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Product Monitoring & Post-Approval
Lifecycle Management of Biotech
Products
Ron Taticek, Ph.D
Sr. Director, Product Quality Management
Pharma Technical Quality BiologicsGenentech, South San Francisco, CA
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• Background – Need for integrated product quality management
• Process Monitoring and Data Trending – Roche/Genentech Approach
• Post-Approval Lifecycle Management• Commercial Product Quality Steward role – Product quality
oversight by linking system, data, and people
Presentation Outline
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• 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.
• Use quality risk management to establish the control strategy.
• Provide the tools (e.g., data management and statistical tools) for
measurement and analysis of parameters and attributes identified in the control
strategy
• Verify continued operation within a state of control
• Identify sources of variation affecting process performance and product qualityfor potential continual improvement activities.
• Include feedback on product quality from both internal and external sources
Need for Integrated Product Quality
Management
ICH Q10 Pharmaceutical Quality System, Process Performance andProduct Quality Monitoring System 3.2.1:
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Product Quality Management at Roche
& Genentech
• An End to End view of product quality throughout the product
and process lifecycle
• Strong scientific rigor and technical expertise used to evaluateproduct performance and consistency across sites
• A focus on innovation and continual improvement
• Ensures the safety, efficacy and purity of products produced
and supplied to our patients
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Product Quality Management: Fundamental Elements
Slide 5© 2009 Genentech, Inc.
Product Complaints
• Early warning signals of product quality issues in the
field
Product Assessment & Trending
• Proactive assessment of product quality
attributes across the manufacturing process
Product Quality Stewards
• Single point of Contact for Quality to key stakeholders
• Routine health assessment of product to address trends
• Planning provides foresight and proactive approach
QC testing network support
• Harmonized approach to test method execution & support
• Scalability & flexibility to balance test workload across network
Analytical methods management
Scientific rigor engrained in analytical method performance
Product control systems based on science
Seamless product transfers & assessment of consistency
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• Meets regulatory expectations
• Proactively identifies and reduces variations in the test
methods and manufacturing processes
• Provides science and risk - based approach for CAPAactivities
• Ensures product consistency from site to site
• Ensures reliability of product supply and guarantees anefficient Supply Chain
Benefits of Process Monitoring and
Trending
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• Background – Need for integrated product quality management
• Process Monitoring and Data Trending – Roche/GenentechApproach
• Post-Approval Lifecycle Management
• Commercial Product Quality Steward role – Product qualityoversight by linking system, data, and people
Presentation Outline
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Process Monitoring and Data Trending:
Roche/Genentech Approach
• Key elements in the continuous monitoring of commercialproducts
Process and analytical life cycle validation
Align inter-related inputs – process, methods, product quality attributes
Definition of statistical state of control (control charts etc.)
• Examples of Data Trending
Product Data Monitoring
Analytical Method Monitoring
Proper assessment of process capability consistent product quality
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Validation
System
Suitability
Transfer
RoutineTesting
MethodMonitoring
Periodic
Review
• Method development & qualification throughout
clinical stages
• Commercial method validation pre-licensure
• Commercial control system established at firstlaunch
• Analytical method transfer support commercial
production globally
• On-going cross-site method monitoring ensures
state of control throughout method and productlife cycle
Life Cycle Approach to Analytical
Method Management
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Product Quality Data Evaluation
• Dependent on both Analytical and Process Monitoring
• Proper assessment of manufacturing process capabilities relies on
QC method performance assessment
• Product quality assessment, as measured by QC test methods,
relies on assurance that analytical methods are consistent and are
in a state of control
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Fundamental Steps in Monitoring
• Establish statistical monitoring systems: – Appropriate monitoring attributes
– Appropriate statistical method (Control charts, Histogram, Pareto, etc.)
– Analyze data and establish trend/control limits from historical data
– Establish Rules for monitoring and trending – Timely evaluate of the impact of product and process changes
• Establish business process to assess out-of-trend (OOT) resultsand to assure that the process is in a state of statistical control
• Formal investigations and communication to stakeholders
required for OOT and Out-of-specification (OOS) event todetermine root cause (Discrepancy and CAPA)
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• Critical Quality Attributes (CQAs)
• Key QC test methods
• Critical process parameters (CPP)
• Key process performance indicators (KPI)
• Periodic vs. real time monitoring
• Site versus global monitoring
Criteria for Monitoring
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• Moving range chart – used
to track process variation
and detect the presence of
“special causes”.
• The moving range - equal todifference between
successive pairs of numbers
in a data set.
Data Trending: Moving Range Chart
Sample Number
I n d i v i d u a l V a l u e
10997857361493725131
170
160
150
_ X=164.22
UC L=173.00
LCL=155.43
Sample Number
M o v i n g R a n g e
10997857361493725131
20
10
0
__
MR=3.30
UC L=10.79
LCL=0
11
11
1
111
1
111
11
1
1
1
1
I-MR Chart of Drug Substance
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Examples of Process Trend
Chart: Process Data
• Top Histogram: A capable process
(Centered & well- within process
limits)
• Middle histogram: Similar process
(with lower mean) against the same
limits
(Not centered or contained by
limits)
• Bottom histogram: Actual run chart
data for the top process
A set of random product data is
presented against the acceptance
criteria over a period of time:
E l f I t ti P & A l ti l M th d
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• Top: Product vs.
reference material
data trend chart
demonstrating a
robust process
• Bottom: Product vs.
reference material
data trend chart for a
variable process
Example of Integrating Process & Analytical Method
Monitoring
f
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16
• Top graph shows a
capable process
• Lower graph shows a
capable QC method
that supports theproduct specification
A Well behaved
Process & Method
Example of Process vs. Analytical
Method Capability Trend Chart
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QC Method Monitoring Program
• Integral to the analytical method LCM
• Ensures that the method performance across complexmanufacturing network & testing sites is consistent
• Provide analytical trending support to process/product trending
Additionally:
• A key component of the Annual Product Review (APR) –regulatory requirement by Health Canada
• Stability investigation support• Serves as an inspection tool for analytical methods
C t S f M th d M it i
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• Commercial biologics
• All QC testing sites including partners and CMOs
• Incorporates new sites after method transfer
• Currently focus on purity and potency methods• Monitor key quantitative attributes
• Analysis of data from reference material, assay controls, and
product controls
Current Scope of Method Monitoring
Program
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• Based on available historical data
• Use statistical analysis
• Cross site harmonization of data submission format
• Centralized group to perform trending analysis and report results
Monitoring Criteria and Data
Examples of QC Method Monitoring Results
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S y s t e m s
u i t a b i l i t y l i m i t s
M e t h o d M
o n i t o r i n g l i m i t sTop: Reference Material data trend
chart for all valid assays across 6 global
testing sites
Bottom: Site Mean trend chart for the 6sites showing that the method
performance is consistent throughout all
sites
Examples of QC Method Monitoring Results
A MAb product, Ion Exchange Method
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• Concern regarding lack of quantitative system suitability criteria for achromatography method
• Method monitoring provided strong evidence that method performance ina state of control, and sufficiently supporting release specification (≥ 98%)
Data (n>1000) from 4 years and 5 sites
Mean=99.8%
SD=0.05
RSD=0.05
Example: Method Monitoring Supports Inspection
Response
A MAb product: Size Exclusion Method
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• Background – Need for integrated product quality management
• Process Monitoring and Data Trending – Roche/Genentech Approach
• Post-Approval Lifecycle Management
• Commercial Product Quality Steward role – Product qualityoversight by linking system, data, and people
Presentation Outline
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• Process changes to improve yield
• Process changes to improve product quality
• Process monitoring/continual process verification
• Control system
Post-Approval Lifecycle Management
Post-Approval Lifecycle Management: Process
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Changes toCPPs or Process
within
Design Space
Ranges
Changes tonon-CPPs
outside of reported
MARs/ranges or
Changes to
Non-Critical Steps
Changes toCPPs or Process
outside of
Design Space
Ranges
Self Managed Self Managed
Require Prior Approval
Comparability Requirements Assessed via
“Comparability Decision Tree” if appropriate)
Notify Health
Authorities of
Change (by
exception)
Notify Health
Authorities of
Change (by
exception)
Report per
Pre-Negotiated
Agreement
Post Approval Lifecycle Management: Process
Parameters
Post Approval Lifecycle Management: Comparability
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Post-Approval Lifecycle Management: Comparability
Decision TreeNo Pre-Execution Product Comparability Testing
Confirmation at Full Scale (1 lot)
Control System Testing
No or limited KPI Comparability
CaM = Comparability and Monitoring Testinga May include stability testing of 1 or more full scale lots.
n
e
n
i
s
Pre-Execution Product Comparability Testing
Confirmation at Full Scale (1 lot)
Control System + CaM Testing
KPI Comparability
Pre-Execution Product Comparability Testing
Confirmation at Full Scale (≥1 lot)
Control System + More Extensive CaM TestingKPI Comparability
Additional Continuous Process Monitoring
Post Approval Lifecycle Management: Pre
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Requires
FDA Pre-
Approval to
Implement
Comparability Criteria filed in Registration
Dossier for existing multi-product ExpandedChange Protocol (eCP) covering change
Change not covered by either product-specific
CP or existing multi-product eCP
Change covered by product-specific
Comparability Protocol (CP)Potential
for
Reduced
Reporting
Category
Standard
Reporting
Category
File Submission
Per
Pre-Negotiated
Agreement
Post-Approval Lifecycle Management: Pre-
Negotiated Change Management
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Post-Approval Lifecycle Management: Changes to
non-CPPs
Repeat Previous Studies
With Expanded Ranges
and/or Process Change
Acceptable Result: MARs
are extended &
Results are available for
Review at Compliance Audit
Unacceptable Result: Parameter(s)
become CPPs & HA Notified
of change to parameter classification& Design Space
Changes to
non-CPPs outside of reported
MARs/ranges or ProcessChange to Non-Critical Step
Post-Approval Lifecycle Management: Continuous
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Post Approval Lifecycle Management: Continuous
Process Monitoring
Routine Process
Monitoring
Every Run Every Nth
RunComparability
For Fixed Duration and Re-Assess
Control System Assessment
Part of Control System (IP, Lot Release, Stability)
• Done under a validation
protocol
• Pre-defined acceptance
criteria for monitoring
• Frequency and duration
indicated
• Monitoring done using
validated or suitable
assays
Post-Approval Lifecycle Management: Control
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Post Approval Lifecycle Management: Control
System
• Over the product lifecycle, the QA criticality and testing strategy will be re-
evaluated at a regular interval incorporating the following:
– new knowledge about the Quality Attributes gained from additional clinical, non-clinical
and characterization studies
– trending of Quality Attributes from both the process (via IP, lot release, process
monitoring testing) and stability testing
– assay performance
– availability of new assays• Re-evaluation could result in the change of criticality of a QA, the testing strategy
(IP, lot release, stability, monitoring or none) and potentially, the assay used to
monitor the QA
• Any of these changes would be reportable and require prior-approval before
implementation• Evaluation is done in response to out-of- trend results, as a result of the Annual
Product Review (APR) process or every 5 years or as part of a significant process
change
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• Background – Need for integrated product quality management
• Process Monitoring and Data Trending – Roche/Genentech Approach
• Post-Approval Lifecycle Management
• Commercial Product Quality Steward role – Product qualityoversight by linking system, data, and people
Presentation Outline
Commercial Supply Chain Teams:
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External
Quality
Product Quality
Sub-Team
Quality
Steward
Product
Complaints
InvestigationsStability
Lot
Disposition
QC IP/FP
Ad Hoc Quality Sub Team Members
• Change Control
• Methods Mgmt and Technology
• Inspection Mgmt
• Compliance
• External QC
• Validation
PROP
Finance
PTTL DS
Quality
Steward
CMC
RegA
Planning
Launch
STL Dev CMC
STL
PMTL
PTTL DP
PSCT
Commercial Supply Chain Teams:
Product Steward Concept
Role of the Commercial Product
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Role of the Commercial Product
Quality Steward
Product Supply Chain Team
• Acts as the Voice of Quality (QA & QC) and provides Qualityexpertise and leadership on Product Supply Chain Team (PSCT)
•Serves as the communication conduit between PSCT and Qualityfunctional areas/departments
• Develops and manages the implementation of Quality-relatedactivities required to meet the product strategy and priorities
• Ensures Quality requirements are met during PSCT driven
activities and changes
Role of the Commercial Product
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Role of the Commercial Product
Quality Steward
Product Quality Monitoring:
• Monitors and reports on product quality across the End-to-End(E2E) network
• Partners with Quality subject matter experts (SMEs) to resolve
product quality issues to ensure no impact to patient/productsupply
• Conducts an annual Product Quality Risk Assessment; drivesresolution of identified risks
•Generates the monthly Product Quality Report
• Reviewers of Annual Product Review (APR)
Role of the Commercial Product
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Quality Steward
Lifecycle Management• Drive changes to ensure appropriate product quality life cycle
management spanning across the network, contract sites, andpartners
• Own and maintain the Process Specification File: Quality-controlled document that is a summary of current license rangesand commitments
• Accountable to ensure lifecycle commitments are completed
• Knowledge management
• Sharing of best practices
C l i
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• Background – Need for integrated product quality management
• Process Monitoring and Data Trending – Roche/Genentech Approach
• Post-Approval Lifecycle Management
• Commercial Product Quality Steward role – Product qualityoversight by linking system, data, and people
Conclusions
A k l d t
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• Deborah Baly
• Claudia Lin
• Gladys Sanders
• Dieter Schmalzing
Acknowledgements