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ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
Quality Risk Management Drives QbD and Process Improvements
-A New Facility Case Study
Timothy P. Howard, PE, CPIPVice President
Commissioning Agents, Inc.
Topics1. Introduction to Quality Risk Management
Program
2. Risk Management Report (RMR): Content & Logic
3. Quality Risk Management (QRM) Program Structurea) Process Level – Unit Operationsb) Systems Level – Automation & Utilitiesc) Product Quality Level – QC Assays
Topics (cont.)
4. QRM and Quality System Integrationa) Linkages Between Quality by Design, Quality Risk
Management, & Quality Systemsb) Benefits
5. QRM: Process Knowledge Driver
6. ICH Q8, Q9, and Q10 Perspective
7. Summary – Lessons Learned / Take-Awaya) Success Factorsb) Rules of the Gamec) Lessons Learned
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
1 – Introduction to Site Quality Risk Management
FocusPhase 1 – Process Risk Assessments• Unit Operation … End-to-End … Warehouse through Distribution Center• Process versus Equipment
EquipmentBasis: User Requirement Specifications (URS)Evaluation: Presumes URS Adequately Addresses Product Quality Hazards
ProcessBasis: Safety, Quality, Identity, Purity, and PotencyEvaluation: Direct Assessment of Controls and Detection Mechanisms’ Capability to Prevent / Mitigate Hazards
Phase 2 – Systems and Quality Control Assay Risk Assessments• Automation Systems• Utilities• QC Assays
1 – Introduction to SiteQuality Risk Management
Outcome35 Risk Management Reports (RMRs)• 12 Unit Operations• 3 Automation Systems• 5 Utility Systems• 15 Quality Control Assays
Risk Management Report (RMR) Main Content• Foundation
• Process / System / Assay Description• Subject Matter Expert Participant List• Hazards Assessed
• Risk Assessment Findings (FMEA)*• Unacceptable Risk List & Remediation Plans• Risk Control Strategy (Acceptable Risks)• Characterization & Cycle‐Development Studies
* - Failure Mode and Effects Analysis
Fill-Finish Support Systems
Fill-Finish Process
Unit Operation RMRs
AutomationRMRsUtility RMRs Quality Control
Assay RMRs
Risk ManagementReport (RMR)
Foundation
Unacceptable Risk List & Remediation Plans
Risk Control Strategy
Risk Assessment
Characterization & Cycle-Development
Studies
2 – Risk Management Report (RMR) Content & Logic
RiskAssessment
Sub-Process Steps• Hazards• Risk Pathways
• Severity Score• Design Controls• “Soft” Controls (SOPs)• Occurrence Score• Detection Mechanisms• Detection Score• Risk Priority Number
Risk Control Strategy• Process Variables to Monitor• SOPs and Training• Equipment Set-Up• Batch Records• Preventative and Predictive
Maintenance• Calibration Activities• Critical Parts Management• Enterprise Systems – Recipe
Controls• Critical Aspects of Equipment
RPN*<192?
Remediation Plans
Risk Management Report (RMR)
YES
NO
Characterization andCycle-Development Studies
UnacceptableRisk
AcceptableRisk
Undetermined
* - Risk Priority Number
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
3 –QRM* Program Structure: Process Level
* - Quality Risk Management
Warehouse
Distribution Center
Empty Vial Automated Inspection
Bulk Thaw/Freeze
Buffer Preparation//Formulation
Component Preparation: Stopper Processing,Autoclave, & Parts Washing
Filling: Vial Washing, Depyrogenation, Fill, & Capping
Lyophilization
Liquid Product Automated Inspection
Lyophilized Product Automated Inspection
Packaging
HFF Unit Operations
Tank Management
1
2
3
4
5
6
7
8
9
10
11
12
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
HFF Quality Risk Management
3 – QRM* Program Structure: Support Systems Level
HFF Quality Risk Management
Compressed Air & Process Air
Nitrogen
Reverse Osmosis & Water-for-Injection
Clean Steam
HVAC
HFF Utility Systems1
2
3
4
5
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Management Execution System (MES)
Information Management System (IMS)
Process Control System (PRC) &Environmental Management System (EMS)
HFF Automation Systems1
2
3
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
Risk Assessment Risk Control Strategy Risk ManagementReport
* - Quality Risk Management
3 – QRM* Program Structure: Product Quality Level
* - Quality Risk Management
UV-Vis Spectrophotometry
Particulates
Bioburden
Limulus Amebocyte Lysate ( LAL)
pH
Color, Appearance, & Clarity (CAC)
Clarity, Opalescence, & Coloration (COC)
Osmolality
Karl Fisher Titration
HFF QC Assays
Size Exclusion Chromatography (SEC)
1
2
3
4
5
6
7
8
9
10
11
12
Total Organic Carbon (TOC)
Volume-in-Container
Polysorbate
13
14 Conductivity
15 Sterility
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
Measurement System Analysis
Risk Control Strategy
Risk ManagementReport
Risk Assessment
HFF Quality Risk Management
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
* - Quality Risk Management
4 – Linkages: QRM* & Quality System Integration
Process Characterization & Cycle-Development Studies
Prove Process DesignMeets Product Requirements
Quality Control Assay Measurement System Analyses
Prove Assay Designis Reliable
Quality Control AssayRisk Management
Reports
Profile Assay Risks & Identify Controls /
Detection Mechanisms
PRO
CES
SK
NO
WLE
DG
ER
ISK
KN
OW
LED
GE
&C
ON
TRO
L / D
ETEC
TIO
NPR
OD
UC
T Q
UA
LITY
MA
NA
GEM
ENT
Unit OperationRisk Management
Reports
Profile Process Risks & Identify Controls /
Detection MechanismsCritical Utilities
Risk Management Reports
Profile Utilities’Risks & Identify
Controls / Detection Mechanisms
Automation SystemRisk Management
Reports
Profile Automation Risks & Identify
Controls / Detection Mechanisms
FEED / SUPPORT UNIT OPERATION RISK CONTROL STRATEGIES
VALIDATIONCHANGE CONTROL
DISCREPANCY MANAGEMENT
QUALITY SYSTEMSTECHNOLOGY
TRANSFER
QUALITY RISK MANAGEMENT
QUALITYby
DESIGN
CAPA
4 – Benefits: QRM & Quality System Integration
RMRs enable …Technology Transfer• Compliance with Corporate Quality Standard• Manage 12+ Product Transfers, 30+ Configurations• Standardized Approach
• RMR is the “guidebook” to evaluate Product Quality Hazards per Unit Operation
• Risk Assessment and Risk Control Strategy identify Controls and Detection Mechanisms per UnitOperation per Product
• Knowledge Management• Risk Assessment sessions and Risk Control
Strategy development:• “Level Set” process facts• Permit evaluation of Controls and Detection
Mechanisms’ capability
Risk Control Strategy• Process Variables to Monitor• SOPs and Training• Equipment Set-Up• Batch Records• Preventative and Predictive
Maintenance• Calibration Activities• Critical Parts Management• Enterprise Systems – Recipe
Controls• Critical Aspects of Equipment
4 – Benefits: QRM & Quality System Integration
RMRs enable …Discrepancy Management
•Compliance with Corporate Quality Standard•Standardized Approach
• RMR is the “guidebook” for consistent and rapid “event” evaluation and disposition
• Evaluation focus: “event” impact on Controls and Detection Mechanisms
•Risk Management Effectiveness Monitoring• “Event” evaluation in combination with RMR:
• Determines the reliability/capability of the Controls and Detection Mechanisms
• Identifies Risk Control Strategy strengths and weaknesses
Risk Control Strategy• Process Variables to Monitor• SOPs and Training• Equipment Set-Up• Batch Records• Preventative and Predictive
Maintenance• Calibration Activities• Critical Parts Management• Enterprise Systems – Recipe
Controls• Critical Aspects of Equipment
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
4 – Benefits: QRM & Quality System Integration
RMRs enable …Change Control
•Compliance with Corporate Quality Standard•Standardized Approach
• RMR is the “guidebook” for consistent and rapid evaluation of change and its impact to Product Quality
• Evaluation focus: change impact on Controls and Detection Mechanisms
•Knowledge Management• Change Control in combination with RMR:
• “Highlights” control/detection mechanism interdependence
•Minimizes potential for change to de-stabilize unchanged controls/detection mechanisms
Risk Control Strategy• Process Variables to Monitor• SOPs and Training• Equipment Set-Up• Batch Records• Preventative and Predictive
Maintenance• Calibration Activities• Critical Parts Management• Enterprise Systems – Recipe
Controls• Critical Aspects of Equipment
4 – Benefits: QRM & Quality System Integration
RMRs enable …
Re-Validation and Periodic Review•Compliance with several Corporate Quality Standards
•Knowledge Management
• RCS “Critical Aspects of Equipment” section lists controls/detection mechanisms that require validation
• In combination with Predicate Rule, Discrepancy Management, and Change Control, the RMR contributes to determining Re-Validation frequency
Two Dimensional Risk Prioritization
AcceptableRisk Level
UnacceptableRisk Level
New /Developing
Mature /Developed
Risk Priority Number
TechnologyExperience
Risk #1Risk #4
Risk #3Risk #6Risk #7Risk #10
Risk #2Risk #9
Risk #5Risk #8
Priority Work:• Design of Experiments• Process Engineering /
Characterization Studies
5 – QRM Process Knowledge Driver
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
5 – QRM Process Knowledge DriverRisk Control Strategy – Equipment Set-Up
Goal• Improve process performance by defining the optimum
mechanical equipment set up through hands-on experimentation
Scope• Each critical equipment sub-component highlighted by the
Risk Control Strategy for each unit operationExperiment Design and Execution• Collect input from SME’s and vendors to identify:
• Key mechanical parameters • Product quality criteria
• Hands-On experimentation determined preliminary mechanical parameter operating ranges
• Experiments (DoEs) designed and executed to study parameter interactions and their product quality impact
• DoE results identify key mechanical parameters and define Equipment Set-Up operating windows
Example – Packaging5 – QRM Process Knowledge Driver
Equipment Set-Up Design ofExperiments
AcceptableRisk Level
UnacceptableRisk Level
New /Developing
Mature /Developed
Risk Priority Number
TechnologyExperience
Engineering / Process Characterization Studies
Labeling - Starwheel• Vial Damage
Cartoning – Pick Arm• Vial Damage
Cartoning – Place Arm• Vial “Seating”• Transit Damage
Labeling – Temp./RH• Misbranding (adhesive)
Cartoning – Weight Check• Misbranding (count)
Case Packing – Weight Check• Misbranding (count)
5 – QRM Process Knowledge DriverMechanical DoE – Labeling – Star
WheelHazard: Vial DamageDoE Execution
• Pre-inspected, unlabeled vials• Star Wheel Parameters
• Torque and Phase• Line speed• Trunnion Roller and Star Wheel Gap
• Parameter variation• Sufficiently induced significant vial
jamming rate increase• Defined limits of viable physical
operating range DoE Findings
• No reportable critical or non-critical vial defects were observed within the evaluated operating range
• Defined acceptable Star Wheel Parameter operating ranges
• Established Standard Operating Procedures
10-1
2.0
1.5
1.0
0.5
0.0
10-1
10-1
2.0
1.5
1.0
0.5
0.0
10-1
Star Wheel Phase
Mea
n
Star Wheel Torque
Line Speed Trunnion Siko Setting
Main Effects Plot for Star Wheel Parameters for Eject OverloadData Means
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
5 – QRM Process Knowledge Driver
Hazard: Vial Damage
DoE Execution• Pre‐inspected, unlabeled vials
• Pick Arm Parameters varied within the equipment capability•Horizontal Distance, X•Depth/Reach Distance, Y•Height, Z•Rotation, Rz
DoE Findings• No reportable critical or non‐criticalvial defects were observed.
• Cosmetic defect frequency did not vary significantly within the operating space
• Defined acceptable Pick Arm operating ranges
• Established Standard Operating Procedures
0
1
01
0
2
-1-1
0
1
Non Reportable Defects
Rz Position (deg)
X Position (mm)
Surface Plot of Total Non Reportable Defects vs Pick X Pos (mm) and Rz Pos (deg)
Mechanical DoE – Cartoning – Pick Arm
5 – QRM Process Knowledge DriverMechanical DoE – Cartoning – Placement Arm
Hazard: Vial Damage / Cap RemovalDoE Execution
• Pre-inspected, unlabeled vials
• Placement Arm Parameters• Horizontal Distance Parallel to Conveyor, X• Horizontal Distance Perpendicular to Conveyor,
Y• Vertical Distance above Conveyor/Carton, Z• Rotation Relative to Conveyor/Carton, Rz
DoE Findings• X position is a Main Effect• Vial Seating = ƒ (X position)• X is a Packaging Risk Control Strategy“Process Variable to Monitor”
10-1
1.2
0.9
0.6
0.3
0.010-1
10-1
1.2
0.9
0.6
0.3
0.010-1
X Position (mm)
Mea
n
Y Position (mm)
Z Position (mm) Rz Position (deg)
Main Effects Plot for Place Parameters for Number of Incorrectly Seated VialsData Means
HFF Packaging DoE “Corrected” Risk Probability5 – QRM Process Knowledge Driver
Equipment Set-Up Design ofExperiments
AcceptableRisk Level
UnacceptableRisk Level
New /Developing
Mature /Developed
Risk Priority Number
TechnologyExperience
Engineering / Process Characterization Studies
Labeling - Starwheel• Vial Damage
Cartoning – Pick Arm• Vial Damage
Cartoning – Place Arm• Vial “Seating”• Transit Damage
Labeling – Temp./RH• Misbranding (adhesive)
Cartoning – Weight Check• Misbranding (count)
Case Packing – Weight Check• Misbranding (count)
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
6 – ICH Q8, Q9, & Q10 Perspective
QRMApplication(Where?)
QRMDrivers(Why?)
QRMActivities(What?)
QRMObjectives /Outcome(Benefit?)
QRMResourceDeployment(Time Allocation)
• Unit Operations• Utilities• Automation Systems• Quality Control Assays
• Obtain Process Technical Documentation and Current Risk Management Reports
• Build Process Maps; Identify Key Inputs and & Outputs (potential risk controls and detection mechanisms
• Identify Relevant Product Quality Hazards & Failure Modes/Pathways
2009 . . . . . ~ 5%2010 . . . . . ~10%2011 . . . . . ~30%
2009 . . . . . ~95%2010 . . . . . ~85%2011 . . . . . ~15%
2009 . . . . . ~0%2010 . . . . . ~5%2011 . . . . . ~55%
• Convert Process Maps into Risk Assessment Table (RAT)
• Determine Priority Risk Number (SxO) and, if necessary, Risk Priority Number (SxOxD) and Rank Risks
• Create Risk Reduction Plans (Unacceptable Level Risks) and Prepare Risk Acceptance Rationales (“Borderline” Risks”)
• Convert RAT into Risk Control Strategy (Acceptable Level Risks) to Prove Control and Prepare Risk Effectiveness Monitoring
• Obtain Process Design and Capability Consensus (“Single Source of Truth”)
• Identify Risk Controls and Detection Mechanisms
• Unit Operations• Utilities• Automation Systems• Quality Control Assays
• Unit Operations• Utilities• Automation Systems• Quality Control Assays
• Monitor Risk Management Effectiveness• Retrospectively
• DMS• CAPA• Re‐Validation/Periodic Review• Prospectively
• Change Control• Process Variables to Monitor
• Stability (SQC/SPC)• Capability (Cpk)
ICH Q8Process Knowledge
ICH Q9Risk Assessment, Management
(Control Strategy), & Communication
ICH Q10Risk Management
Effectiveness Monitoring
• Achieve Continuous Quality Verification (CQV)
• Realize Cost Reduction• Less Re‐Validation• Avoid Scrap
• Produce Risk Profiles • Unit Operations, Utilities, Automation Systems, QC Assays
• Sub‐Process (risk density)• Hazard Type (hazard density)
• Identify Improvement Opportunities
6 – ICH Q8, Q9, & Q10 PerspectiveStatistical Process Control (SPC)
1.Measures the “X” of Y=ƒX
2.Process Input Monitoring
3.Prospective Analysis
4.Leading Indicator
5.Direct Process Stability (Control) Measurement
6.Measures Process Stability ... Clear View of Process Health
7.Supports Root-Cause Analysis when Product is Out-of-Specification or Product Quality Attributes (SQC) are Out-of-Control
8.Solid Planned, Predictable Performance Assessment … Demonstrates process control and trends/forecasts future … supports “predictive”maintenance
9.Process Monitoring to determine (predict) Product Quality (correlation)
10.Transparent approach to ICH Q10 (Risk Management Effectiveness Monitoring)
7 – Summary / Take-AwaySuccess Factors
Prep Work• Process Area Walk Through
Site Leadership / Business Process Manager
Dedicated Facilitator and Scribe
Core Team
Agreed to Standard Hazards (Traceable to SQIPP)
Increase in Collective Knowledge Level Benefit
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
7 – Summary / Take-AwayRules of the Game
Driver: Product Quality• Patient Safety Requires Additional Expertise
Ignored Upstream or Downstream Unit Ops
Equipment Failures Not Assessed … but Process Hazards were
Corporate Quality Standard Established Scoring System
Challenged Process Knowledge (Critical Process Parameters)
7 – Summary / Take-AwayLessons Learned
Pre-Determine Output Management• Paper vs. Database• RMR Approval: Initial & Updates
• Version Control vs. Real-Time Update
Process Knowledge a must have …• … to complete Risk Control Strategy but …• … incomplete knowledge not an obstacle to conducting
Risk Assessment
• Cross-functional representation a must have
• Pre-determine who “owns” the Risk Control Strategy
Workshop Agenda
• Cause and Effect Diagrams• Boston Matrix• Workshop 1• FEMA/FMECA• Workshop 2
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
Cause and Effect Diagram
• AKA: Fishbone or Ishikawa diagram• Widely used for Root Cause Analysis• Used to examine:
– Man, Method, Machinery, Materials• Effective when output coupled with
another tool
7 June 2010 28
Sample Formulation Process
• Formulation Tank CIP/SIP• Buffer Prepared• Bulk Drug Substance Thawed• Buffer and Formulation Added to
Formulation Vessel• Mixed and Sampled• Transferred to Filling Area
7 June 2010 29
Formulation ProcessWFI / CIP /
SIPWFI / CIP /
SIP
SterilizingFilter
To Intermediate Vessel in Filling Area
FORMULATIONVESSEL
Thawed BulkDrug Substance
Sterile Transfer
VentFilterTransfer
Manual AdditionOf Buffer Kit
Buffer PrepVessel
Pump
7 June 2010 30
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
Hazards to Process
• Wrong Formulation• Protein Degrades or Denatures• Contamination
– Microbial– Cross Product– Endotoxin– Foreign Material / Dirt
Cause and Effect Diagram
7 June 2010 32
Cause and Effect Diagram
7 June 2010 33
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
Cause and Effect Diagram
7 June 2010 34
Cause and Effect Diagram
7 June 2010 35
Cause and Effect Diagram
7 June 2010 36
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
Cause and Effect Diagram
7 June 2010 37
Cause of Cause
Boston Matrix
• 80 / 20 Rule• Drive focus to area of most need• Drive focus to actions with most impact• Drives discussion• Documents decisions
Response to Design Review
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
FAT Planning
Work Shop Assignment Part 1
Use Cause and Effect Diagram (Ishikawa) for Formulation Process
Microbial Contamination, Protein Degrades or Denatures, Cross Product Contamination, Endotoxin Contamination, Foreign Material
Contamination
WFI / CIP / SIP
WFI / CIP / SIP
SterilizingFilter
To Intermediate Vessel in Filling Area
M
FORMULATIONVESSEL
Thawed BulkDrug Substance
Sterile Transfer
VentFilterTransfer
Manual AdditionOf Buffer Kit
Buffer PrepVessel
M
Pump
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
Cause and Effect WorkshopAnalyze one of the previously identified hazards
– Microbial Contamination– Protein Degrades or Denatures– Cross Product Contamination– Wrong Formulation– Endotoxin Contamination– Foreign Material Contamination
• Identify at least three 1st Tier Causes• Identify at least six 2nd Tier Causes
Report Results
FMEA / FMECA
• Typically applied to an equipment or system boundary
• Level of effort may not be justified– Use as deep dive for high risk items
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
Process FMEA Example
List Process Steps
Assess Severity of
Risks to Patient
Assess Probability
of Occurrence
Assess Probability
of Detection
Identify Hazards to
Patient
List the severity of each hazard listed in previous step. The severity rating is independent of design features or detection mechanisms.
With an understanding of the design features and other risk control mechanisms, assess the probability of occurrence
With an understanding of the detection mechanisms and design features, assess the probability of detection
Critical Aspects = Those design features and functions that serve to reduce probability of occurrence or enhance probability of detection
Scoring Options
• Use a 3 to 5 point scale (Quantitative)– 1, 3, 5 1, 5, 10 1, 4, 7 10 1,10, 100
• Qualitative– Low, Med ,High– Negligible, Low, Med, High, Unacceptable
• RPN Limits or Thresholds– Risk is Acceptable or Unacceptable– Grey Zone Suggested
Aseptic Filling Line - Isolator• Isolator Sanitized with VHP• Product Transfer Line cleaned with CIP and sterilized with SIP• Filling Head parts cleaned in Washer and sterilized in Autoclave• Tubing Replaced each lot
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
Process Steps
• Prepare Equipment• Load Vials• Wash Vials• Depyrogenate Vials
• Fill Vials• Weigh Vials• Stopper Vials• Convey Vials
Hazards to Patient
• Wash Vials– Dirty Vials not
adequately Washed resulting in contaminated dose
– Contamination from Water or Air ???
• Depyrogenation– Vials do not reach time
at temperature resulting in endotoxin dose contamination
– Contamination from Air???
Example Output
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
Example Output (Quantitative)
Critical Aspects
• Belt Speed Control, Indication, Alarm• Tunnel Temperature Control, Indication,
Alarm• Airflow Velocity, Loss of Airflow Alarm• Acceptance Criteria driven by process
requirements
Example Delta Output
ISPE Washington Conference 7-10 June 2010
Washington D.C. USA
Process FEMA Workshop• Using the filling line example• Score using a quantitative scale
– Identify Two or more hazards• Score Severity
– Identify Quality system controls• SOPs, Training Points of Emphasis, Equipment set up, Maintenance and
Calibration Items, Batch Record Controls, others.• Score Probability of Occurrence
– Identify Detection Mechanisms• Alarms, “In Process” Checks, End of Lot QC, others.• Score Probability of Detection
Questions or Comments
Timothy P. Howard, CPIP, PE
Vice President
Commissioning Agents, Inc.