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Agenda
Todays Regulatory
Environment/Considerations
Six Sigma and Operational
Excellence
Tips for Success
A Shift in Thinking
David Graham testifies to Congress that
there are 5 approved drugs that in his
opinion represent a risk to public safety
Flu-Vaccine shortage/Avian Flu Pandemic
Part 11 Guidance-industry backlash
Timeline
September 2003 FDA Releases:
Final report Pharmaceutical cGMPs for the 21st Century - A RiskBased Approach
Guidance for Industry- Quality Systems Approach to
Pharmaceutical Current Good Manufacturing Practice
Regulations
Guidance for Industry Sterile Drug Products Produced by Aseptic
Processing cGMP
Guidance for Industry PAT A Framework for Innovative
Pharmaceutical Development, Manufacturing, and Quality
Assurance encourages industry to adopt online testing,
characterization and control
8
Timeline
Timeline
10
10
Timeline
November 2005 - ICH Releases:
Q8 Pharmaceutical provides guidance for the
Pharmaceutical Development section of an ICH regulatory
submission. Indicates areas where the effective application of
risk management and pharmaceutical and manufacturing
sciences can create a basis for flexible regulatory approaches
Q9 Quality Risk Management provides guidance on the
principles and some of the tools of quality risk management
that can enable more effective and consistent risk based
decisions, both by regulators and industry, regarding the
quality of drug substances and drug (medicinal) products
across the product lifecycle
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11
Quality
by
Design
12
12
Risk Assessment
Risk Identification
R
I
S
K
Risk Analysis
R
I
S
K
C
O
M
M
U
N
I
C
A
T
I
O
N
Risk Evaluation
M
A
N
A
G
E
M
E
N
T
Unacceptable
Risk Control
Risk Reduction
Risk Acceptance
Ongoing
Review
T
O
O
L
S
Risk Control
Risk Review
13
13
The Challenge
14
Drug Development
Today
Drug Development
Tomorrow
R- Guidance Centric
Q- Inspection Centric
P- Product Centric
D- Subjective
R- Science/Risk Based
Q- Critical Parameters
P- Process Centric
D- Objective
14
The Challenge
Drug Development
Today
Product centric CMC
Inspections based
validation
Systems Based
Inspections
15
Drug Development
Tomorrow
PQAS- process based
CMC
Risk Based Validation
PAT
Risk Based Inspections
15
16
16
Improve
Performance
LEAN
Reduce
Waste
LEAN/
SIX SIGMA
Sustain
Performance
Reduce
Variation
SIX SIGMA
Avoid
Variation
17
17
18
18
19
19
20
20
Act
Study
(Check)
Do
21
Right Process:
Analyze
Improve
Define
Measure
I
n
p
u
t
s
Process
O
u
t
p
u
t
s
Control
22
22
23
A Customer
Focused Synergy
Me
as
ur
es
$tability
ds
ho
et
M
Management
24
- Variance Reduction
- Passive Analysis
- MSA / Gauge R&R
- Hypothesis Testing
- Active Analysis
- Strategic Planning
- Project Charters
- DMAIC Projects
- Control Plans
- Process Control
24
$tability
ds
ho
et
M
Management
25
- Variance Reduction
- Passive Analysis
- MSA / Gauge R&R
- Hypothesis Testing
- Active Analysis
- Strategic Planning
- Project Charters
- DMAIC Projects
- Control Plans
- Process Control
25
Off-Target
LSL
USL
LSL
Center
Process
26
Centered
On-Target
USL
Reduce
Spread
26
Understanding
Process Variation
Number Measured
15
10
0
47
27
48
49
50 51 52 53
Continuous Measure
27
Understanding
Process Variation
LSL
Anatomy of the
Normal Distribution USL
Average
-3 -2
-1
Continuous Measure
28
28
Measures:
LSL
-3 -2
-1
USL
Continuous Measure
29
29
The Process
Operating Window
LSL
USL
-1.5 +1.5
Process
Operating
Window
-3 -2
30
-1
31
<1% Defects
(Considered good
quality today...)
+4
3-Sigma Quality
-3
(Considered world-class
quality today!)
+6
4-Sigma Quality
-4
<0.01% Defects
<10% Defects
(Considered good
quality 20 years ago...)
+3
2007 ISPE SF Chapter Vendor Night
31
32
32
DPMO
6.0
3.4
5.5
32
5.0
233
4.5
1 350
4.0
6 210
3.5
22 750
3.0
66 810
~70X
~30X
~10X
33
1,000,000
Order Write-up
100,000
10,000
Restaurant Bills
Average
Company
1,000
100
Best-in-Class
Sigma Level
Source: Six Sigma: A Breakthrough Strategy, Quality Progress, May 1998.
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34
99.99966% Good
Postal System
20,000 Lost Articles
Of Mail / Hr
Airline System
1 Short / Long
Per 5 Years
Two Short/Long
Landings / Day
Medical Profession
68 Wrong Drug
Prescriptions
35
7 Lost Articles / Hr
35
A Customer
Focused Synergy
Me
as
ur
es
$tability
ds
ho
et
M
Management
36
- Variance Reduction
- Passive Analysis
- MSA / Gauge R&R
- Hypothesis Testing
- Active Analysis
- Strategic Planning
- Project Charters
- DMAIC Projects
- Control Plans
- Process Control
36
Active Analysis
37
Sub Step 3
Sub Step 1
Sub Step 2
Sub Step 2
Sub Step 1
Step 5
Sub Step 3
Sub Step 2
Sub Step 1
Step 4
Sub Step 3
Sub Step 1
Step 3
Sub Step 3
Sub Step 3
Importance (15)
Customer Needs
Man
Step 2
Sub Step 2
Material
Good
Measurement
Step 1
Sub Step 1
R elationship
9 Strong
3 Medium
1 Weak
Sub Step 2
Sub-Process
Steps
Process:
Total
Total
Effect or
Problem
Fast
Cheap
Environment
Methods
Total
Machine
Process Flowcharts:
Customer*
The Process
Engineering
Tooling
The Sub-Process
Production
Field Service
The Micro-Process
Focus Area
Good
(quality)
Fast
(speed)
Cheap
(cost)
38
Measure
Increment
minute
hour
day
batch
# or % of Commitments missed
day
week
month
shift
batch
Cost of rework
transaction
38
ANALYZE
Interrelationship Digraph
Logical
Creative
Tree Diagram
Prioritization
Matrices
Criteria
A
Criteria
B
Criteria
C
Criteria
D
Issue 1
Issue 2
Issue 3
40
Issue 4
170
Issue 5
123
Issue 6
28
Total
38
68
Matrix
Diagram
Tasks Known
Tasks
Unknown
TASK
Item ID
Completed?
Define.
1
2
3
4
IMPROVE
39
5
6
7
8
9
PDPC
Chart
Activity
Network
Diagram
FEB
MAR
APR
MAY
JUN
JUL
Yes
Yes
No
Yes
No
No
No
No
Yes
Measure.
1
JAN
No
No
No
No
Gantt Chart
39
AUG
40
40
41
41
Capability Histogram
Sample Mean
UCL=52.719
LSL
USL
S pecifications
LS L
50
U S L 55
52.5
_
_
X=51.994
52.0
51.5
LCL=51.269
1
11
13
15
17
19
50.25
R Chart
51.00
51.75
52.50
53.25
54.00
54.75
Sample Range
UCL=2.658
2
_
R=1.257
1
0
LCL=0
1
11
13
15
17
19
50
Last 20 Subgroups
Values
Within
S tDev 0.540435
Cp
1.54
C pk
1.23
52
51
42
10
Sample
54
Capability Plot
53
52
15
20
Within
O v erall
O v erall
S tDev 0.590414
Pp
1.41
P pk
1.13
C pm
*
S pecs
42
Reducing Variation by
Robust Design
Process "Y"
Transfer
Relationship
$$$
Input
Input
Alternate Method of Reducing Variation
43
$tability
ds
ho
et
M
Management
44
- Variance Reduction
- Passive Analysis
- MSA / Gauge R&R
- Hypothesis Testing
- Active Analysis
- Strategic Planning
- Project Charters
- DMAIC Projects
- Control Plans
- Process Control
44
Critical to
Quality
Key Output
Measure
Critical
Customer
Requirements
VOC
CTQ
Key Y
CCR
Customer
concerns or
needs
Customer
needs
translated into
process terms
Key leading or
lagging
measure(s)
that reflects
the CTQ
Requirements
for the Key Ys
Explanation
Voice of the
Customer
Abbreviation
Start Here
45
45
46
46
Functional
GreenBelts
BeltsBelts
Trained
Assigned
byCorporate,
Corporate,
Black
Trained
by
Blackbelt/Greenbelt Deployment
Functional
Placed
Back
Projects
in Business
Blackin
Belt
Deployment
Placed
Business
and in Six Sigma Org.
Functional and Pooled Blackbelts
IT
Improvement Initiative
Function
Function
BU
Function
BU
BU
Improvement Initiative
MBB
BU
MBB
BU
Improvement
Initiative
Function
Function
BU
MBB
Training
BG
B
G
B
G
BU
Improvement
Initiative
BU
BU
BU
BU
B
B
G
47
Fin.
G
B
B
G
47
BU
BU
BU
High
Low
Low
Med
High
Effort
Desirable Opportunities
Low
Low
Med
High
Effort
Reasonable Opportunities
Benefits Include:
Strategic Fit
Revenue Growth
Cost Reduction
Capital Reduction
48
New Approach
Benefit
Med
Present Approach
Benefit
Med
High
Effort Include:
Personnel Needs
Length of Project
Capital Cost
Project Risk
48
49
50
50
51
51
52
Emerging Biopharma/Device/Diagnostics
VC funded: SS provides the framework for
objective scientific inquiry. Better
milestone performance. Manage you burn
Toll gate reviews keep everyone on the
same team
Always keep the business objectives first
and foremost in your justification. Cash is
King , but so is COPQ (TTM, clinical
performance)
53
53
Summary
The expectations for the regulatory
environment demands an objective
approach to drug development
Six Sigma can provide the roadmap for
effectively satisfying the new science/risk
based cGMPs
Balancing financial/quality and business
requirements will ensure your SS initiative
will gain traction
54
54
55
55