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

Stage 3
Stage 1 Stage 2
PPQ
Continued Process Verification
Process Design
(CPV)

Prior
3 Knowledge
What is the Value of Validation Runs?
• 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).
Characterization Design Space

Process Validation
Acceptance Criteria
Action Limits

Operating
Limits

• What does running in the middle of your validation

acceptance criteria tell you about your process???
4
 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
PPQ requires an integrated process
validation lifecycle approach
Magnitude of post approval changes can
take process back into Development

Commercialization
FIH Process Comm. Process Process Conf. & PAI & Launch Post-approval
Process Development Development Char. File prep Prep Development

Production Activity P3 Conf.

Phase 1 & 2 Campaigns Commercial Production
Campaign Camp.

Stage 1 Stage 2 Stage 3

Process Design PPQ Continued Process Verification (CPV)
As defined in the FDA Process
Validation Guidance (Jan 2011)

Tool - Continuous
Prior Knowledge PPQ Size improvement of the
control strategy via
(product specific and
APR
platform knowledge)
Use of prior knowledge to support
effective process design

Stage 3
Stage 1 Stage 2
PPQ
Continued Process Verification
Process Design
(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 Stage 2 Stage 3

Process Design PPQ 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
or
• Assess for gaps in Stage 1 knowledge

Result: Data / risk driven and structured approach to a PPQ strategy vs.
one size fits all strategy
 Goal: Leverage information from Stage 1 using
a decision making tool to inform size of PPQ

Stage 1 Stage 2 Stage 3

Process Design PPQ CPV
Stage 1 Stage 2 Stage 3
•Design of Experiments •PV protocols •Control charting for
•Multiple Risk Assessments •Validation report numerous quantitative
Activities •Critical Quality Attribute •Product comparability parameters
Matrix •Process comparability •Stability trending
•Comparability •NC trending •Process capability
•Control strategy •Etc. assessment
•Prior Knowledge •Analytical method
•Biological Characterization performance
•Product Characterization •NC trending
(including degradation •Etc.
profile)
•Etc.

Integrate Stage 1 information plus indirect performance of the facility

using a decision making tool
Tool is used to score the knowledge gathered
during Stage 1 Process Design
•Tool organizes knowledge into 3 categories that drive
Stage 1 product variation
Process Design
•Process/Product •Tool consists of qualitative statements for each category
•Manufacturing (statements are focused on molecule, site, equipment and
experience scale specific)
•Extent of process
characterization •A statement = a piece of information from Process Design
•Process scale up and
that provides understanding of variation
site transfer history
•Risk assessments
•Raw Materials •Each statement is assigned points based on
Understanding importance in product/process understanding
•Facility
•Facility and equipment •Points are accumulated when information is incomplete or
configuration missing at the time the PPQ strategy is being developed
•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
Snapshot of PPQ Lot Tool scoring—Example
Performance Factor Status Scoring Weight
Characteristic (True/False) (Fixed: 0 to 9)
Product/Process Product Quality Risk True 0 False =5
Assessment is complete and
high risk items have been
mitigated
DP only: Experience with False 3 False=3
multiple DS ages
Process Characterization is True 0 False=7
complete
Raw Materials Experience exists for True 0 False=7
multiple lots for complex raw
materials per supplier
Facility Receiving plant has a True 0 False=3
successful inspection history
(3/25)100%=
SCORE
12%
Compute the weighted mean and convert to a %
15
PPQ Lot Tool: Action threshold table

# of Lots for
Score (%) Justification
PPQ
Recognition of limited process understanding and
> 70% 6 to 8
experience (e.g., novel technology)
Recognition of moderate process understanding
> 30% to ≤ 70% 3 to 5
and experience
Recognition of a well understood process and
≤ 30% 1 to 2
significant experience

Example score: 12% would require 1 to 2 lots for the PPQ campaign

Determination of number of lots is based upon the confidence in

the totality of the understanding of our process variability

16
Use of CPV to Continuously
Improve the Commercial Control
Strategy

Stage 1 Stage 2 Stage 3

Process Design PPQ Continued Process Verification (CPV)

Continuous
improvement of the
control strategy via
APR
 CPV leverages existing Quality Management
Systems • Specifications
• IPCs
• CAPA • Stability Protocols
Trends, low capabilities and • Change Control • Analytical Methods
excursions to controls are • MPs & SOPs
investigated and corrective • Valdn Protocols
actions taken to ensure processes
remain in a state of control
Improve Plan
Comprehensive

Ensure
Annual

Quality

APR Monitor Execute

Review Frequency
Data Set

• Manufacturing
Monthly Data
• Analytical Testing
Review
Programs that directly
monitor mfg process • Process Monitoring (IPCs)
Program-specific

performance • Product Monitoring (Specs)

~Real-time*

• Complaint trending
Programs that indirectly
monitor mfg process • NC trending
performance • Stability trending

* Frequency of review varies by program and is based on availability of the data

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
Q1 Q2 Q3 Q4

Monitor the process throughout the year

Any
Execute the
No parameter
Annual Product
requires
Review (APR)
evaluation?

Yes

Determine appropriate action Findings may also be

used to improve the
development and assessment
processes and to increase
Need to organizational knowledge
No change the
control
strategy?

Change the Yes

impacted control
document
Control strategy is assessed when the process
hits defined action triggers
• SOPs describe action triggers to address good and poor performance
• Assessment is a science- and risk-based evaluation of all
representative data

Action triggers: Additional considerations:

• Statistical evaluation of process control • Number of data points (must be > 30)
indicates an unstable process
• Performance of the analytical method
• Statistical evaluation of process
performance (Ppk) against applicable • Purpose & criticality of the parameter
limits under review
• Identification of NC trend, product- • Regulatory commitments
impacting NC(s) or complaint
investigation implicates the effectiveness
of the control strategy

Poor performance actions

 Investigations, increased monitoring and/or process improvement
Good performance actions
 Reduced monitoring, tightened limits when justified
 Monitoring level is influenced by demonstrated
process performance and planned events

Drop parameters Drop parameters

with sufficient data with sufficient data

Reduce sampling based Reduce sampling based

on process performance on process performance

Significant
Process Change
APR APR APR APR

Control Strategy update Control Strategy

update
# of Parameters Monitored

PPQ PPQ
PPQ sampling baseline
30 lots 30 lots
Change opportunity is with non-
critical parameters

Baseline monitoring to
maintain control

Monitoring levels may step down when Monitoring levels may step up when we need to
the process is stable and capable monitor more for understanding and control

Note: Magnitude of the changes to the monitoring plan are not to scale; they are for illustration purposes only
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)