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Risk Management through Electronic Enforcement FDA Regulatory and Compliance Symposium Managing Risks – From Pipeline to Patient.

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Presentation on theme: "Risk Management through Electronic Enforcement FDA Regulatory and Compliance Symposium Managing Risks – From Pipeline to Patient."— Presentation transcript:

1 Risk Management through Electronic Enforcement FDA Regulatory and Compliance Symposium Managing Risks – From Pipeline to Patient

2 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 2 WHAT WE HAVE: A collection of manufacturing assets, products and technologies, that continue to be insufficient, and are by design, incapable of meeting the new challenges. Weve had a few problems scaling up from the lab Source: Medical Manufacturing, New Technology Imperative, James Bradburn, IBM Life Sciences Life Science Manufacturing Realities?

3 Hazard Risk Potential source of harm Probability of the occurrence of harm and the severity of that harm. Introduction Hazard

4 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 4 HazardPotential source of harm RiskProbability of the occurrence of harm and the severity of that harm Risk AnalysisSystematic use of available information to identify hazards and estimate risk. Risk EvaluationBased on the risk analysis, a judgment of whether a risk is acceptable based on societal values. Risk AssessmentProcess of completing risk analysis and risk evaluation. Risk ControlProcess through which decisions are reached and protective measures are implemented for reducing or maintaining risks within specified levels. Residual RiskRisk remaining after protective measures have been taken. Risk ManagementSystematic application of management policies, procedures, and practices toward analyzing, evaluating, and controlling risk. Definitions

5 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 5 Time to focus on Operational Excellence Basics The cost of nonconformance extends beyond the direct costs of quarantining, recall and rework, and fines to the destruction of brand equity.The cost of nonconformance extends beyond the direct costs of quarantining, recall and rework, and fines to the destruction of brand equity. Compliance strategy needs to be centrally developed and coordinatedit cannot be delegated to individual manufacturing sites.Compliance strategy needs to be centrally developed and coordinatedit cannot be delegated to individual manufacturing sites. The silos of quality and manufacturing must be broken down, and a tighter integration of technology is required to sense, correct, prevent, and report effectively on manufacturing nonconformance events.The silos of quality and manufacturing must be broken down, and a tighter integration of technology is required to sense, correct, prevent, and report effectively on manufacturing nonconformance events. This problem is endemic to the pharma and life science industry. Disconnects exist between different parts of the manufacturing product supply, regulatory, and commercial functions.This problem is endemic to the pharma and life science industry. Disconnects exist between different parts of the manufacturing product supply, regulatory, and commercial functions. This is primarily a business process problem, as process requirements and written procedures are not consistent throughout the organization. But many pharma and life science organizations still have not reengineered their processes and organizational structures, relying on inconsistent and manually enforced compliance processes.This is primarily a business process problem, as process requirements and written procedures are not consistent throughout the organization. But many pharma and life science organizations still have not reengineered their processes and organizational structures, relying on inconsistent and manually enforced compliance processes. Source: AMR Research, Compliance Trouble at Boston Scientific: An Isolated Incident or Part of a Growing Industry Liability?, February 09, 2006; Hussain Mooraj, Colin Masson, Roddy Martin

6 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 6 Multiple Compliance Fronts Management of Regulatory Compliance Management of Regulatory Compliance Sarbanes Oxley Sarbanes Oxley HIPAA 21 CFR Part CFR Part 11 cGMP Chief Compliance Officer Regulatory Affairs CAPA Ex Com QA/QC CIO / IT FDA SEC EPA OIG Source: AMR Research, Compliance Webinar, Roddy Martin, Joseph Vinhais, May 2004

7 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 7 How do you drive Governance and Compliance into Manufacturing? Drive Compliance Time to Market Share Holder Value Who are the stake holders?

8 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 8 Synchronizing change, execution, and enforcement Compliance and process improvement are both based on following documented processes. Three mechanisms need to be coordinated: Execute process Train employees on the process, assess their performance, and, if necessary, take steps to improve their performance and adherence to it by improving training or other actions. Enforce controls Compliance adds a duty to control the process actively, perhaps by technical means, such as workflow. Companies must also audit the results to ensure that the controls work and detect any changes in the process, systems, or people that affect compliance. In addition, companies must constantly evaluate the controls to see if they are in fact meeting the desired control objectives. Change process For both compliance and business improvement purposes, companies need to evaluate their processes constantly and look for ways to improve them. This starts a new cycle of process design, followed by a project to implement the changed process. Source: AMR Research, 2003

9 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 9 Medical Devices ISO 14971, Application of Risk Management to Medical Devices Pharmaceuticals cGMPs for the 21 st Century A Risked-Based Approach FDAs 5 Part Strategic Plan Quality Systems-based Inspections 1.Quality System 2.Facilities & Equipment system 3.Materials System 4.Production System 5.Packaging & Labeling System 6.Laboratory Control System 1.Quality System 2.Facilities & Equipment system 3.Materials System 4.Production System 5.Packaging & Labeling System 6.Laboratory Control System 1.Management Responsibility 2.Design Control 3.CAPA 4.Production and Process Control 5.Records/Document Change Controls 6.Materials Controls 7.Facilities & Equipment Controls 1.Management Responsibility 2.Design Control 3.CAPA 4.Production and Process Control 5.Records/Document Change Controls 6.Materials Controls 7.Facilities & Equipment Controls 1.Efficient Science- Based Risk Management 2.Patient & Consumer Safety 3.Better Informed Customers 4.Counterterrorism 5.A Strong FDA 1.Efficient Science- Based Risk Management 2.Patient & Consumer Safety 3.Better Informed Customers 4.Counterterrorism 5.A Strong FDA cGMP Compliance

10 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 10 Source: ISO13485:2003 – An Overview (Bangkok, Thailand, June 2005), Gunter Frey, GHTF SG3 Global Medical Devices - Quality System Requirements

11 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 11 ICH Q9 Quality Risk Management

12 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 12 Implementation of Risk Control Measures Culture on Risk Communication RM Policy An Integrated Risk Management Process (for all phases of the life of the product) Training Of Personnel Post Production Monitoring Risk Graph Residual Risk Hazard Cause Verification Of Effectiveness Source: ASQ Biomedical 09 December 2004, Alfred M. Dolan EU14971:2003 Corporate Risk Management Program

13 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 13 Low impactMedium impactHigh impact Select good IT practiceSelect generic & specific controls Select generic controls Periodic review and evaluation Step 5 Step 4 Identify generic hazards Assess severity & likelihood Identify generic & specific hazards Assess probability of detection Derive risk priority Consider risks Identify the electronic records and signatures Assess impact of records and signatures Step 3 Step 2 Step 1 The GAMP 4 Risk Model for Electronic Records and Electronic Signatures (ERES) Source: FDANews, 2005 GAMP 4 and Part 11

14 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 14 GHTF Risk Management Activities in Design & Development

15 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 15 Source: GHTF How risk management can be integrated into the CAPA process

16 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 16 Risk Analysis Intended Purpose Identification Hazard Identification Risk Estimation Risk Evaluation Risk Acceptability Decision Risk Control Options analysis Implementation Residual Risk Evaluation Overall Risk Acceptance Post-production Information Post-production experience Systemic Procedures Identification of new Hazards Change Control & Feedback Loop Risk Assessment Risk Management Preliminary Hazard Analysis Fault Tree Analysis Functional Analysis Tolerability of Risk Cost-Benefit Analysis Socio/Ethical Analysis FMECA HACCP HAZOP PAT Six Sigma SPC CAPA Complaint Mgmt. Aligning Risk Management Tools

17 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 17 Source: GHTF Risk Chart for Communicating Internal Risk Management Activities

18 Site Risk Potential (SRP)

19 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 19 Product quality and performance achieved and assured by design of effective and efficient manufacturing processes Product quality and performance achieved and assured by design of effective and efficient manufacturing processes Product specifications based on mechanistic understanding of how formulation and process factors impact product performance Product specifications based on mechanistic understanding of how formulation and process factors impact product performance Continuous "real time" assurance of quality Continuous "real time" assurance of quality Source: The Process Analytical Technology Initiative: PAT and the Pharmacopeias, Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science CDER, FDA Desired State

20 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 20 all critical sources of variability identified and explained variability managed by the process product quality attributes can be accurately and reliably predicted product specifications based on understanding of how formulation and process factors impact product performance Source: PDA, PAT & Risk Based Initiatives, Implementation Issues: C. Cambell Know your processes!

21 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 21 Materials Methods Man Medium Machine Measurement Input ProcessOutput Management Source: PDA, The Harmonized PAT Solution: Application of Risk-Based Tools & PAT Strategies in Pharmaceutical Product Manufacture: J. Priem Process Variation - Seven (7) Ms

22 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 22 I N P U T S (x) Machine - Equipment Method - Process Medium - Environment Materials Measurement Man - People Inputs to the process control variability of the output of the output Output y = f(x) y Variability - source of the Process risks to the product Source: Risk Reduction in Pharmaceutical Manufacturing using Process Analytical Technology, Brian Davies, Thermo Electron Corporation Sources of Variability Example 50 Products X 10 Operations X 10 Orders per Year X 10 Lots/Batches/Units per Order X 12 Months (30 days per order) X 10 Transactions per Unit per Operation = 6,000,000 Transactions per year Spec Limit Percent Defects per Opportunity (traditionally PPM) +/- 1 sigma ,700 +/- 2 sigma ,700 +/- 3 sigma (most companies) 66,810 +/- 4 sigma ,210 +/- 5 sigma /- 6 sigma (near perfect) (top companies) 3.4

23 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 23 Work Processes AbnormalNormal Non Value Add UnnecessaryNecessary EliminateReduce Value Add Flow eliminate the abnormal and the unnecessary non- value added tasks reduce the non-value added but necessary, e.g. regulatory place the value-added processes into a natural sequence Evaluation of Process Steps

24 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 24 Value-creating tasks: Actions necessary for making products, such as welding or drilling. Incidental work: Actions necessary to make products, but that dont create value from the customers standpoint. Such actions include reaching for a tool or clamping fixture. Waste: Actions that (a) create no value from the customers perspective and (b) can be eliminated from a process; e.g. walking to get tools that can be positioned within reach of a worker. In a typical company, the greatest percentage of time is spent on tasks that are pure waste. Source: Lean Advisors Inc. Source: Manufactures Get Lean to Trim Waste, William Leventon, Medical Device & Diagnostic Industry, September 2004 Identifying value added and non-value added Value-Stream Mapping

25 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 25 Incoming Materials. Specifications Relevant to Process-ability Incoming material attributes used to predict/adjust optimal processing parameters within established bounds (more flexible bounds) PAC PAC PAC PCCP LTCMIT Direct or inferential assessment of quality and performance (at/on-line) Control of process critical control points (PCCP). Process end point (PEPs) range based on performance attributes. PEPs Chemometrics (CM) and IT Tools for real time control and decisions At-line In/On-Line Process Analytical Chemistry Tools Laboratory or other tests LT Development/Optimization/Continuous Improvement (DOE, Evolutionary optimization, Improved efficiency) Multivariate Systems Approach Risk Classification and Mitigation Strategies Source: ACPS, Process Analytical Technologies (PAT) Sub-Committee Report: T. Layloff, Ph.D PAT Conceptual Framework

26 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 26 Strength Purity Quality Identity Potency Failure Mode Cause Effect Ishikawa FMECA Criticality Matrix DOE Multivariate Analysis SPC Raw Material DispensingGranulationDryingMillingMixingTablettingCoating Source: ISPE-Boston, Feb PAT Example

27 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 27 Site Risk Potential ProductProcessFacility C D1 C D2 C P1 C P2 C F1 Top Level Components Categories of Risk Factors (quantitative or qualitative variables) Dosage form; intrinsic chemical properties Poor cGMP compliance history Measuring; mixing; compression; filling FDAs SRP Hierarchy (Sept. 04)

28 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 28 Systems Direct Indirect Non gmp gep + Components CriticalNon Critical comm. qual. comm. + cGMP Impact Assessments & Source: PDA, PAT & Risk Based Initiatives, Implementation Issues: C. Cambell Physical Risk

29 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 29 Class-IClass-IIClass-III Intolerable Risk cannot be justified except in extraordinary circumstances Undesirable Tolerable only if risk reduction is impracticable or the costs are grossly disproportionate to the improvement gained Tolerable Tolerable if the cost of the risk reduction would exceed the improvement gained Negligible Tolerable if the cost of the risk reduction would exceed the improvement gained IEC Functional Safety: safety-related systems Class-IV Source: PDA, PAT & Risk Based Initiatives, Implementation Issues: C. Cambell Functional Risk

30 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 30 Probability Risk Class HighImpactMediumImpact Low Impact High332 Medium321 Low211 Risk Class Risk Priority HighDetectionMediumDetectionLowDetection 3MHH 2LMH 1LLM Class f (probability, impact) Priority f (class, detection) Source: PDA, PAT & Risk Based Initiatives, Implementation Issues: C. Cambell Process Risk

31 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 31 Physical Risk CN Functional Risk III III IV Process Risk MLH0 Standard Components Standard Operations Standard Parameters SRP Mitigation Plan Source: PDA, PAT & Risk Based Initiatives, Implementation Issues: C. Cambell Risk Integration

32 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 32 C N I II III H M L IQOQPQPVPATQADQ XXXX FDA Process Risk Functional Risk Physical Risk XXXX XXXX X ? X Source: PDA, PAT & Risk Based Initiatives, Implementation Issues: C. Cambell Risk Dividend

33 Electronic Enforcement

34 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 34 Execution Systems Orchestrate Production Machine Line Plant Enterprise Controls Parameters Data Readings Status People Shop Packet Work Status Production Status ERP Product & process data definitions Product & process data definitions Production Orders Execution System Set points Equipment PLM/EDM Manufacturing Process Product & process data definitions Traceability Inventory Picklist Consumption PACPCCP CMIT PEPs PAT Source: IBM Life Sciences, James Bradburn

35 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 35 PLM CRM ERP Financials BOM Order Fulfillment Inventory Automation and Data Capture Raw Material MachiningCleaningAssemblyTestingPackaging QMS AQP Auditing Training Inspection Test NCR (CAR, SCARs) CAPA Complaints Service Oriented Architecture & Integration Framework Process & Equipment Optimization Layer Manufacturing Execution Batch Control Line Monitoring Weigh & Dispense Material Flow & Lot Tracing Container Management Data Collection, Reporting, Metrics/KPIs Alarms & Escalations Statistical Process Control WIP Tracking Equipment Management Process Planning Work Order Management MBOM Work Instructions & Procedures Operator Tracking (change, execution, and enforcement) Operational/Transactional Control Enterprise Manufacturing Compliance Risk Management File Align Enterprise Applications

36 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 36 Initiate Containment Action Initiate Root Cause Analysis Initiate CAPA Process Request for CAPA Plan Review CAPA Plan CAPA Plan Approved? Initiate Implementation Implement & Sign-Off Verify Effectiveness Close CAPA PROCEDURE REGULATION Client Reporter CRM Sys. Paper Trail begins, Notifications to appropriate parties Complaint Submission Process Acknowledgement Letter to Customer Issue a CAPA to Plant Review Edit/ Close Regulatory Submission ( Such as 30 day MDR 5 day MDR, Summary) Complaint Coordinator Process Complaint Coordinator Plant Complaint Coordinator Closure Letter To Client SOP CORPORATE POLICY Existing Regulatory Process Control

37 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 37 Electronic Enforcement

38 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 38 Regulatory/Compliance Process Management Start jobs based upon: Web service external event Web service start job request Repository updates (filtered) from MES, MCS or other data sources Scheduled start Multiple workflow paths depending on event Run Rules and Reports for decision support Context filtering and evaluation Synchronization with multiple start events or wait for events Multiple responses possible depending on flow path Execute web service calls to external systems such as MES, ERP, CAPA and others Execute , logging, exporting SQL, external applications, and other executions Manufacturing Compliance Framework

39 FDA Regulatory and Compliance Symposium© 2006 Brooks Software 39 GHTF, Implementation of risk management principles and activities within a Quality Management System, May 20, 2005 FDANews, Introduction to GAMP Good Practice Guide: A Risk-Based Approach to E-Record Compliance, Per Olsson FDA, A Risk-Based Approach to Pharmaceutical Current Good Manufacturing Practices (cGMP) for the 21st Century PAT & Risk-Based Initiatives: Implementation Issues; PDA New England - 08 Dec 2004, Cliff Campbell B.E., C.Eng The Harmonized PAT Solution: Application of Risk-Based Tools & PAT Strategies in Pharmaceutical Product Manufacture; PDA New England – 08 Dec 2004, Jeffrey A. Priem Process Analytical Technologies (PAT) Sub-Committee Report ACPS Meeting 21 October 2002, Tom Layloff, Ph.D. Risk Management, From Basic to Advanced; RAPS – 11 October 2004, Kevin P. Bassett; Matthias M. Buerger; Oliver P. Christ Importance and Impact of ISO 13485:2003, RAPS – 13 October 2004, Ed Kimmelman, JD Risk Management of Medical Devices: Implementation, ASQ Biomedical 09 December 2004, Alfred M. Dolan Implementation of Risk Management Principles within a Quality Management System, 09 December 2004, Kimberly Trautman ISO 14971:2000, Essentials 1 st Edition, A practical handbook for implementing the ISO Standards for medical devices, Canadian Standards Association IEE Tolerability of Risk Framework hsc36, Health and Safety Briefings - October 2000 FDA, A perspective on Risk Analysis for the GMP Initiative - April 2003, H. Gregg Claycamp, Ph.D., CHP Risk Reduction in Pharmaceutical Manufacturing using Process Analytical Technology, Brian Davies Risk-Based Method for Prioritizing cGMP Inspections – September 2004, Department of Health and Human Services U.S. Food and Drug Administration Pharmaceutical Manufacturing: New Technology Opportunities – 16 November 2001, G.K.Raju, Ph.D PAT Progress Report: 13 April 2004 ACPS Meeting, Ajaz S. Hussain, Ph.D. Deputy Director Office of Pharmaceutical Science CDER, FDA Guidance for Industry, PAT - A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance DRAFT GUIDANCE Process Analytical Technology (PAT): Whats in a name? – 09 April 2004, D. Christopher Watts, Ph.D. Office of Pharmaceutical Science, CDER, FDA Sources

40 Thank You Joseph Vinhais


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