The Harmonized PAT Solution: Application of Risk-Based Tools & PAT Strategies in Pharmaceutical Product Manufacture Jeffrey A. Priem Cubist Pharmaceuticals
Presentation Objectives Provide Overview of FDA s PAT Initiative Provide Overview of Risk Management & Risk Assessment Tools Provide PAT Strategy for Pharma Industry Present Case Example on PAT Strategy Take Home Message PAT = Understanding + Risk Mitigation Page 2
PAT Elements Understanding Principles & Tools PAT Tools Multivariate Data Acquisition & Analysis tools Analyzers Control Systems Risk-Based Approach Integrated Systems Approach Real Time Release PAT A Framework for Innovative Pharmaceutical Development, Manufacturing, & Quality Assurance, Sept 2004 Page 3
PAT Challenges Technology Regulatory Driver Product Pipelines Automation Product Characterization Understanding, Variation, Specificity, Robustness, Technology, & Regulatory Uncertainty Page 4
Risk, Risk Assessments & Risk Management Page 5
Risk Assessment: Applications Risk Assessment Project Type Regulatory Proactive Situation Due Diligence GCP & GMP Assessment New Product (Beginning of Lifecycle) Risk Assessment Application Reactive Situation Crisis Management Regulatory Issues Complaints & Adverse Events Consent Decree & Warning Letter Product (Patient Focus) Drug Development Drug Development Remediation Re-Engineering (Middle of Development Lifecycle) Mature Risk Mitigation Financial Merger & Acquisition Feasibility Crisis Management Page 6
Quality System Applications & Risk Assessments Drug Development Change Control Acceptance Testing Product Traceability CAPA Purchasing Controls Production & Controls Root Cause Analysis Validation Complaints Environmental Control Design Page 7
text Risk Analysis Approaches Risk Matrixes Probability vs. Severity = High, Medium, or Low Risk Definition & Categorization Level I = Level II = Level III = Pre-Defined Question & Decision Tree If then, else Yes Occurrence Medium Risk Low Risk Do Control Measure(s) exist for the identified hazard? Yes No Does this step eliminate or reduce the likely occurrence of a hazard to an acceptable level? No Could the identified hazard(s) occur in excess of acceptable level(s) or could it increase to an unacceptable level(s)? Yes Will a subsequent step eliminate the identified hazard(s) or reduce its likely occurrence to an acceptable level? High Risk Severity Is control at this step necessary for Intended Use (SQUIPP)? Yes No Not A CCP Yes Modify Step, or Product No Critical Control Point Page 8
Risk Assessment Tools FMEA - Failure Modes Effects Analysis FMECA - Failure Modes Effects & Criticality Analysis FTA - Fault Tree Analysis HACCP - Hazard Analysis Critical Control Points And Combination Methods Tools & Approaches Page 9
Combination Methods Overview Key Questions to Ask & Understand What is the Risk Focus? What are the Risk Requirements? What are the Risk Metrics to be quantified & Measured? What is the Outcome of the Exposure? As well as What is it you need? How do you plan to do it? What is the ultimate outcome? What are the challenges? Balance RA Tools vs. RA Approaches Format Content Context Intent Implementation Integration Effectiveness Page 10
Risk Management: Applications Risk Assessment Categories (Project Type) Regulatory Proactive Situation Due Diligence GMP Assessment New Product (Beginning of Lifecycle) Risk Assessment Application Reactive Situation Crisis Management Regulatory Issues Consent Decree Warning Letter FDA-483 Product Product Development Design Control (Beginning of Lifecycle) Re-Engineering (Middle of Development Lifecycle) Design Control (Middle of Design Lifecycle or After Design) Mature Risk Mitigation Financial M&A Feasibility Crisis Management Page 11
Risk Management Concept ICH Q9: Quality Risk Management Risk Assessment Risk Analysis Risk Evaluation Risk Control ISO 14971 Risk Management Monitoring & Performance Measurement Risk Management Planning Page 12
The Harmonized PAT Solution Page 13
The Simplified Model Requirements Performance Regulators Organization Customer Metrics Measurement Monitoring Requirements DRIVE Performance Page 14
Understanding Concept: Variation People Materials Methods Input Output Environment Equipment Measurement Page 15
Harmonized PAT PAT Elements Risk Management PAT Tools Provide Risk Multivariate Data Based Decision Acquisition & Analysis es Tools Provide Modern Rationale on Analyzers / process where to apply analytical chemistry Technology tools Provide & Endpoint Framework to monitoring & control facilitate tools Understanding & Continuous Decision Making Improvement & KM Provide Understanding Framework to Risk-Based Approach execute Riskbased strategies Integrated Systems Approach Real Time Release PAT Strategy Understanding Analysis Identify critical attributes Identify automation attributes Identify monitoring & control elements Obtain Knowledge of product & process specifications & requirements Provide understanding of QS interfaces Analyze risk at product, process, & quality systems perspective Define Mitigation Strategy Optimization Implement test strategies Optimize Implement Optimization points Apply Technology Page 16
PAT Application Example Technology Transfer & Validation Page 17
Understanding Identify product requirements Define how they were derived Quantify robustness & adequacy Correlate Attributes to Interfaces System Component Specification Identification Map Flow Diagram Harmonized PAT Solution Activity Key Elements Identify Each Step Identify Elements for Variation: Equipment, Measurement, Personnel, Methods, Materials, Environment, Controls & Monitoring Flow Identify Step Outcome Map Key Inputs: Data / Information and Procedures / guidance Map Outputs & Deliverables Identify Quality System Interfaces, Performance Measures, & Milestones Page 18
Understanding Identification Deliverable Matrix of those Elements of Variation Page 19
& Filename: KM Doc Development PFD rdr0.vsd Workflow Key Inputs Data / Information Procedures / Guidance Services Provided / CS Group Established Documents / CS Group Index of Documents needed to support services Rationale to Drive Consensus Template Document Technical Content Documents (References) CS Group Input / Feedback on Technical Content Preliminary Draft Document Technical Content Documents (References) KMI Document / Tracking # Draft Document Technical Content Documents Approved Document KMI Document Management & Change Control Procedure Product and Planning Document Development Document Review Review & Approval Deployment PAREXEL / KMI Policies: Change Control Posting / Handling of knowledge asset Continuous Improvement KMI Document Review & Revision Plan Flow Diagram "Knowledge Document" Development & Responsibilities Determine Documents to be developed Determine Priority Determine Schedule / Milestones Determine Resource Obtain Responsible CS Group Approval Obtain KMI Exec Management Approval Key Outputs (Outputs from Step) CS Group Specific Service & Documents Matrix MD CA SC QS VC IT CS Group Approval Services Documents Resources Exec Mgmt Approval Resources Timelines Deliverables Quality System Interfaces or Performance Measures QS Interfaces: Personnel: KMI Executive Management CS Group Directors KMI Strategic Plan Resource Utilization / Planning Critical Success Factors: Understanding of concept & context of project by Exec Mgmt & CS Group Directors Obtain Buy-in from Exec Mgmt Obtain Buy-in from CS Group Directors Obtain Template QS Interfaces: Format Personnel: CS Group SME's KM for Templates & Technical Content Determine searches Technical Content BO - Administration for KMI Documents for Document - Reference Resources CS Group Consensus on Performance Measures: Solicit feedback Deliverable Conformance to approved scheduled Conformance to template standard Preliminary Draft & Develop Draft Critical Success Factors: Document Document Templates established to focus on Technical Content Issues Author Time to develop document Staying on track with development (Focused) Perform Internal Quality System Interfaces: CS Group Review CS Group "QA" Review & SMEs of Document BO - Administration (Document Review Edit's & Management Log-in) Perform "QA" Map Red-lines KM - Facilitate process review & technical content review Performance Measures: Conformance to approved scheduled Conformance to template standard Revise Conformance to Technical Content Draft reference materials & interpretation Document Forward document to KM Critical Success Factors: Reviewer time commitment Document Staying on track with schedule Log Document & Tracking & Log Accessibility of SME's in event tech Establish Tracking Entry content is not available / accessible Forward document to KMI Cross functional Review Board Perform review CS Grp Dir & KM KMI Exec Mgmt, CS Grp Dir & KM CS Grp Dir CS Grp Dir & SME's CS Grp Dir, Author, & SME's KM KM KMI Rev Tm KM Edits Required? Yes KM No Yes Transition for Implementation: Change Control Internal Training Deployment on Knowledgebase CS Grp Dir & Author Consider Comments CS Grp Dir Incorporate & Author recommended No changes No Provide rationale why changes not made Yes KMI (?) Document Approved? Review & Revisions KM Review Comments Justification / Rationale Approved Document Document Deliverable Training Materials Knowledgebase Access Quality System Interfaces: KMI Review Team - Cross-Functional Management Review Team (Principal / Senior Consultant) to review, provide feedback & approval KM - Facilitate process CS Group Author & Mgmt - process feedback Performance Measures: Conformance to approved scheduled Conformance to Technical Content reference materials & interpretation Critical Success Factors: Reviewer time commitment Accessibility of Reviewers Staying on track with schedule Accessibility of SME's in event tech content is not available / accessible Focused Reviewers Reviews (Mitigating the propensity to word smith & redesign document) Quality System Interfaces: BO - Administration (Document Management) EO - Internal Training - Website Quality System Interfaces: BO - Administration (Document Change Control) CS Group's - Review & Revision KM - Facilitate Performance Measures & CSF's: To be determined Outcomes Obtain consensus on services that each CS Group provides, documents needed to support services, and resources required to support the development of those documents Obtain Approval to proceed for: Personnel Commitments Timelines Deliverables Deliverables format Established Draft document which satisfies CS Group Service needs Document developed conforms to select industry standards & KMI has established position on how KMI conforms to such requirements Obtain CS Group Consensus on approach and deliverable Capture draft document (something is better than nothing) Obtain collective KMI Technical Review on document & components presented (Consensus & Agreement) Approved, controlled, deployed & trained document Implement KMI Document Review & Revision es to KMI Knowledge Documents 2002 KMI, a division of PAREXEL International, LLC KMI, a division of PAREXEL International LLC, (KMI) considers this document to be confidential & for the sole use of KMI. All rights reserved. No part of this document may be reproduced or transmitted in any form, by any means (electronic, photocopying, recording, or otherwise) with written permission of KMI Specifications Procedures Materials Equipment / Systems Environment Measurement Personnel Map Workflow Flow diagram of processes & activities Outcome Per each level Key Inputs Date & Information into the Procedures & Guidance that Drive Key Outputs Deliverables Result for Activities Result from Quality System Interfaces Quality Program Linkage Points Performance Measurement Metrics to measure performance Page 20
Analysis Define Product Risks Identify Risks Identify Quality System Risk Areas Correlate Risks to Mitigation Strategies Page 21
Analysis Risk Assessment Fault Tree Analysis Tree Example Failure of Sterility Fermentation Sampling QC Test Equip 1149 Failure QC Test Eq 1149 out of Calibration Page 22
Analysis HACCP Deliverables Hazard Identification Hazard Analysis Critical Control Points HACCP Plan Level of Detail & Effort Time Focus is on those Critical Elements of the! Page 23
Analysis Quality System Risk Quantification PDA Scale Boston Low: December, 0 to 3.92004 Medium: 4.0 to 7.9 High: 8.0 to 10 Page 24
Optimization Define Analysis Areas Implement Corrective Action Plan Execute Optimization Strategies Implement Technology & Solutions Page 25
Deviation Management MFG Flow Diagram & Map Deviation Management No Forward approved change to implementation team leader Create a Change Implementation Plan If appropriate, establish a method for determining the effectiveness of the change Is the Change Implementation Plan approved? Yes Proceed with plan and provide progress updates according to schedule Prepare for senior management periodic summary reports. Complete Change Implementation Plan Submit documentation of completed implementation to Change Control Manager Has implementation been completed? Yes Is change effectiveness monitoring required? Yes Collect & evaluate effectiveness data Was change effective? Yes Submit CRF to CCM for MCF closure Close MCF MFG End No No No Change Control Out of Specifications Cross-Functional Implications Out of Specifications Systems-Based Model & Top-Down Approach Integrated Quality Systems Pre-Planned Linkages for Risk Management & Performance Measurement MFG Change Control Page 26
Implementation Measure Control & Monitor Analyze Review Refine Revise Again Requirements DRIVE Performance Page 27
Risk Management Define Scope Approach Interfaces Outcome Page 28
Risk Management & Drug Development Lifecycle Product Lifecycle: Discovery Development Manufacturing Distribution Basic Research Pre-Clinical Clinical I II III III B IV Product Launch Production Marketing and Sales Bottoms-Up Approach Risk Management & Drug Development Page 29
Risk Management & Drug Development Lifecycle Product Lifecycle: Discovery Development Manufacturing Distribution Basic Research Pre-Clinical Clinical I II III III B IV Product Launch Production Marketing and Sales Top Down Approach Risk Management & Product Lifecycle Page 30
Risk Management System Inputs Observation Records & Preliminary Investigation Formal Investigation & Action Identification Action Implementation Action Database & Follow-up Protocol Failure: Validation, Stability, Action Implementation OOS Results Deviations From Procedure Clinical Study Failures Complaints Adverse Events Audit Observations Deviation Mgmt / NCMR Data observed of Exception Preliminary evaluation & Investigation CAPA Adverse Trends in data Data exceptions Preliminary evaluation & Investigation Level II / III Action analysis team review for level III & optional Level II Review Formal Investigation, action identification & authorization for Level II/III Results Regulatory Review for Level III & Optional Level II Review Level I Level II/III Level II Action implementation Planning Protocol Creation & Implementation Level II/III Action Database Audits Effectiveness Assessment Follow-up Product Design Level I N... Page 31 Reference: "Risk Management Basics", DeSain, Vercimak, Sutton
Risk Management System Inputs Observation Records & Preliminary Investigation Formal Investigation & Action Identification Action Implementation Action Database & Follow-up Protocol Failure: Validation, Stability, Action Implementation OOS Results Deviations From Procedure Clinical Study Failures Complaints Adverse Events Audit Observations Deviation Mgmt / NCMR Data observed of Exception Preliminary evaluation & Investigation CAPA Adverse Trends in data Data exceptions Preliminary evaluation & Investigation Level II / III Action analysis team review for level III & optional Level II Review Formal Investigation, action identification & authorization for Level II/III Results Regulatory Review for Level III & Optional Level II Review Level I Level II/III Level II Action implementation Planning Protocol Creation & Implementation Level II/III Action Database Audits Effectiveness Assessment Follow-up Product Design Level I N... Page 32 Reference: "Risk Management Basics", DeSain, Vercimak, Sutton
Outcomes Page 33
PAT Application Project Outcomes Improved Product Quality Optimization of es & Interfaces Reduction in Production Cycle Time Variation Mitigation Epiphany: The Ah Ha! Factor Cost Savings & Optimized Resources Technology Personnel ROI Defendable Compliance vs. Minimal Compliance Page 34
The Harmonized PAT Solution: Application of Risk-Based Tools & PAT Strategies in Pharmaceutical Product Manufacture By: Jeff Priem Tel: 781.860.8661 Email: jeffrey.priem@cubist.com