Implementing Quality by Design with Outsourced Partners: Challenges and Solutions

1. 1
Implementing Quality
By Design with
Outsourced Partners:
Challenges and
Solutions
Janis Hall
Janis.Hall@theavocagroup.com

2. 2
● The
Avoca
Group
and
Avoca
Quality
Consor7um
(AQC)
● AQC
Quality
Oversight
Framework
and
Process
Oversight
● Quality
by
Design
Best
Prac7ces
Guideline
and
Tools
● Terminology
and
Defini7ons
● Implemen7ng
QbD
with
Outsourced
Partners:
Challenges
● Industry
Status
Applying
QbD
Methods
for
Clinical
Trials
● Implemen7ng
QbD
with
Outsourced
Partners:
Solu7ons
● Key
Messages
and
Conclusions
● Resources
and
References
list
Topics
Implementing QbD with Outsourced Partners:
Challenges and Solutions

3. 33
Who
is
The
Avoca
Group?
• The
Avoca
Group,
Inc.,
founded
in
1999,
is
a
consul7ng
and
survey
research
firm
that
develops
and
implements
global
rela7onship
and
alliance
management
programs
for
biopharmaceu7cal
companies
and
pharmaceu7cal
service
providers.
The Avoca Group
The Avoca Quality Consortium
What
is
The
Avoca
Quality
Consor8um?
• Founded
in
2011.
Today
the
Consor7um
has
over
35
biopharm
and
CRO
member
companies.
• Purpose:
Help
companies
op7mize
their
approaches
to
proac7ve
quality
management
with
an
emphasis
on
bringing
sponsors
and
CROs
into
greater
alignment.
• Vision:
To
serve
as
a
catalyst
for
the
accelera7on
of
best
prac7ces
and
industry
standards
for
proac7ve
quality
management.

4. 44

5. 5
Quality Oversight Framework for
Proactive Quality Management
Governance/
Organizational
Construct
Governance
Sourcing Models
Committee
Construct
Decision Models
Ctrs of
Excellence
Teams/Functions
Quality Units
Issue Escalation
Technical/
Project Oversight
Functional
Project Team
Business
Technology
Process
Oversight
Delegated
Processes
Shared Processes
QbD Principles
QMP
Process
Development/
Improvement
Communication
Communication
Communication
Plan
Escalation Plan
Oversight
Leadership
Requirements
Leadership
Leadership Styles
Oversight
Leadership
Characteristics
Talent
Management
Metrics /
Analytics /
Technology
Leading
Indicators
KPIs
KQIs
Desktop On-
Demand
Real Time
Accuracy
Roles /
Responsibilities
Sponsor
Oversight
Sponsor
Operations
CRO Oversight
CRO Operations
Proactive Risk /
Opportunity
Management
Risk Identification
Risk
Management
Opportunity
Management
Quality Risk Plans
Timeline Risk
Plans
Cost Risk Plans
Recovery or
Transition Plans
Governance
Sourcing Models
Committee
Construct
Decision Models
Ctrs of
Excellence
Teams/Functions
Quality Units
Issue Escalation
Communication
Communication
Plan
Escalation Plan
Leadership
Leadership Styles
Oversight
Leadership
Characteristics
Talent
Management
Governance
Sourcing Models
Committee
Construct
Decision Models
Ctrs of
Excellence
Teams/Functions
Quality Units
Issue Escalation
Technical/
Project
Oversight
Functional
Project Team
Business
Technology
Process
Oversight
Delegated
Processes
Shared Processes
QbD Principles
QMP
Process
Development/
Improvement
Communication
Communication
Plan
Escalation Plan
Leadership
Leadership Styles
Oversight
Leadership
Characteristics
Talent
Management
Metrics /
Analytics /
Technology
Leading
Indicators
KPIs
KQIs
Desktop On-
Demand
Real Time
Accuracy
Roles /
Responsibilities
Sponsor
Oversight
Sponsor
Operations
CRO Oversight
CRO Operations
Proactive
Risk /
Opportunity
Management
Risk Identification
Risk
Management
Opportunity
Management
Quality Risk Plans
Timeline Risk
Plans
Cost Risk Plans
Recovery or
Transition Plans
Governance/
Organizational
Construct
Governance
Sourcing Models
Committee
Construct
Decision Models
Ctrs of
Excellence
Teams/Functions
Quality Units
Issue Escalation
Communi-
cation
Communication
Communication
Plan
Escalation Plan
Oversight
Leadership
Requirements
Leadership
Leadership Styles
Oversight
Leadership
Characteristics
Talent
Management
Completed
In
Development
Planned
for
2014
Process Selection

6. 6
Best Practices for Proactive Quality Management and
Quality Oversight
Process
Oversight
Guideline
• Process
Tool-­‐1-­‐
Elements
of
Process
Oversight
• Process
Tool-­‐4-­‐
Quality
by
Design
Principles
• Process
Tool-­‐1a-­‐
Task
Ownership
Matrix
• Process
Tool-­‐4a-­‐
QbD
for
Pharma
GMP
Ac8vi8es
• Process
Tool-­‐1b-­‐
Template
Task
Ownership
Matrix
• Process
Tool-­‐4b-­‐
QbD
for
Pharma
GCP
Ac8vi8es
• Process
Tool-­‐2-­‐
Transfer
of
Regulatory
Obliga8ons
• Process
Tool-­‐4c-­‐
Opera8onalizing
QbD
for
Clinical
Trials
• Process
Tool-­‐2a-­‐
Template
Transfer
of
Regulatory
Obliga8ons
• Process
Tool-­‐4d-­‐
QbD
Template
CTQ
Table
• Process
Tool-­‐3-­‐
Process
Document
Control
• Process
Tool-­‐4e-­‐
QbD
Template
IMP
Interven8on
Risk
• Process
Tool-­‐3a-­‐
Process
Tracking
Table
• Process
Tool-­‐4f-­‐
QbD
Template
Design
and
Methods
Risk
• Process
Tool-­‐3b-­‐
Joint
Process
Development
• Process
Tool-­‐4g-­‐
QbD
Template
FMEA
• Process
Tool-­‐3c-­‐
Six
Sigma
SIPOC
Tool
• Process
Tool-­‐4h-­‐
QbD
Best
Prac8ces
when
Outsourcing
• Process
Tool-­‐3d-­‐
Six
Sigma
Swim
Lane
Tool
• Process
Tool-­‐4i-­‐
QbD
Supplier
Risk
Assessment
• Process
Tool-­‐3e-­‐
Template
for
Joint
Process
Documenta8on
• Process
Tool-­‐5-­‐
Joint
Quality
Management
Plan
• Process
Tool-­‐3f-­‐
Process
Improvement
• Process
Tool-­‐5a-­‐
Supplier
Assessment
Report
Template
• Process
Tool-­‐3g-­‐
Lean
and
Kaizen
Events
• Process
Tool-­‐5b-­‐
Central
Supplier
Assessment
Tracking
Table
• Process
Tool-­‐3h-­‐Root
Cause
Analysis
• Process
Tool-­‐5c-­‐
Project
Supplier
Tracking
• Process
Tool-­‐3i-­‐Template
RCA
Fishbone
Diagram
• Process
Tool
5d-­‐
Approved
Supplier
List
• Process
Tool-­‐3j-­‐Sta8s8cal
Process
Control-­‐
Control
Chart
• Process
Tool-­‐6-­‐
Change
Management
Best
Prac8ces
• Process
Tool-­‐3k-­‐Process
Mapping
Instruc8ons
• Process
Tool
6a-­‐
Change
Management
Plan
Template
Focus
for
Presenta7on
Quality
by
Design
Best
Prac7ces

7. 7
Quality by Design Terms and Definitions
QbD-­‐
is
an
approach
to
development
that
begins
with
predefined
objec7ves
and
emphasizes
product
and
process
understanding
and
process
control,
based
on
sound
science
and
quality
risk
management
(ICH
2009)
Design
space-­‐
the
mul7dimensional
combina7on
and
interac7on
of
input
variables
and
process
parameters
that
have
been
demonstrated
to
provide
assurance
of
quality;
when
defining
a
design
space,
the
applicant
should
keep
in
mind
the
type
of
opera7onal
flexibility
desired.
(ICH
Q8
R1)
Cri8cal-­‐to-­‐Quality
(CTQ)
is
an
aXribute
of
a
product
or
process
that
has
a
direct
and
significant
impact
on
its
actual
or
perceived
quality
and
should
be
within
an
appropriate
limit,
range,
or
distribu7on
to
ensure
the
desired
quality
(derived
from
ICH
Q8
R1)

8. 8
Quality by Design- Terms and Definitions
RBM
(Risk-­‐Based
Monitoring)-­‐
(FDA
Aug
2013
Guidance)
“monitoring”
refers
to
the
methods
used
by
sponsors
(or
CROs)
to
oversee
the
conduct
of
and
repor7ng
of
data
from
clinical
inves7ga7ons,
including
appropriate
clinical
inves7gator
supervision
of
study
site
staff
and
third
party
contractors.
Centralized
vs.
On-­‐site
vs.
Off-­‐site
(remote)
site
monitoring
● Centralized
monitoring-­‐
A
“remote
evalua7on
carried
out
by
sponsor
personnel
or
representa7ves
(e.g.
Data
Manager,
Sta7s7cian,
or
Monitor)”
(FDA
Guidance).
● On-­‐site
Monitoring-­‐
An
in-­‐person
evalua7on
carried
out
by
sponsor
personnel
or
representa7ve(s)
at
the
site(s)
at
which
the
clinical
inves7ga7on
is
being
conducted”
(FDA
Guidance).
● Off-­‐site
Monitoring-­‐
Monitoring
ac7vi7es
as
defined
either
within
process
documents
or
in
the
monitoring
plan
that
occur
away
from
the
study
site
loca7on
(TransCelerate)

9. 9
Quality by Design Terms and Definitions
Source
Data
Verifica8on
(SDV)
vs.
Source
Data
Review
(SDR)
(TransCelerate)
SDV-­‐
data
within
the
CRF
(or
other
data
collec7on
systems)
are
compared
to
the
original
source
to
confirm
that
the
data
were
transcribed
accurately
(i.e.
source
data
vs.
data
in
the
CRF)
SDR*-­‐
review
source
documenta7on
to
check
quality
of
source,
review
protocol
compliance,
ensure
the
Cri7cal
Processes
and
source
documenta7on
(e.g.
accurate,
legible,
complete,
7mely,
dated)
are
adequate,
to
ascertain
Inves7gator
involvement
and
appropriate
delega7on,
and
assess
compliance
to
other
areas
(e.g.
SOPs,
GCP).
.
.
not
a
comparison
of
source
data
against
CRF
data.
.
.
.
necessary
to
evaluate
areas
that
do
not
have
an
associated
data
field
in
the
CRF
or
system
available
for
more
7mely
remote
review.
*Requires
cri8cal
thinking
skills
and
judgment

10. 10
Implementing QbD with Outsourced
Partners: Challenges (1)
New,
evolving
thinking
• Concepts
are
new
and
developing
• Not
established
as
standard
prac7ces
• Imbalance
of
knowledge,
experience
and
acceptance
• Concepts
not
equally
mature
across
clinical
trial
process
• High
profile
and
poten7al
for
high
expecta7ons
beyond
capabili7es
Stakeholders
Engagement/Understanding/Capabili7es
• Not
all
stakeholders
are
engaged
• Sponsor/Supplier/Inves7gators
• Unequal
understanding/commitment/involvement
with
methods
development
• Func7onal
area
and
geographic
imbalance
of
understanding

11. 11
Implementing QbD with Outsourced
Partners: Challenges (2)
Culture,
behaviors
and
resources
• Tradi7onal
risk
averse
behavior-­‐
Paradigm
shif-­‐focus
on
high
risk
factors
• Staff
challenges
• “Hard-­‐wired”
• Reluctant,
unwilling
or
unable
to
change
• Func7onal
area
imbalance
of
knowledge
• Poten7al
reassignment
or
removal
of
resources
to
fit
new
needs
• Sponsors/CROs
• “Walk
the
talk”
• Demonstrate
tolerance
of
low
risk
events
• Reinforce/reward/recognize
adop7on
Contracts
• Transparency
• Complexity
vs.
tradi7onal
• Flexibility

12. 12
How would you rate your current understanding of
QbD processes, as applied to clinical development?
Only approximately half of the respondents stated that they had at least a “good
understanding” of QbD processes, as applied to clinical development.
10%
14%
40%
43%
43%
39%
7%
4%
0% 20% 40% 60% 80% 100%
Sponsors
CROs
Very strong understanding Good understanding Fair understanding Poor understanding
N
235
153
Data from 2014 Interim AQC Research

13. 13
How would you rate your company’s current application
of QbD principles in clinical development?
CRO respondents were more likely than sponsor respondents to report frequent
or consistent application of QbD principles in clinical development, but sponsors
don’t appear to be very aware of CRO’s application of these approaches.
9%
2%
19%
31%
22%
38%
48%
55%
38%
12%
20%
4%
0% 20% 40% 60% 80% 100%
Sponsors re
own
companies
Sponsors re
their clinical
service
providers
CROs
Consistent application Frequent application Inconsistent application Little application
N
228
228
144
Data from 2014 Interim AQC Research

14. 14
On average, how satisfied are you with your own company’s or your
counterpart’s implementation of these key practices of quality and
risk management?
Sponsors re
own
company
CROs re
sponsors
CROs re own
company
Sponsors re
CROs
N= 231 136 150 218
Quality planning overall 3.5 3.3 3.8 3.0
Quality control overall 3.6 3.4 3.8 3.1
Quality improvement overall 3.5 3.2 3.8 3.0
Use of Failure Mode Effects Analysis (FMEA)
methodology
3.1 2.9 3.1 2.7
Proactive risk assessment overall 3.3 3.1 3.7 2.7
Design of training materials, monitoring plan, audit
plan, data management plan, taking into account
identified risks
3.5 3.3 3.8 3.2
Adaptation of safety monitoring plan according to
trial-specific risks
3.6 3.4 3.7 3.3
Adjustment of conventional GCP methods to
identified risks (e.g. on-site vs. central monitoring;
targeted source document verification)
3.4 3.2 3.7 3.1
Proactive risk mitigation overall 3.3 3.2 3.6 2.8
For QbD-related practices, mean ratings among sponsor and CRO respondents
were generally in the neutral to satisfied range, with each group feeling more
positively about its own practices than about its partners’ practices.
Data from 2014 Interim AQC Research

15. 15
Industry Status in Applying QbD Methods
Broad
use
15%
New
user
19%
Pilot
one
trial
10%
Establishing
infrastructure
29%
No
plans
to
use
8%
Unsure/Don't
know
19%
Is
your
organiza8on
applying
QbD
methods
for
clinical
research
and
if
so,
to
what
degree?
(select
one)
N=52
Survey
data
gathered
March
21
and
26,
2014
during
an
Avoca
Quality
Consor7um
Quarterly
Webinar:
QbD
Best
Prac7ces

16. 16
Industry Status in Applying QbD Methods
Yes
44%
No
23%
Unsure/Don't
know
33%
Has
your
organiza8on
used
QbD
approaches
for
assessing
protocol
risk?
(select
one)
N=48
Survey
data
gathered
March
21
and
26,
2014
during
an
Avoca
Quality
Consor7um
Quarterly
Webinar:
QbD
Best
Prac7ces

17. 17
Industry Status in Applying QbD Methods
0%
10%
20%
30%
40%
50%
60%
70%
80%
Clinical
program
planning
Protocol
design
Data
collec7on
Site
monitoring
Pharmacovigilance
Other
Not
applying
methods
yet
Is
your
organiza8on
applying
QbD
methods
to
any
of
these
areas?
(Check
all
that
apply)
N=43
Survey
data
gathered
March
21
and
26,
2014
during
an
Avoca
Quality
Consor7um
Quarterly
Webinar:
QbD
Best
Prac7ces

18. 18
Industry Status in Applying QbD Methods
Internal
–
culture
(risk
averse)
10%
Internal-­‐
infrastructure
(tools/systems)
24%
Internal-­‐
skills
(right
resources/training)
19%
Internal-­‐
other
2%
External-­‐
inves7gator/
site
(capabili7es/
knowledge)
5%
External-­‐
suppliers
(capabili7es/knowledge)
14%
External-­‐
other
2%
Not
applying
QbD
methods
yet
24%
As
a
sponsor
or
CRO
organiza8on,
when
it
comes
to
applying
QbD
methods,
what
is
your
greatest
challenge?
(select
one)
N=42
Survey
data
gathered
March
21
and
26,
2014
during
an
Avoca
Quality
Consor7um
Quarterly
Webinar:
QbD
Best
Prac7ces

19. 19
Implementing QbD Approaches with
Outsourced Partners
CROs
and
Sponsors
should
1. Assess
suppliers
for
knowledge,
experience
and
exper7se
implemen7ng
QbD
methods
2. Deploy
best
prac7ces
for
conduc7ng
supplier
risk
assessments
for
outsourced
services
3. Joint
collabora7on
with
partners
to
ensure
appropriate
implementa7on
of
QbD
processes
4. Build
QbD
methodologies
into
vendor
contracts

20. 20
Solutions when Outsourcing:
Supplier Expertise Assessment (1)
● Need
for
transparency
since
this
is
a
rapidly
evolving
space
● Balance
of
knowledge
● CRO
has
more
experience
than
sponsor
● Sponsor
has
more
experience
than
CRO
● Level
set
knowledge
and
expecta7ons
before
commiong
to
working
together
1.
Assess
suppliers
for
knowledge,
experience,
exper7se
implemen7ng
QbD
methods

21. 21
Solutions when Outsourcing:
Supplier Expertise Assessment (2)
How
to
assess
knowledge,
experience,
exper7se
implemen7ng
QbD
methods?
● Capabili7es
presenta7ons
● Case
studies
● Technology
● Training/Resource
assignments
● Tools/templates
● Integra7on
into
their
infrastructure
● Expert
group
par7cipa7on
● Publica7ons/white
papers
● Speaking
at
conferences
1.
Assess
suppliers
for
knowledge,
experience,
exper7se
implemen7ng
QbD
methods

22. 22
Solutions when Outsourcing:
Supplier Risk Assessments (1)
2.
Sponsors
and
CROs
should
deploy
best
prac7ces
for
conduc7ng
supplier
risk
assessments
for
outsourced
services
Derived
from
M.
Fields,
Seaqle
Gene7cs
presenta7on
on
protocol
complexity
Aug
2011-­‐
Clinical
Quality
Oversight
Conference

23. 23
Solutions when Outsourcing:
Supplier Risk Assessments (2)
2.
Sponsors
and
CROs
should
deploy
best
prac7ces
for
conduc7ng
supplier
risk
assessments
for
outsourced
services
iiDerived
from
K.
Sprenger,
Pfizer,
Oct
2013
CTTI
Presenta7on

24. 24
Solutions when Outsourcing:
Supplier Risk Assessments (2)
2.
Sponsors
and
CROs
should
deploy
best
prac7ces
for
conduc7ng
supplier
risk
assessments
for
outsourced
services

25. 25
Solutions when Outsourcing:
Supplier Risk Assessments (2)
2.
Sponsors
and
CROs
should
deploy
best
prac7ces
for
conduc7ng
supplier
risk
assessments
for
outsourced
services

26. 26
Solutions when Outsourcing:
Supplier Risk Assessments (2)
2.
Sponsors
and
CROs
should
deploy
best
prac7ces
for
conduc7ng
supplier
risk
assessments
for
outsourced
services

27. 27
Solutions when Outsourcing: Joint
Collaboration for Implementation (1)
Joint
collabora7on
with
partners
to
ensure
implementa7on
of
QbD
processes
● Seong
Expecta7ons
● QbD
Roles
and
Responsibili7es
● QbD
across
Clinical
Trial
Process
● Clinical
Program
● Study
Design/Protocol
Development
(Process
Tools
4e/4f)
● Study
Execu7on
● Data
Management
● Sta7s7cal
Analysis
and
Repor7ng
● Medical
Wri7ng
3.
Joint
collabora7on
with
partners
to
ensure
appropriate
implementa7on
of
QbD
processes

28. 28
Solutions when Outsourcing: Joint
Collaboration for Implementation (2)
Joint
collabora7on
with
partners
to
ensure
implementa7on
of
QbD
processes
● Seong
Expecta7ons
● QbD
Roles
and
Responsibili7es
● QbD
across
Clinical
Trial
Process
● Clinical
Program
● Study
Design/Protocol
Development
(Process
Tools
4e/4f)
● Study
Execu7on
● Data
Management
● Sta7s7cal
Analysis
and
Repor7ng
● Medical
Wri7ng
3.
Joint
collabora7on
with
partners
to
ensure
appropriate
implementa7on
of
QbD
processes

29. 29
Solutions when Outsourcing: Joint
Collaboration for Implementation (3)
Joint
collabora7on
with
partners
to
ensure
implementa7on
of
QbD
processes
● Seong
Expecta7ons
● QbD
Roles
and
Responsibili7es
● QbD
across
Clinical
Trial
Process
● Clinical
Program
● Study
Design/Protocol
Development
(Process
Tools
4e/4f)
● Study
Execu7on
● Data
Management
● Sta7s7cal
Analysis
and
Repor7ng
● Medical
Wri7ng
3.
Joint
collabora7on
with
partners
to
ensure
appropriate
implementa7on
of
QbD
processes

30. 30
Solutions when Outsourcing:
Build QbD into Contracts (1)
CROs
and
Sponsors
should
build
QbD
methodologies
into
vendor
contracts
● Transparency,
complexity,
flexibility-­‐
document
it
● Task
ownership
matrix
● Statement
of
Work
● Contract
4.
CROs
and
Sponsors
should
build
QbD
methodologies
into
vendor
contracts

31. 31
Solutions when Outsourcing:
Build QbD into Contracts (2)
CROs
and
Sponsors
should
build
QbD
methodologies
into
vendor
contracts
● Transparency,
complexity,
flexibility-­‐
document
it
● Task
ownership
matrix
(Process
Tools
1a/1b)
● Statement
of
Work
● Contract
4.
CROs
and
Sponsors
should
build
QbD
methodologies
into
vendor
contracts

32. 32
Implementing QbD Approaches with
Outsourced Partners
CROs
and
Sponsors
should
1. Assess
suppliers
for
knowledge,
experience
and
exper7se
implemen7ng
QbD
methods
2. Deploy
best
prac7ces
for
conduc7ng
supplier
risk
assessments
for
outsourced
services
3. Joint
collabora7on
with
partners
to
ensure
appropriate
implementa7on
of
QbD
processes
4. Build
QbD
methodologies
into
vendor
contracts

33. 33
QbD Best Practices: Key Messages
● Paradigm
shif
● Fit
for
GCP
ac7vi7es/clinical
trials
● Health
authori7es
accept/expect
risk-­‐based
approaches
to
be
applied
● Industry
is
developing
methods
and
tools
● This
new
approach
is
a
BIG
WIN:
● Prac7cal
and
sustainable
● Cost
containment
● Improve
quality
● Increase
safety
● Improve
data
integrity
● Drive
more
quality
submissions
● Drive
more
product
approvals-­‐
WHICH
IS
WHAT
WE
DO

34. 34

35. 35
Thank you!
Janis.Hall@theavocagroup.com
1-252-676-3103