Continuous &
Continued Process
Verification
Presented by Eoin Hanley
4 July, 2016
This session will cover
Quick recap on PV Lifecycle stages & Annex 15
Continued (Onoing) Process Verification
Continuous Process Verification (PAT)
Continuous Manufacturing: benefits, challenges &
examples
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US FDA “Process Validation”
1. Process
Design
Process
2. Process
Improvement
Qualification
& Innovation
3. Continued
Process
Verification
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US FDA “Process Validation”
Basic principle is that a drug should be produced
that is fit for its intended use.
This is achieved by:
• Ensuring that quality, safety and efficacy are
designed/built into the product
• Quality cannot be adequately assured merely
by I-P and FP inspection/testing
• Each step of a manufacturing process is controlled
to assure that the FP meets all quality attributes
including specifications
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What does a successful PV program
look like?
• To establish control:
• Understand the sources of variation
• Detect the presence and degree of variation
• Understand the impact of variation on
process/product
• Control the variation in a manner commensurate
with the risk to process/product
• Throughout the lifecycle-including changes
• Evaluation of the state of control
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Annex 15: Process Validation
Design
Space
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Annex 15: Process Validation
Process
Design
Continuous Process
Improvement Validation
Continuous
Process
Verification
Ongoing
Process
Verification
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Continued Process Verification
• “Continued or Ongoing Process Verification”
• Continual assurance-system for detecting unplanned
departures/undesired process variability
• Change in the validated state of the process could
impact product. Detected by:
• Change Control
• Periodic Monitoring
• Data Trending Review
• Calibration and PM
• Knowledge of operational parameters (Control Strategy)
and Design Space
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Continued Process Verification
US FDA: “Continued monitoring & sampling of
process parameters and quality attributes at
the level established during the process
qualification stage until sufficient data are
available to generate significant variability
estimates”
Basis for routing sampling and monitoring:
• Level of sampling
• Frequency of sampling
• Can be adjusted to a statistically appropriate
and representative level
• Periodically assessed
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Continued monitoring
Process PV Commercial
Design (PPQ) Manufacturing
Change/
Level of QC Lab Testing
improvement
Post- introduced
periodic
review
Could signal PAT
vary implemented
based on
approach
Variability
estimate
Monitoring
established
QC Testing
Time / Process Knowledge
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CPP’s and process alarms
Control range of Critical Parameters
Control Strategy around Critical Process Parameters
Within the Design Space
Easy to implement and control
Demonstrates proper performance of the process
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Change Control
Maintain validated state via review and approval of changes made
Further understanding of the process & variations
Changes of materials, FSE, personnel and procedures
Review by cross-functional SME’s
Pre-approval by Quality
All changes tracked & trended
Planned & unplanned
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Periodic monitoring
Demonstrates consistency of initial results
Ongoing feedback programs to collect and analyse data
Part of an approved protocol (Annex 15)
Evaluate the state of control of the process
• Statistical process control
• Data from automation
Risk-based Routine Monitoring Program
May identify process/product problems
May indicate areas for process improvements
• Back to Stage 1 and Stage 2
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Data trending & review
• Even well-designed processes must
include in-process control procedures
• Verify the quality attributes are
appropriately controlled
• Action & alert levels for process
parameters
• Analytical data from routine monitoring
• Samples must represent the batch under
analysis
• Sampling Plan must result in statistical
confidence
• Intra- and inter-batch variation
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Data trending & review
• Batch must meet predetermined
specification
• Trending helps identify potential issues
• May feed into a CAPA system
• Specifications must be correctly derived
• It is all about evaluating process stability
and process capability
• Should guard against overreaction to
individual events as well as failure to detect
unintended process variability
• Must be reviewed by the Quality Unit
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Statistical tools & techniques
Determine the
Detect variation Characterise it
root cause
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Maintenance
• Ensures process remains in control
• Maintain the qualification status of
facility, utilities, systems and
equipment
• Monitoring & scheduling
• Maintenance (planned &
unplanned)
• Calibration
• Assess the data periodically
• Re-qualification required?
How much?
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Training
Training on revised procedures & forms
Specific training-statisticians or trained
personnel
New personnel
Re-training of operators based on operator
errors
Periodic training-personnel may have an
impact on variation?
Re-training for certain processes i.e. process
simulation/media fills, gowning practices etc
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Annual Product Review/Product
Quality Review
• Overall periodic review of the validated state
• Also product quality complaints, adverse events etc
• Frequency of the review may be based on a risk
assessment (also refer to new US FDA Guidance for
Industry Request for Quality Metrics, July 2015)
• Review of regulations/CGMP
• Documented with conclusions
• Recommend planned improvements
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Continuous Process Verification
“An alternative approach to process validation in which
manufacturing process performance is continuously
monitored and evaluated” (ICH Q8)
An alternative to traditional PV
Can be part of a hybrid approach
Processes must be shown to be
robust and ensure consistent
product quality before any product
is released to the market
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Continuous Process Verification
• High degree of assurance in the science-based control
strategy
• Quality by Design approach
• Undergo regular evaluation
• PAT/SPC may be used as tools
• Need to determine the number of batches to
demonstrate process capability
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Process Analytical Technology
• Intended to support innovation, efficiency and risk-based
decisions
• Industry is slow to adopt innovative systems
• Timely analysis of critical quality attributes
• Control loops to adjust processing conditions-output
remains constant
• Can provide a higher degree of process control
• Will have different Design & Process Qualification stages
• US FDA Framework and ASTM guides
“Quality cannot be tested into products;
it should be built-in or should be by design”
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Process Analytical Technology
Looking for gains in quality, safety and/or efficiency:
• Reducing cycle times
• On/in/at-line measurement/control
• Prevent rejects/re-processing
• Real-time release
• Increasing automation to reduce human errors
• Improving energy/material use
• Increasing capacity
• Facilitating continuous processing to improve
efficiency & manage variability
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Continuous Manufacturing processes
Innovative to
Continuous
Definition of pharma
flow reactors
“batch” and industry, but
(US FDA and
“Batch” vs “lot” in CFR’s not to
University of
“Continuous” are applicable petrochemical,
Washington)
to continuous food,
using Raman
processes. automotive,
data
etc
Slide 25 © PharmOut 2015
Continuous Manufacturing processes
Considerations:
• Residence Time Distribution (RTD)
• Sampling
• Process control & monitoring
• Real Time Release Testing
• Collection of product
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Residence Time Distribution (RTD)
• Continuous material flow into the system
• RTD describes the non-ideality of flow
• Can be evaluated by tracer studies
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Sampling
Sample frequency should be suitable for
the system dynamics
• Capable of seeing potential disturbances
Probe/sample location(s) representative
of entire vessel
Sample interface
• Remains constant over the process (no fouling)
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Sampling considerations
Sample acquisition time
• Compare to unit dose Is the measurement
(volume/mass) representative of the
• Consider flow past the probe whole?
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Process control
Long periods of operation in CM
High degree of automation
• E.g. Product diversion to waste if out of specification
Ensure process is operating as intended
• Control start-up, shutdown
• Control of critical parameters
• Detect process upsets
• Correct process drifts
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Process monitoring
• It would be challenging to assure
quality in many continuous
manufacturing systems without
appropriate on-line monitoring
and/or multivariate tracking and
trending.
• Adequate monitoring allows
rejection of non-conforming
material made during process
upsets, while keeping the ‘good’
material.
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Real Time Release Testing
“The ability to evaluate and ensure the quality of in-
process and/or final product based on process data,
which typically include a valid combination of measured
material attributes and process controls” -ICH Q8(R2)
Continuous manufacturing naturally lends itself to RTRT
approaches
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Collection of product considerations
Material traceability
• Multiple lots of raw material and API may be used in
a single run
• Should have the ability to trace raw material and API
lots to finished products. (Importance of RTD)
Traceability of disturbances through the system
• Diversion of material made during disturbances
• Clear definition of criteria for determining “good”
product
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Collection of product considerations
When is product deemed acceptable to collect?
During process After a Have all
start-up and disturbance components
shut-down (spike in feed reached desired
periods? rate)? state?
Example: For concentration or material property?
• Are measurements other than concentration of active
component(s)needed?
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Considerations for Batch/Lot
How to define a batch/lot at the product collection
step?
Amount of
Production
material
time period?
processed?
Production
variation (e.g., Other
different lots definition?
of feedstock)?
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Example: CM of tablets
• Traditional oral solid dosage process:
• High inventory
• Long lead times (i.e. actual time is 2 days but total
time is 30-60 days)
• Long changeovers
• Off-line analysis etc
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Example: CM of tablets
GEA ConsiGma™
• Powder supply
• High shear mixing &
granulation
• Segmented fluid bed
dryer
• Granule conditioning unit
• Rotary tablet press
• Continuous coater
http://www.gea.com/global/en/solutions/continuous-manufacturing.jsp
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Example: CM of tablets
Easier to move 1 kg than 1 tonne
Minimum amount of product in the
process
No scale-up. Same size equipment
from pilot to CM.
Time saved from lack of scale-up
Removes “inertia” from the
manufacturing system
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Section recap?
Continued Process Verification
Continuous/Ongoing Verification
PAT & Continuous Manufacturing
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Thank you for your time.
Questions?
Eoin Hanley
Technical Manager
eoin.hanley@pharmout.net
www.pharmout.net
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