Devices and
Drug Products
Homework
2/21/2013
41

42. Ajaz S. Hussain, Ph.D.
Summary: Objective of this lecture
2/21/2013
42
 To frame the current challenges in (the implementation of)
Pharmaceutical QbD in a manner that will provide an
opportunity to
 Leverage your prior learning about medical device QSR to inform and
understand issues in pharmaceutical QbD
 Provide an example of a ‘real world’ uncertainty that you should not
hesitate to take-on based on the fundamentals of engineering science
and practices you have learned