the journey from gmp to pharmaceutical quality systems · the journey from gmp to pharmaceutical...
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What is a good quality system?
ANTICIPATE!
A harmonized pharmaceutical
quality system applicable across
the lifecycle of the product
emphasizing an integrated
approach to quality risk
management and science
(Q10)
Quality beyond compliance
Effective Quality Systems ensure:
Rigorous clinical study protocols, execution, oversight and interpretation of all results
• Well understood drug safety/efficacy profile in support of label
• Robust formulations, manufacturing processes and control
strategies
• Complete and transparent NDAs/ANDAs based on good
science
• Consistent high-quality product
Meaningful specifications and measures
GMP compliant Quality Systems
Reliable processes and Batch Execution
Effective Quality Systems ensure:
Storage and distribution systems that maintain product quality and integrity
Predictable, consistent access to
necessary products
• Compliant and ethical sales and marketing practices.
• Sensitive responsive pharmacovigilance program
A recent Benchmark indicated:
•Benchmark indicated underinvestment for several years in quality training and skill building. As a consequence overstretched quality personnel and insufficient knowledge of quality practices across its network as its growth accelerated.
Lack of quality capabilities
•Accelerated growth and cost pressures increased. Despite at one time being best in class, these companies lost focus on quality: quality issues began when quality and compliance personnel were cut as part of a strong focus on containing costs. Rapid growth of 60 percent between 2000-08 led to a weakening of quality controls with suppliers, due to pressure to expand supply and control costs increase
Loss of quality focus as company
• Responsibility for quality was pushed to the Quality function as operators were increasingly asked to focus on delivery. The supplier network grew, the transparency and ownership of a consistent set of quality practices were lost.
Lack of quality ownership
•As quality issues began to surface at Company A, the focus was placed on immediate issue closure rather than root cause problem solving; even when multiple similar issues emerged, these were downplayed and common causes were not identified. The lack of adherence to quality practices also prevented underlying issues from being uncovered and therefore addressed.
Weak processes and lack of root cause problem solving
•By not investing in manufacturing improvements and quality systems, these companies created environments that were not compliant with regulatory guidelines.
Lack of proactive measures
So why do they fail?
Reactive instead of proactive management systems to prevent problems, mitigate risk and foster continuous improvement.
Drive to low-cost suppliers of ingredients/components and services due to inadequate due diligence, risk assessment, qualification and governance... with potential significant direct and indirect risks
Industry and Consumer Litigation prevalent... with expressive costs
Unprecedented number of compliance issues resulting in regulatory Warnings, “Voluntary” Programs or Legal Action.
1- Fit for Purpose
2- Product Assessment and Metrics
3- Quality System Elements
4- Governance / Risk Management
Are the manufacturing strategies
adequate to support the
business?
Are the products and processes in
state of control?
Does the Quality System result in
sustainable compliance?
Does governance & risk
management show predictable &
consistent decisions ?
Critical leadership role in terms of shifting the paradigm * Source:Quantic methodology
Focus on diagnosing critically products,
systems, people
Pharma Industry Today The Promise of Q10
Deviations
Rejects
Data gaps
Few surprises
Data-driven
Competitive advantage
Quality beyond compliance
Use PQS for the intended purpose
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102
99
96
In
div
idu
al V
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e
_X=99,294
UCL=101,384
LCL=97,204
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2
1
0
Mo
vin
g R
an
ge
__MR=0,786
UCL=2,568
LCL=0
6560555045
101
100
99
Observation
Va
lue
s
104,4102,6100,899,097,295,4
LSL USL
LSL 95
USL 105
Specifications
1021009896
Within
O v erall
Specs
StDev 0,696753
C p 2,39
C pk 2,05
Within
StDev 0,882446
Pp 1,89
Ppk 1,62
C pm *
O v erall
1
1
Process Capability Sixpack of TERBINAFINE HCL
I Chart
Moving Range Chart
Last 25 Observations
Capability Histogram
Normal Prob PlotA D: 0,531, P: 0,168
Capability Plot
Use PQS for the intended purpose
61554943373125191371
102
99
96
In
div
idu
al V
alu
e
_X=99,294
UCL=101,384
LCL=97,204
61554943373125191371
2
1
0
Mo
vin
g R
an
ge
__MR=0,786
UCL=2,568
LCL=0
6560555045
101
100
99
Observation
Va
lue
s
104,4102,6100,899,097,295,4
LSL USL
LSL 95
USL 105
Specifications
1021009896
Within
O v erall
Specs
StDev 0,696753
C p 2,39
C pk 2,05
Within
StDev 0,882446
Pp 1,89
Ppk 1,62
C pm *
O v erall
1
1
Process Capability Sixpack of TERBINAFINE HCL
I Chart
Moving Range Chart
Last 25 Observations
Capability Histogram
Normal Prob PlotA D: 0,531, P: 0,168
Capability Plot
Rolling review
Data collection
Control Charts
Capability Six-Pack
Set next release limits
A journey of mindset changes
AS COMPETITIVE ADVANTAGE
EXCELLENCE
COMPETENCE
UNDERSTANDING
AWARENESS
INNOCENCE
Competitive advantage through
prevention of quality issues
Quality mindset in all functions
Design quality in and anticipate
issues
Quality systems and metrics
reveal reality, and drive action
Quality Unit will identify the
issues
Quality mainly outsourced to
regulators
Description
“I’m good because I passed
the last inspection”
“It’s good as long as quality
approves it”
“We review quality along with
other aspects of the business”
“Tolerance to problems and
mistakes is minimal”
“Failure to integrate quality is
not even an option”
Mindset
Science, “not only” compliance
61554943373125191371
102
99
96
In
div
idu
al V
alu
e
_X=99,294
UCL=101,384
LCL=97,204
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2
1
0
Mo
vin
g R
an
ge
__MR=0,786
UCL=2,568
LCL=0
6560555045
101
100
99
Observation
Va
lue
s
104,4102,6100,899,097,295,4
LSL USL
LSL 95
USL 105
Specifications
1021009896
Within
O v erall
Specs
StDev 0,696753
C p 2,39
C pk 2,05
Within
StDev 0,882446
Pp 1,89
Ppk 1,62
C pm *
O v erall
1
1
Process Capability Sixpack of TERBINAFINE HCL
I Chart
Moving Range Chart
Last 25 Observations
Capability Histogram
Normal Prob PlotA D: 0,531, P: 0,168
Capability Plot
Invest in new technologies
Root Causes of Recalls
Intermixing
14%
Packaging 11%
Other
Aim to make the product "impossible" to be wrong:
e.g. “enforce” vision systems
But again, understand where your processes stand...
FMEA for each packaging line, re prevention of product
mix-up, including human intervention (intentional mix-
up). Reliability
Administrative
Quality
Operators
Procurement
Supply Chain
Manufacturing
Research & Development
Quality Lever
1000:1
PRODUCT
DEFINITION 100:1
PRODUCT
DESIGN 10:1
PROCESS
DESIGN 1:1
PRODUCTION
PRODUCT
IMPROVEMENT
LOW VISIBILITY
LOW REWARD
HIGH VISIBILITY
HIGH REWARD
Approach to Quality by Design
Product X
Product
Regulatory approval
Application to new products
A fad
Diluted across many projects
Over-reaching
REAL…
NOT…
•Flow
•Integration (end to end)
•Integrated control strategy
•Leaps, not incremental
•Incorporate new technology
•Promote mindset change
Think the “impossible”
106
105
104
103
102
101
100
99
98
97
1 10 19 28 37 46 55 64 73 82 91
Ind
ivid
ua
l V
alu
e
Observation
Launch Volumetric fill on tabletting process
Sieve size change Recirculation channel change
Understand the product/process
I Chart of Assay Product X % by Changes
106
105
104
103
102
101
100
99
98
97
1 10 19 28 37 46 55 64 73 82 91
Ind
ivid
ua
l V
alu
e
Observation
Launch Volumetric fill on tabletting process
Sieve size change Recirculation channel change
I Chart of Assay Product X % by Changes
Understand the product/process
ATTACK THE BASE!
1
10
100
10,000
100,000
Recalls
Batch Rejections
Critical deviations/Complaints
Deviations
Non-Q. focused behaviors
Understand the leading and lagging indicators
ATTACK THE BASE!
External Traditional focus
for management
Early Warnings
New focus for management
Internal
Implementing a people development strategy, linked with a
manufacturing strategy and underlying organization and
product plan
Formalize Quality Planning to Diagnose Periodically Continuously Periodically
Metrics & KQIs Monitoring & Evaluation
CAPAs Correction & Prevention
Self Inspections Internal Audits External Audits Regulatory Intelligence
Q Risk Assessment Site/Unit
Product Review APR-PQR
Annual
Quality Plan
Q-Systems Review
All of this requires leadership and
management support
Cross functional committees Q Unit functional committees
Site
Division Division
Compliance
Site
Compliance
& Audit
Systems
& Standards
Executive Q. Team
Development Tech Ops Development Tech Ops
CEO & Executive Team
The traditional view of quality systems based upon lagging indicators must be shifted to a focus on leading indicator in anticipation of risks.
37
Our job to shift the paradigm
Our responsibility with our patients for
reliable supply of high quality products.
Quality beyond Compliance
1. Achieve product realisation
2. Establish and maintain a
state of control
3. Facilitate continual
improvement
(Q10) HOLISTIC
„
applies…throughout the product
lifecycle(§3.1)
• Pharmaceutical Development
• Technology Transfer
• Commercial Manufacturing
• Product Discontinuation”
Quality beyond Compliance
INSIGHT
(Q10)
“…applies to the systems supporting
the development and manufacture of
pharmaceutical drug substances (i.e.,
API) and drug products, including
biotechnology and biological
Products
…application is appropriate and
proportionate to lifecycle stage
...includes…new and existing
products.”
Quality people can lead improvement
Lay foundations for continuous
improvement
Lead innovations in manufacturing
The patient is the customer
41
Innocence Understanding
Dominant
Focus
Absent Detect/Correct
Dominant
Result
Unpredictable Outcomes Chronic Firefighting/Right
Second Time
Failure Mode Surprises Brute Force
Cost of
Quality
External Failures/Internal Failures Internal Failures/Appraisal
42
Excellence Competence
Correct/
Prevent
Prevent Correct/Prevent
Right First
Time/
Consistent &
Predictable
Never Fails/
Adaptive and Intelligent
Right First Time/Consistent and
Predictable
Risk of
Decay
Pursuit of Perfection Risk of Decay
Appraisal/
Preventive
Preventive Appraisal/Preventive
EXCELLENCE
COMPETENCE
UNDERSTANDING
AWARENESS
INNOCENCE
Quality Culture Maturity Model
Quality mainly outsourced to
regulators
I’m good because I passed
the last inspection
EXCELLENCE
COMPETENCE
UNDERSTANDING
AWARENESS
INNOCENCE Quality mainly outsourced to
regulators
Quality Unit will identify the issues
Quality Systems and metrics reveal
reality, and drive action
Quality mindset in all functions
Design Quality in & anticipate issues
Competitive advantage through
prevention of Quality issues
I’m good because I passed
the last inspection
It’s good as long as Quality
approves it
We review Q. along with other
aspects of the business
Tolerance to problems and
mistakes is minimal
Failure to integrate Quality is
not even an option
Quality Culture Maturity Model
EXCELLENCE
COMPETENCE
UNDERSTANDING
AWARENESS
INNOCENCE
“Diagnose” where you are!
Quality mainly outsourced to
regulators
Quality Unit will identify the issues
Quality Systems and metrics reveal
reality, and drive action
Quality mindset in all functions
Design Quality in & anticipate issues
Competitive advantage through
prevention of all Quality issues
Comprehensive Product Assessment and
Trending (CPAT)
Product X
It is critical that we know where we stand with our
products and processes:
• Assessment of Regulatory Compliance
• Assessment of Quality Systems, e.g.:
•Laboratory Controls
•Equipment Controls
• State of Process Validation
This should happen prior to
any improvement actions.