interphex 2011 howard qrm and qbd€¦ · •risk assessment findings (fmea)* • unacceptable risk...

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


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


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












HFF Quality Risk Management

3 – QRM* Program Structure: Support Systems Level


Compressed Air & Process Air

Nitrogen

Reverse Osmosis & Water-for-Injection

Clean Steam

HVAC

HFF Utility Systems1

2

3

4

5






Management Execution System (MES)

Information Management System (IMS)

Process Control System (PRC) &Environmental Management System (EMS)

HFF Automation Systems1

2

3





3 – QRM* Program Structure: Product Quality Level


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 ManagementReport

Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment




Risk Assessment



Washington D.C. USA


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





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





Washington D.C. USA


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





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


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



New /Developing

Mature /Developed



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


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



New /Developing

Mature /Developed



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)


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



• 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


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


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


Washington D.C. USA

Hazards to Process

• Wrong Formulation• Protein Degrades or Denatures• Contamination

– Microbial– Cross Product– Endotoxin– Foreign Material / Dirt


7 June 2010 32


7 June 2010 33


Washington D.C. USA


7 June 2010 34


7 June 2010 35


7 June 2010 36


Washington D.C. USA


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


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


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


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


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


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


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.