the changing world of validating manufacturing...
TRANSCRIPT
The Changing World of Validating Manufacturing Processes
Darrin Cowley, PhD
Executive Director Corporate Product Quality
IV SYMPOSIUM – SINDUSFARMA – IPS/FIP
1
Agenda
• Introduction
• Use of prior knowledge to support effective process design
• PPQ Lot Tool: Determining the number of lots in PPQ
• Use of CPV to continuously improve the commercial Control Strategy
• Closing Remarks
2
Introduction
3
Stage 1
Process Design Stage 2
PPQ
Stage 3
Continued Process Verification
(CPV)
Prior
Knowledge
• They tell you if you can run your commercial process under well controlled, center point oriented operating parameters and reproducibly produce quality product for three – five runs and make product that meets the required product quality (specification).
• What does running in the middle of your validation acceptance criteria tell you about your process???
What is the Value of Validation Runs?
4
Characterization Design Space
Process Validation
Acceptance Criteria
Action Limits
Operating
Limits
FDA’s Process Performance Qualification (PPQ) Guidance in 2011 and Recent EU Proposals Highlight Expectations for Early Validation Lifecycle Activities
Stage 1 - Process Design/Process Development
• Overall goal is development of an effective commercial control strategy
• Expectations include: – Understanding and justifying product quality requirements
– Understanding sources of process variability that impact product quality
– Designing effective controls to consistently deliver required product quality
Stage 2 - Performance Qualification/Validation
• Goals include demonstrating control strategy effectiveness and consistency in commercial manufacturing setting
• Expectations include (for PPQ): – Identification of relevant performance indicators
– Establishing expected and acceptable performance and variability
– Demonstration that process performs as intended against prospective criteria
Stage 3 – Continuous monitoring
• Continuous improvement of the control strategy
PPQ Doesn’t end after the PPQ runs themselves
• Passing PPQ alone does not guarantee the process is in control on a continuing day to day basis – During validation, you are on your ‘best behavior’
– Increasing numbers of production runs
– Changes in raw materials, personnel, procedures
– Increasing cycles of equipment and materials use and cleaning
– Non-conformances
– OOT’s
• Continued Process Verification confirms state of control and/or identifies areas of concern
Post-approval
Development PAI & Launch
Prep
Conf. &
File prep
Process
Char.
Comm. Process
Development
FIH Process
Development
Commercialization
Process
As defined in the FDA Process
Validation Guidance (Jan 2011)
Conf.
Camp.
P3
Campaign Phase 1 & 2 Campaigns Production Activity Commercial Production
PPQ requires an integrated process validation lifecycle approach
Magnitude of post approval changes can
take process back into Development
Stage 1
Process Design Stage 2
PPQ
Stage 3
Continued Process Verification (CPV)
Prior Knowledge
(product specific and
platform knowledge)
Tool -
PPQ Size Continuous
improvement of the
control strategy via
APR
Use of prior knowledge to support effective process design
Stage 1
Process Design Stage 2
PPQ
Stage 3
Continued Process Verification
(CPV)
Prior
Knowledge
The PPQ Paradigm Requires New Approaches to Process Design
• Enhanced approaches provide the overall framework:
– Assessment of product attribute criticality
– Development of risk and knowledge based integrated control strategy
• Knowledge from many sources is being integrated:
– Product design and selection
– Process development
– Product and process characterization
– Pilot and clinical manufacturing experience
– Mathematical modeling (i.e., computational fluid dynamics)
– Prior/platform knowledge from other products
Changes provide more systematic focus on product quality and risks
Reflecting prior knowledge in regulatory files presents a challenge
• Prior knowledge is extremely valuable because it integrates and builds on Amgen’s vast experience:
– More than a dozen products at various lifecycle stages, decades of “product years” experience
– 100s of manufacturing lots
– 1000s of raw material lots
– 100s of DOE studies
– 10s of thousands of pages of technical reports that contain specific product information to confirm and optimize the process and product
• The challenge is to effectively convey prior and developmental knowledge in regulatory files in a manner that:
– Provides sufficient information to support the study design and conclusions
– Is effective and practical to facilitate to Agency’s understanding and review
10
PPQ Lot Tool: Determining the Number of Lots in PPQ
Stage 1
Process Design Stage 2
PPQ
Stage 3
Continued Process Verification (CPV)
Tool -
PPQ Size
Process Validation Guidance: Necessity for Justification of Number of PPQ Lots
PPQ Lot Tool provides an assessment of factors that may have impact on product/process understanding
• Quantify the amount of Stage 1 process design information
• Quantify the quality of the Stage 1 process design information
• Incorporate indirect measures of performance
• Adjust the PPQ size based on the amount and quality of process design information
• Assess for gaps in Stage 1 knowledge
Result: Data / risk driven and structured approach to a PPQ strategy vs.
one size fits all strategy
or
Goal: Leverage information from Stage 1 using a decision making tool to inform size of PPQ
Stage 1
Process Design
Stage 2
PPQ
Stage 1
•Design of Experiments
•Multiple Risk Assessments
•Critical Quality Attribute
Matrix
•Comparability
•Control strategy
•Prior Knowledge
•Biological Characterization
•Product Characterization
(including degradation
profile)
•Etc.
Activities
Stage 2
•PV protocols
•Validation report
•Product comparability
•Process comparability
•NC trending
•Etc.
Stage 3
•Control charting for
numerous quantitative
parameters
•Stability trending
•Process capability
assessment
•Analytical method
performance
•NC trending
•Etc.
Integrate Stage 1 information plus indirect performance of the facility
using a decision making tool
Stage 3
CPV
Tool is used to score the knowledge gathered during Stage 1 Process Design
Stage 1
Process Design
•Process/Product
•Manufacturing
experience
•Extent of process
characterization
•Process scale up and
site transfer history
•Risk assessments
•Raw Materials
Understanding
•Facility
•Facility and equipment
configuration
•Experience in facility
A final score is generated from the tool which describes the knowledge at
the time of PPQ Score is translated into a lot count guidance
14
•Tool organizes knowledge into 3 categories that drive
product variation
•Tool consists of qualitative statements for each category
(statements are focused on molecule, site, equipment and
scale specific)
•A statement = a piece of information from Process Design
that provides understanding of variation
•Each statement is assigned points based on
importance in product/process understanding
•Points are accumulated when information is incomplete or
missing at the time the PPQ strategy is being developed
Snapshot of PPQ Lot Tool scoring—Example
Performance
Characteristic Factor Status
(True/False)
Scoring Weight
(Fixed: 0 to 9)
Product/Process Product Quality Risk
Assessment is complete and
high risk items have been
mitigated
True 0 False =5
DP only: Experience with
multiple DS ages False 3 False=3
Process Characterization is
complete True 0 False=7
Raw Materials Experience exists for
multiple lots for complex raw
materials per supplier
True 0 False=7
Facility Receiving plant has a
successful inspection history True 0 False=3
SCORE
Compute the weighted mean and convert to a %
(3/25)100%=
12%
15
PPQ Lot Tool: Action threshold table
Score (%) # of Lots for
PPQ Justification
> 70% 6 to 8 Recognition of limited process understanding and
experience (e.g., novel technology)
> 30% to ≤ 70% 3 to 5 Recognition of moderate process understanding
and experience
≤ 30% 1 to 2 Recognition of a well understood process and
significant experience
Determination of number of lots is based upon the confidence in
the totality of the understanding of our process variability
Example score: 12% would require 1 to 2 lots for the PPQ campaign
16
Use of CPV to Continuously Improve the Commercial Control Strategy
Stage 1
Process Design Stage 2
PPQ
Stage 3
Continued Process Verification (CPV)
Continuous
improvement of the
control strategy via
APR
CPV leverages existing Quality Management Systems
• Manufacturing• Analytical Testing
• Specifications• IPCs
• Stability Protocols• Analytical Methods
• MPs & SOPs• Valdn Protocols
• CAPA• Change Control
APR
Monthly Data Review
• Process Monitoring (IPCs)
• Product Monitoring (Specs)
Programs that directlymonitor mfg process
performance
• Complaint trending
• NC trending• Stability trending
Programs that indirectlymonitor mfg process
performance
* Frequency of review varies by program and is based on availability of the data
Trends, low capabilities and excursions to controls are
investigated and corrective actions taken to ensure processes
remain in a state of control
Monitor Execute
Improve Plan
Ensure
Quality
An
nu
al Re
view
Freq
ue
ncy
~Re
al-time
*
Co
mp
rehen
sive Data Set
Pro
gram-sp
ecific
CPV activities are performed today, but we are developing tools and integrating
processes to make the improvement cycle more efficient, timely and robust
Transition from Stage 2 to Stage 3
• CPV procedurally begins with the first lots produced after the PPQ campaign
• Use Stage 1 / 2 data to establish variability estimates as early as possible – Representative clinical, engineering and PPQ data may be used in
control limit and capability calculations
• CPV uses PPQ sampling plan and acceptance criteria as a starting point – Parameters are sorted into categories based on their purpose and
criticality
– Action Limits may be updated with commercial-scale data from PPQ
– Parameters may be dropped from monitoring with sufficient data
The control strategy should reflect the performance of the commercial
process in order to execute effective control
CPV can be used to optimize the commercial control strategy
Control Strategy = IPCs, Specs, Monitoring Plans
Execute the
Annual Product
Review (APR)
Any
parameter
requires
evaluation?
Determine appropriate action
Change the
impacted control
document
Monitor the process throughout the year
Yes
No
Q1 Q2 Q3 Q4
Findings may also be
used to improve the
development and assessment
processes and to increase
organizational knowledge Need to
change the
control
strategy?
Yes
No
Control strategy is assessed when the process hits defined action triggers
Action triggers:
• Statistical evaluation of process control indicates an unstable process
• Statistical evaluation of process performance (Ppk) against applicable limits
• Identification of NC trend, product-impacting NC(s) or complaint investigation implicates the effectiveness of the control strategy
Additional considerations:
• Number of data points (must be > 30)
• Performance of the analytical method
• Purpose & criticality of the parameter under review
• Regulatory commitments
• SOPs describe action triggers to address good and poor performance
• Assessment is a science- and risk-based evaluation of all
representative data
Poor performance actions
Investigations, increased monitoring and/or process improvement
Good performance actions
Reduced monitoring, tightened limits when justified
Drop parameters
with sufficient data
PPQ sampling baseline
Reduce sampling based
on process performance
Control Strategy update
PPQ PPQ
# o
f P
ara
me
ters
Mo
nit
ore
d
30 lots
APR APR APR APR
Baseline monitoring to
maintain control
Drop parameters
with sufficient data
Reduce sampling based
on process performance
Significant
Process Change
30 lots
Control Strategy
update
Monitoring level is influenced by demonstrated process performance and planned events
Note: Magnitude of the changes to the monitoring plan are not to scale; they are for illustration purposes only
Change opportunity is with non-
critical parameters
Monitoring levels may step down when
the process is stable and capable
Monitoring levels may step up when we need to
monitor more for understanding and control
Approaches to Stage 3
• Filed (or regulatory commitments) CPV parameters (i.e., in-process controls, specifications) provide assurance of consistent product quality
• Additional enhanced process monitoring (i.e., non-critical parameters, multivariate statistical models) is extremely useful for:
– Identifying subtle causes of variation
– Identifying improvement opportunities
– Troubleshooting process performance
– Increasing at scale process knowledge, etc.
• To be fully realized, enhanced monitoring needs to be treated as a continuation of Stage 1 process design, i.e.:
– Flexibility to timely add and subtract parameters, revise limits, perform complex analyses, avoid non-value added numerical limits without prior regulatory approval (these could be confirmed by agencies upon inspection)
– Parameters identified thorough enhanced monitoring as critical would be added to licensed CPV program
Closing Remarks
• Process Performance Qualification concepts , stage 1-3, should be built into our process validation systems
• The proposed approaches represent a standardized approach to inform PPQ plans and CPV
• Additional pre-filing discussions with Agencies are warranted regarding:
o Effective implementation these process validation tools
o Information to be submitted in license applications to facilitate the Agency’s review
o Changes to be handled by the organizations Quality Management System (QMS)