3/10/2018

Process Validation
Process Performance and
Product Quality Monitoring
System (PPPQMS)
Maurice Parlane
ISPE PV Team
CBE Pty Ltd

ISPE Indonesia/ISPE Singapore 2018

Agenda
• PPPQMS as part of the Pharmaceutical Quality System
• Implementation of PPPQMS
• Statistical considerations
• CAPA
• Management of Change
• Product Stewardship

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Pharmaceutical Quality System (Q10)

• Quality for the entire Product Lifecycle

• More than just cGMP – includes
management responsibilities, PQS
elements and enablers
• “System” focus (PDCA cycle)
• Enables rigor and continual
improvement

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Pharmaceutical Quality System (Q10)

Pharmaceutical Technology Commercial

Discontinuation
Development Transfer Manufacturing

Investigational products GMP

Management Responsibilities
Process Performance & Product Quality Monitoring System
PQS Corrective Action / Preventive Action (CAPA) System
elements Change Management System
Management Review
Knowledge Management
Enablers
Quality Risk Management
ICH Q10, November 2010

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Pharmaceutical Quality System (Q10)

3.2.1 Process Performance and Product Quality Monitoring System
Pharmaceutical companies should plan and execute a system for the monitoring of process
performance and product quality to ensure a state of control is maintained. An effective monitoring
system provides assurance of the continued capability of processes and controls to produce a
product of desired quality and to identify areas for continual improvement. The process performance
and product quality monitoring system should:
(a) Use quality risk management to establish the control strategy. This can include parameters and
attributes related to drug substance and drug product materials and components, facility and
equipment operating conditions, in-process controls, finished product specifications, and the
associated methods and frequency of monitoring and control. The control strategy should
facilitate timely feedback / feedforward and appropriate corrective action and preventive action;
(b) Provide the tools for measurement and analysis of parameters and attributes identified in the
control strategy (e.g., data management and statistical tools);
(c) Analyse parameters and attributes identified in the control strategy to verify continued operation
within a state of control;
(d) Identify sources of variation affecting process performance and product quality for potential
continual improvement activities to reduce or control variation;
(e) Include feedback on product quality from both internal and external sources, e.g., complaints,
product rejections, non-conformances, recalls, deviations, audits and regulatory inspections and
findings;
(f) Provide knowledge to enhance process understanding, enrich the design space (where
established), and enable innovative approaches to process validation.
ICH Q10, November 2010

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Pharmaceutical Quality System (Q10)

Quality Risk Management

Knowledge Management

ICH Q10, November 2010

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The Product Lifecycle

Process PV
Commercial Manufacturing
Design (PPQ)

Change
Post periodic
introduced/
Level of QC Lab Testing 

review
Could vary signal
CAPA
based on PAT
approach Implemented

Variability
Estimate Monitoring
Established

Control Strategy is  dynamic over the lifecycle QC Testing

Time/Process Knowledge

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Implementation of a PPPQMS

ISPE PQLI Part 4 - PP & PQMS GPG

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Implementation of a PPPQMS
• Calculation of baseline performance to provide SPC
limits and process capability measurements
• Determination of tracking, trigger and action boundaries
• Establishment of rules for monitoring and trending
• Define out of trend (OOT) limits and establishment of a
process for managing OOT results
• Formalize process & communication re OOT
investigations and CAPA
• Process for updating baseline calculations based on
amount of data generated, process change
implementation, etc.

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PPPQMS Planning
Establish a CQA monitoring plan
• Select attributes and parameters
• Data trending tool/s
• Capability analysis
• Set Control & Action Limits
• Data evaluation
• OOCL/OOT processes
• Impact to Product Release
• Review & Reporting
• Knowledge Management

How will you manage this

activity within your current PQS
ISPE Discussion Paper CPV, 2015.

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Statistical Assumptions
Significant
event? Loss on Drying - T rend Plo t
0 .38

Upper 3-sigm a li m i t
0 .36
Upper specificati on
.
l im i t = 08
0 .34
i s not shown.

0 .32
Start-up Significant effect
effect 0 .30
(what changed?)
LOD

0 .28 m ean

0 .26

0 .24

0 .22

0 .20
1 13 25 37 49 61 73 85 97 109 121
7 19 31 43 55 67 79 91 103 115 127

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A Real Process
Limits will change
• Biopharm processes do not always
behave independently or randomly
• How do we respond to this?
• Do we change limits every time? Process
Raw
Material
Adjustment Change
Consider Process
Established Different
• Capability Machine

• Magnitude of excursion
• Historical behavior
• Process and measurement
knowledge
Short term
All limits are not created
the same!! Long term

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Statistical Signals
Statistical packages
• Will process data
• Will apply rules
• When is red
actually RED Red = non-
normal data
(not random)

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Trigger Signals
Amend and Approve CQA Monitoring Plan
1. Assess criticality of quality attribute (QA) 
2. Assess each Unit Operation & parameter impact to the QAs
3. Assess Material Variability impact to the QA
4. Assess process operations variability impact on the QAs

Collect additional 
data or consider need 
Sufficient data collected to  No
for control strategy 
demonstrate control and capability?. and/or process 
Yes modification.

Move to Routine Monitoring Program

Trigger Signal

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Corrective Action
• Procedure for determining significance of shift
• Root cause investigation
• Grounds for changing action/alert limits?
• Heightened monitoring?
• Reportable event?
• Change Management process
• Feed-back process/knowledge capture

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Other statistical distributions

Discrete

Continuous

It is possible to “transform” distributions

using approximations or assumptions…

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Statistics or SPC?
• Pure statistics is about modelling known
distributions to data collected from samples
• SPC is about managing/controlling a process
based on its inherent variability
Neither is significant to a patient if the process
capable of meeting specifications
Use pragmatism: always consider:
• Tolerance intervals
• Clinical relevance
• Uncertainty

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CQA Monitoring Plan

BPOG Paper, 2014, Based

on A-Mab Case Study

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Change Control

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Stewardship
• Product responsibility
• Product or process based
• Training needs?
• Knowledge owner
• Reporting role (supports
Management Review)
• Continual Improvement
prioritization
• Transfer planning

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SUMMARY
• PPPQMS underpins the Pharmaceutical Quality System
• The PPPQMS manages the transfer of knowledge and
systems for lifecycle PV activities
• Product performance and quality
monitoring should use scientific
and risk based tools together with
product and process knowledge.
• PPPQMS must consider systems
for CAPA and Change Management
and their interface with the PQS
• Product stewardship is required to
support PPPQMS

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