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8/9/2019 Change Managament Enabling Quality
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8/9/2019 Change Managament Enabling Quality
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WHY CHANGE ?
WHY CHANGE ?
It is not the strongest of the species that survive, nor the
most intelligent, but the one most responsive tochange.
~Author unknown, commonly misattributed to Charles Darwin
P10: Change Management By Bernadette Doyle, PhD
8/9/2019 Change Managament Enabling Quality
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….
“Double S” curve of Improvement ”
Improvement
Time
Transformational
(disruptiveintervention)
Incremental
(continuousimprovement)
P10: Change Management By Bernadette Doyle, PhD
8/9/2019 Change Managament Enabling Quality
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ICH Q10 and Change Management
Change Management A systematic approach to proposing, evaluating, approving,implementing and reviewing changes (ICH Q10)
The scope of change management is much broader thanchange control, which was typically applied to one changeat a time
Change management includes the oversight andmanagement of the entire portfolio of changes and thechange process, including all the components of changecontrol
In a Pharmaceutical Quality System (PQS) developedaccording to Q10, change management applies across theentire product lifecycle
Change Management System
A company should have an effective change management system inorder to evaluate, approve and implement changes
The change management system should include the following :
Quality risk management should be utilised to evaluate proposed changes;The level of effort and formality of the evaluation should be commensuratewith the level of risk;Proposed changes should be evaluated relative to the marketingauthorisation, including current product and process understanding and/ordesign space, where established;
Expert teams, with appropriate expertise and knowledge, shouldevaluate proposed changes; An evaluation of the change should be undertaken after implementation toconfirm the change objectives were achieved.
P10: Change Management By Bernadette Doyle, PhD
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ICH Q10 and Continual Improvement
Implementation of ICH Q10 throughout the product lifecycle shouldfacilitate innovation and continual improvement and strengthen thelink between pharmaceutical development and manufacturingactivities (ICH Q10 )Facilitate Continual Improvement
To identify and implement appropriate product quality improvements,process improvements, variability reduction, innovations andpharmaceutical quality system enhancements, thereby increasing theability to fulfil quality needs consistently (ICH Q10)
Key enablers
Quality risk management
Knowledge management
Opportunit ies from implementing Q8, Q9 and Q10?
Product and process understanding, the use of quality riskmanagement principles, supported by the implementationof an effective PQS ( i.e. applying ICH Q8, ICH Q9 and ICHQ10 principles) provides the opportunity to:
optimise science and ri sk based post-approval changeprocesses to maximise benefits from innovation andcontinual improvement (ICH Q10)
P10: Change Management By Bernadette Doyle, PhD
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Applying Q8 and Q9 to Change Management in Q10
Collect datafor critical
parameters
Assessvariation
Change
process,materials,specifications
as required
Monitor/ ContinuousProcess Verification and
update knowledge
Perform Risk Assessment
Business triggerfor change
“ Straightforward” Excipient Supplier Changes ?
12
Impact on Drug Product Control Strategy
Surface of API fluorescesdue to surface peroxidation
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0 5 10 15 20 25 30 35 40Timepoint (Months)
N - O x
i d e
( a / a )
Tighter control of additionsof mineral oil andmanufacturing process
Enhanced GC testperformed by supplier andreviewed by Site prior toshipment
New Excipient supplier deliveredmaterial to agreed specification
Excipient manufacturing processallowed addition of mineral oil tobring batches into specification
Criticality of replacing catalystto control hydrogenation notrecognised
C a s e S t u d y
1
P10: Change Management By Bernadette Doyle, PhD
8/9/2019 Change Managament Enabling Quality
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Fermentation Product Impurity contr ol 2010
SolutionIdentification of interactionbetween rape seed oil quality(fermentation), Crystal Form(Extraction Process) andExtraction equipmentmechanical force (Equipment)Controls put in place to tackleall three causes
C a s e S t u d y
2
Which Tools used?Complex Root Cause Analysis using modified Britest tools Process via Metabolic Pathway andMechanism Map,True root causes verified in controlled conditions using classical experimentation
Benefi t – Failure rate reduced from 15% to zero,No impuri ty levels > 0.6% for five years,Reduction in hidden factory investigations, confidence in process.
Equipmentfailureunderstood
UnivariateControl
Multi variate Control
Problem :Fermentation product producing high levels of impurity restricting supply of critical medicine
Multiple potential root causes.Initial univariate root cause solution only partially solved problem.
• High Cost of Waste and risk of stock out for life ‐saving medication
• Complex system that is inherently close to the edge of failure with respect to its propensity for API aggregation
• Very subtle changes in raw material properties and processing parameters can result in aggregation
• Internal & external experts advised the root cause of the aggregation failure is inherent and linked to the formulation
C
a s e S t u d y
3
P10: Change Management By Bernadette Doyle, PhD
8/9/2019 Change Managament Enabling Quality
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8/9/2019 Change Managament Enabling Quality
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Trend Plot of 2010 batches (mech)
Spreadsheet2 in NewBatches2009.stw
BatchNo
343112348117
358316361789
367138377305
380834386983
390276397687
402227406400
2.8
3.0
3.2
3.4
3.6
3.8
4.0
4.2
2 0 1 0 b a t c h e s
( m e c
h )
Mean
USL
Mean = 2.97 umPpK > 2
Results following Improvements to Functional Specifications
R e
s u
l t s o
f C o r r e c
t i v e
A c t
i o n s
ICHQ10 and Management Responsibili ty
Management should -:
Participate in the design, implementation and monitoring of thepharmaceutical quality system
Ensure a timely and effective communication and escalation processexists to raise Quality issues to the appropriate levels of management….
P10: Change Management By Bernadette Doyle, PhD
8/9/2019 Change Managament Enabling Quality
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How to translate QbD“Effective Control Strategy on the shop floor” A major part of execution is the Batch Document
– It should be articulated into an effective set of instructions, SOPs , guides … leading to:
A clearly understood Control Strategy at a level where the product is made
Effective Control Strategy
Continuous Improvement-:
GEMBA (Go See)
Product Data Trending Review
IPNs/AARs/operator feedback,
Product Quality Control Strategy
Master Batch Document
Validation Continuous Verification
ProductTechnical
RiskAssessment
SB480848 Manufacturing Performance 32Enteric Film Coated Inspected Tablet (160mg) - Individual & Mean Assay (%LC)
Performance Management Systems
P10: Change Management By Bernadette Doyle, PhD
8/9/2019 Change Managament Enabling Quality
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Performance Management Systems
Perfo rmance Management Systems
P10: Change Management By Bernadette Doyle, PhD
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Other Considerations …
Regulatory Challenges to Implement Changes
Lack of a harmonised regulatory system for managing post-approvalchanges
EU vs US vs Japan vs ROW
‘Registered detail’
not a common agreement of what constitutes ‘registered detail’ and whatwe need to change via a variation
Leads to different requirements and timelines for approval, and differenttypes of variations
Particularly challenging when trying to manage manufacturing changesglobally
P10: Change Management By Bernadette Doyle, PhD
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Opportunities
Implementing Q8, Q9 and Q1O provide opportunities to optimisescience and risk based pos t-approval change pro cesses tomaximise benefits from innovation and continual improvement
Legacy products are also improved under the ICH Q10 changemanagement system over the lifecycle
Q8, Q9 and Q10 are moving Industry and Regulators in the rightdirection
Are we realising opportunities or obtaining benefits as quickly as weshould ?
How can we facilitate this?
Summary
Drivers for Change
ICH Q10 and how change can be supported
Implementation of ICH Q8, Q9 and Q10
Case Studies
ICH Q10 and Management Responsibility
Considerations and Opportunities
P10: Change Management By Bernadette Doyle, PhD
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