Current issues and challenges in demonstrating QbD Korea 1 December 2014

2014 Ministry of Food and Drug Safety (MFDS) International Workshop:� Quality by Design (QbD) Implementation and Regulatory Challenges in the�New Pharmaceutical Quality Paradigm�December 1 -2, 2014, Grand Hilton Hotel, Seoul, Korea.

Legitimate pharmaceutical community has practiced QbD for decades; however in ways that vary undesirably.

Demonstration of QbD is multifaceted.

There are serious consequences …in ways that can vary undesirably…

The consequence of “Cheating by Design” are almost always catastrophic.

Perhaps we need to view QbD applications/submissions as an additional layer of protection; to gauge the Culture of Quality.

Legitimate efficiency – is a key business driver, good for the patients, and the society overall.

Proposed ICH Q12: Regulatory Dossier - “regulatory commitments”.

Pharmaceutical Quality System aspects (ICH Q10) – risk and knowledge management system.

Post-Approval Change Management Plans and Protocols.

A reminder of the approach utilized for FDA’s PAT Guidance, Comparability Protocol and Team Approach.

Must focus on integrated implementation.

Team-building and training for Review, Compliance & Inspection functions.

Recognize that QbD Applications/submissions serve as an additional layer of protection; to gauge the Culture of Quality.

1. Current Issues and Challenges in
Demonstrating QbD:
Solutions to Consider
Ajaz S. Hussain, Ph.D.
Insight Advice & Solutions LLC
2014 Ministry of Food and Drug Safety (MFDS) International Workshop:
Quality by Design (QbD) Implementation and Regulatory Challenges in the
New Pharmaceutical Quality Paradigm
December 1 -2, 2014, Grand Hilton Hotel, Seoul, Korea
12/1/2014 [email protected] 1

2. Outline
•A Perspective on Demonstrating QbD
•Current Issues and Challenges
•Solutions to Consider
12/1/2014 [email protected] 2

3. Legitimate efficiency –is a key business
driver, good for the patients, and the
society overall
A Perspective on Demonstrating QbD
12/1/2014 [email protected] 3

4. QbD
•Quality
•By Design
•“….quality cannot be tested into
products, it has to be built in by
design”
•a phrase broadly used and it has
been the foundation of process
validationfor many decades
•For example, the1987 FDA
Guidance on Process Validation.
12/1/2014 [email protected] 4

5. Demonstration of QbD is multifaceted
•Effective Quality Management System
•Continued Process Verification, Reliability, Capability (Process Validation 2011)
•Effective resolution (i.e., system wide, not repeating) of complaints, deviations, CAPA, ..
•Level of understanding and control of critical quality material attributes and
process parameters relevant to the patients (safety and efficacy)
•Right attributes, analytics and acceptance range
•Structured development methodology (not just trial-n-error); asking the right questions, making
assumptions transparent, and pre-defining the level of precision needed in the answers needed
•Legitimate pharmaceutical community has practiced QbD for decades;
however in ways that vary undesirably
•ICH Q8, 9, 10 are intended to improve the common understanding so as to reduce variability and
facilitate continual improvement
12/1/2014 [email protected] 5

6. …in ways that can vary undesirably…
•CMC Review approach in US, EU, Japan,…. (e.g., prior to CTD-P2)
•Historically, very different attitude towards the utility of ‘Development Report’ in the
review process
•Regulatory specifications
•Same product and manufacturing process often with different specifications in US & EU
(often resulting in a higher rate of batch rejections, landfill/incinerator costs in the US)
•Different inspectional approaches
•Audit, System-based, Risk-based; Very different risk-assessment
12/1/2014 [email protected] 6

7. …in ways that can vary undesirably…
•Batch that do not conform to set specifications
•Have to be investigated and often rejected –significant cost/efficiency
implications
•In affluent societies/companies, rejection maybe ‘affordable’
•In less affluent companies and/or emerging economies (now an integral
part of global supply chain) batch rejection may be unaffordable or may
not be the norm; and may occur relatively less frequently than
anticipated;
•This suspicion is currently raising a concern (in the US) that perhaps some
of these ‘data are too good to be true’
12/1/2014 [email protected] 7

8. 92% of GMP Warning Letters in 2014
(until 7/14/14) related to lapses in data
integrity (Alicia M. Mozzachio, July 15, 2014; FDLI, Washington, DC.)
•Not recording activities
contemporaneously
•Backdating
•Fabricating data
•Copying existing data as new data
•Re-running samples
•Discarding data
Challenges in the assurance of Data Integrity
WL in 2013
•+ 31%
WL in 2014 (7/14/14)
•+ 92%
12/1/2014 [email protected] 8

9. This situation, in my opinion, is an
embracement for all of us
•These observations, being noted today, I suggest, have always been
there; and we can expect more of these observation to be noted in
other regions with a reduction in regulator heterogeneity
•Currently, a high level of regulator heterogeneity regarding ability
to detect lapses in data integrity
•For example in India –it is widely known that if a particular FDA
inspector comes to a facility –there is a high likelihood of a
disastrous inspection; if he does not -it is time to celebrate!
12/1/2014 [email protected] 9

10. Consequences of …in ways that can vary
undesirably…
•For example, bad press –often uninformed; contributing
to an erosion of confidence which patients need in their
medicines
•Meds banned in US pose no risk to consumers: TGA
•''Feeble’ Health Canada can't block dodgy drug imports
12/1/2014 [email protected] 10

11. Legitimate efficiency –is a key business driver,
good for the patients, and for the society overall
•In part, this was recognized by the FDA’s Science Board (2001-
2004); however, it is not widely understood or appreciated in the
regulatory community
•Additionally, the pressure of low efficiency on maintaining an
adequate assurance of data integrity, I hope, will soon be more
widely recognized
12/1/2014 [email protected] 11

12. Report to the FDA’s Science Board (2004)
12/1/2014 [email protected] 12

13. Report to the FDA’s Science Board (2004)
12/1/2014 [email protected] 13

14. Report to the FDA’s Science Board (2004)
12/1/2014 [email protected] 14

15. Compendial standards and manufacturing
12/1/2014 [email protected] 15

16. Report to the FDA’s Science Board (2004)
10%
> 1 year
12/1/2014 [email protected] 16

17. 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
documentatio
n not critical
Compendial
testing
sufficient
Indian
regulators
collect & test
samples –no
issue there!
“Testing into compliance”
“Throw-over the wall”
Why ‘testing into compliance’ behavior can occur?
Why it may be easy to rationalize?
Based on interviews conducted in India.
12/1/2014 [email protected] 17

18. Beyond the legitimate pharmaceutical
community
•We are reminded, that there are those who will substitute
a rat poison for an API
•The consequence of “Cheating by Design” are almost always
catastrophic
12/1/2014 [email protected] 18

19. Quality By Design’ is a foundational element of
•Pharmaceutical Culture of Quality
•QbD applications can provide a measure for ‘Culture of Quality’
•Perhaps we need to view QbD applications/submissions as an
additional layer of protection;
•Ameans to weed out suspicion of ‘cheating by design’?
•This can only occur when there is optimal integration
•Of all stakeholder perspectives, know-how and talent in decision making
12/1/2014 [email protected] 19

20. Summary: My Perspective on QbD
•Legitimate pharmaceutical community has practiced QbD for decades;
however in ways that vary undesirably
•Demonstration of QbD is multifaceted
•There are serious consequences …in ways that can vary undesirably…
•The consequence of “Cheating by Design” are almost always
catastrophic
•Perhaps we need to view QbD applications/submissions as an
additional layer of protection; to gauge the Culture of Quality
•Legitimate efficiency –is a key business driver, good for the patients,
and the society overall
12/1/2014 [email protected] 20

21. To QbD or not? That is the question
today; unfortunately
Current Issues and Challenges?
12/1/2014 [email protected] 21

22. The Pharmaceutical Development Section (P2)
provides an opportunity
•To present the knowledge gainedthrough the application of
scientific approaches and quality risk management …..
•Provide a comprehensive understanding of the product and
manufacturing process for reviewers and inspectors.
•The [ICH Q8] guideline also indicates areas where the
demonstration of greater understanding of pharmaceutical and
manufacturing sciences can create a basis for flexible regulatory
approaches.
12/1/2014 [email protected] 22

23. Integrative or Systems Approach to
Pharmaceutical Quality Decisions
•Pharmaceutical exhibit market failure in that the patients or their
health care provider are often unable to judge quality
•Societies empower regulators to be informed on how to judge quality on their
behalf and then to ensure patients have the confidence in medicines
•Assurance of pharmaceutical quality is best approached by
incorporating all stakeholder perspectives, know-how and talent
in decision making
•ICH Q8, 9 and 10, among others, are tools for the various decision makers to be
informed on how to evaluate quality and to utilize methodologies (by design)
that can reliably delivery quality (QbD)
12/1/2014 [email protected] 23

24. Common framework, vocabulary & understanding to
guide decisions in the interest of patients
•For multiple functions and
disciples responsible and
accountable for QbD
•Review, Compliance, Inspection
•Development, QC, QA,
Manufacturing
•ICH Q8, Q9, and Q10, among
others, are intended to provide
a basis to facilitate the
establishment of a common
•Framework
•Vocabulary
•Understanding
12/1/2014 [email protected] 24

25. Intended outcome
•Good decisions -in the interest of the Patients
•Higher efficiency
•Facilitate continual improvement
12/1/2014 [email protected] 25

26. Current Issues and Challenges?
Before (ICH Q8-10)
Good
decisions
Higher
efficiency
Continual
improvement
Expected After (ICH Q8-10)
Good
decisions
Higher
efficiency
Continual
improvement
Integrated:
Framework?
Vocabulary?
Understanding?
Divisive:
Framework
Vocabulary
Understanding
?
12/1/2014 [email protected] 26

27. What are the current challenges?
•Where companies stand on QbD (2010)?
•Ted Fuhr, Mackinsey & Company, June 2010, FDA Advisory Committee
•Little regulatory incentive for industry to pursue continuous improvement
•To QbD or not to QbD? That is the question…..(July 2013)
•“Industry’s view on the regulatory challenges when implementing QbD” –Roger Nosal, Pfizer, ISPE,
December 2013
•EMA-FDA pilot program for parallel assessment of
Quality-by-Design applications
•Final Concept Paper Q12: Technical and Regulatory Considerations for
Pharmaceutical Product Lifecycle Management dated 28 July 2014
12/1/2014 [email protected] 27

28. Where companies stand on QbD (2010)?
None / Novice NCE: 22%
Generic:
40%
Biologic:
17%
Pilot NCE: 33%
Generic:
20%
Biologic:
67%
Rollout NCE: 22%
Generic:
40%
Biologic:
17%
Full
Implemented
NCE: 22%
Generic: 0
%
Biologic;
0%
Ted Fuhr, Mackinsey & Company, June 2010, FDA Advisory Committee
12/1/2014 [email protected] 28

29. Top 10 Challenges (2010)
1 Internal misalignment
2 Lacking a business case
3 Lacking technology
4 Alignment with 3
rd
parties (fully implemented companies)
5 Lack of guidance for industry
6 Inconsistent treatment of QbD across FDA
7 Regulators not prepared to handle QbD (fully implemented companies)
8 Regulatory communication not inspiring confidence
9 Misalignment of international regulatory bodies
10 Interaction with FDA not conducive to QbD (fully implemented companies
Ted Fuhr, Mackinsey & Company, June 2010, FDA Advisory Committee
12/1/2014 [email protected] 29

30. Key challenges by industry segments
New Regulators are not prepared to handle QbD applications
New Misalignment of international regulatory authorities
New and
Generics
R&D incentivized for ‘shots on the goal’; not QbD
Generics
Lack of belief in business case –‘Generics are all about file first;
figure out later’
Biologics Lack of technology to execute
Ted Fuhr, Mackinsey & Company, June 2010, FDA Advisory Committee
12/1/2014 [email protected] 30

31. To QbD or not to QbD? That is the question…(July 2013)
•Context: Biologics; Observations of a Senior Quality Assessor,
MHRA; BioPharma-Reporter.Com
•QbD elements in most [MAA’s] come across as “flights of fancy into
an imaginary parallel world”
•Some companies incorrectly see QbD as a route to accelerate
approval; QbD is not a short-cut.
To QbD or not to QbD? That is the question…..(July 2013)
12/1/2014 [email protected] 31

32. Very different perspectives!
•QbD elements in ~4 MAA’s for biologics submitted “flights of fancy
into an imaginary parallel world”
•A viewpoint of a Senior EU regulator
•The other point –“QbD is not a short-cut”
•It is just the opposite –“over 400 small scale runs using DOE” in the most
promising MAA
To QbD or not to QbD? That is the question…..(July 2013)
12/1/2014 [email protected] 32

33. Some companies incorrectly see QbD as a route
to accelerate approval?
•The foundational premise (ICH ‘Desired State’) has always been to
make better and more efficient decisions in the interest of
patients!
•We should not rule-out QbD as a route to accelerate approvals
•The divergent perspective simply means we have more work to do
•Improve integration of various perspectives (assuming all stakeholder
viewpoints add value and, thefore, are worthy of integration)
12/1/2014 [email protected] 33

34. Illustrative case example: Enoxaparin,
Biosimilar or Generic?
Europe: Biosimilar
•Sandoz-Momenta proposed MAA presented
and discussed
•With MPA & BfArM
•EMEA Workshop on Process Analytical
Technologies for Biologicals (15th March
2007, Room 3A, EMEA)
•A summary preservation at 5
th
EGA
Symposium on Biosimilars, London
USA: Generic
•Sandoz-Momenta ANDA approved July 23,
2010 (first to be approved)
•“This [enoxaparin] approval represents a major
development in US regulatory science and policy
that will likely affect several other complex drug
products...the extensive analytical
characterization, as carried out for enoxaparin,
will be important in the evaluation of protein
products and may help to reduce the scope and
extent of animal and clinical studies for
biosimilars.”
•Sau Lee, et. al., Scientific Considerations in the
Review and Approval of Generic Enoxaparin in the
United States. Nature Biotechnology. Volume 3, 220-
226 (2013)
12/1/2014 [email protected] 34

35. Illustrative case example: Accelerated Approval
–Breakthrough Therapy Designation
Peter Mueller, PhD CSO & Executive Vice President,
Global R&D Vertex Pharmaceuticals, Inc. IFPAC
Conference, January 2013, Baltimore, MD
12/1/2014 [email protected] 35

36. Illustrative case example: Accelerated Approval
–Breakthrough Therapy Designation
IFPAC Conference, January 2013, Baltimore, MD
12/1/2014 [email protected] 36

37. Illustrative case example: Accelerated Approval
–Breakthrough Therapy Designation
IFPAC Conference, January 2013, Baltimore, MD
12/1/2014 [email protected] 37

38. Lets’ be clear
•Continuous manufacturing is not the only way to demonstrate
QbD!
•It does, however, provide the means to a paradigm shift needed to
look at the problem at hand, from a different perspective; I am
aware of several similar example which are rapidly progressing
12/1/2014 [email protected] 38

39. EMA-FDA pilot program for parallel assessment of
Quality-by-Design applications
•Consistent implementation between EU and US of ICH Q8, 9, 10, 11 guidelines in the
assessment
•What are the Agencies’ expectations in a regulatory submission for Quality Target Product
Profile (QTPP)?
•What are the Agencies’ expectations in a regulatory submission for Critical Quality Attributes
(CQAs)?
•Would the Agencies accept a three-tier classification of criticality for process parameters?
•What are the Agencies’ expectations in a regulatory submission for manufacturing process
descriptions?
•What are the Agencies’ views with respect to the use of analytical target profile (ATP) for
analytical methods?
•What are the Agencies’ expectations in regulatory submissions for Method Operational Design
Ranges (MODR)?
•Questions and Answers on Design Space Verification
•EMA and FDA extend pilot programme for parallel assessment of quality-by-design
applications
•Applications can be accepted till March 2016
12/1/2014 [email protected] 39

40. Both Agencies met all their
timelines and milestones
•Over 50% of FDA’s IR questions
common with EMA LoQs
•Close agreement on:
•QTPP and CQAs
•Criticality
•Design Space verification
•Level of detail in manufacturing
process descriptions
•QbD for Analytical Methods
Limited time to reach
agreement for controversial
issues
•Differences in regional requirement
leading to different submission
requirements
•More work needed –NIR, Design
Space development, & Risk
assessment detail in dossier
•A company (1
st
) reported: 35
questions by FDA and 100 by EMA;
only 19 were common!
What worked and what didn't
http://www.pqri.org/workshops/EVP2014/Chatterjee.pdf
http://www.in-pharmatechnologist.com/Regulatory-Safety/Manufacturing-Must-be-Described-Whether-QbD-or-Not-say-EMA-and-FDA
12/1/2014 [email protected] 40

41. Proposed ICH Q12
•“…lack of alignment has led to confusion on the necessary information
and level of detail in the dossier and its impact on change management
and regulatory reporting.”
•“Intended to work with ICH Q8 to Q11 Guidelines”
•“Provide a framework to facilitate the management of post-approval changes in a
more predictable and efficient manner across the product lifecycle”
•“Adoption of this guideline will promote innovation and continual improvement,
and strengthen quality assurance and reliable supply of product, including
proactive planning of supply chain adjustment”
•“It will allow regulators (assessors and inspectors) to better understand, and have
more confidence and trust in a firm’s Pharmaceutical Quality System (PQS) for
management of post-approval CMC changes”
Final Concept Paper. Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. 28 July 2014
12/1/2014 [email protected] 41

42. Summary -Current Issues and Challenges
•Lack of integrated implementation (QMS, GMP not effectively
included)
•Inadequate consensus on the ICH framework, vocabulary,
understanding –Why
•Review focus on data and not on knowledge; increasing burden on
those who were willing to share additional information
•Leading to the question: To QbD or Not?
12/1/2014 [email protected] 42

43. Beyond what has already been
proposed
Solutions to Consider
12/1/2014 [email protected] 43

44. ICH Q12: Issues to be Resolved
•Regulatory Dossier -“regulatory commitments”
•Pharmaceutical Quality System aspects (ICH Q10) –risk and
knowledge management system
•Post-Approval Change Management Plans and Protocols
Final Concept Paper. Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. 28 July 2014
12/1/2014 [email protected] 44

45. What has already been proposed
•ICH Q12
•“…allow regulators (assessors and inspectors) to better understand, and
have more confidence and trust in a firm’s Pharmaceutical Quality System
(PQS) for management of post-approval CMC change.”
12/1/2014 [email protected] 45

46. Human aspects
•Team approach to review and inspection
•Different but equally important functions
•Team-building and training is essential
•Culture of Quality
•Regulatory bodies
•Companies
•Recognize that QbD applications/submissions serve as an
additional layer of protection; to gauge the Culture of Quality
12/1/2014 [email protected] 46

47. Culture of Quality
•Environment that facilitates individuals to guide their behavior to
work consciously in the interest of patients and to continually
improve this ability
•Through our disciplined training and experience –it should be our habit
to work consciously in the interest of patients
•It is a measure of safeguards against pre-conditions to malice or
disregard
•Attitude & Rationalization
•Pressure & Incentive
•Opportunity –“holes” in QMS, supervision, policies,…
12/1/2014 [email protected] 47

48. A framework for Culture of Quality
http://www.slideshare.net/a2zpharmsci/pharmaceutical-culture-of-quality
12/1/2014 [email protected] 48

49. Summary
•Legitimate pharmaceutical community has practiced QbD for decades;
however in ways that vary undesirably
•Demonstration of QbD is multifaceted
•There are serious consequences …in ways that can vary undesirably…
•The consequence of “Cheating by Design” are almost always
catastrophic
•Perhaps we need to view QbD Applications/submissions as an
additional layer of protection; to gauge the Culture of Quality
•Legitimate efficiency –is a key business driver, good for the patients,
and the society overall
12/1/2014 [email protected] 49

50. Summary
•Lack of integrated implementation (QMS, GMP not effectively
included)
•Inadequate consensus on the ICH framework, vocabulary,
understanding –Why
•Review focus on data and not on knowledge; increasing burden on
those who were willing to share additional information
•Leading to the question: To QbD or Not?
12/1/2014 [email protected] 50

51. Summary
•Proposed
•ICH Q12 Regulatory Dossier -“regulatory commitments”
•Pharmaceutical Quality System aspects (ICH Q10) –risk and knowledge management system
•Post-Approval Change Management Plans and Protocols
•A reminder of the approach utilized for FDA’s PAT Guidance, Comparability Protocol and Team
Approach
•Must focus on integrated implementation
•Team-building and training for Review, Compliance & Inspection functions
•Recognize that QbD Applications/submissions serve as an additional layer of protection; to
gauge the Culture of Quality
12/1/2014 [email protected] 51

52. Acknowledging the contributions of the FDA’s
PAT Team…..