Presentation on theme: "Quality Systems and Risk Management Approaches for Networked Drug Development David A. Moyer VP, Regulatory Compliance Programs Fulcrum Pharma Developments,"— Presentation transcript:
1 Quality Systems and Risk Management Approaches for Networked Drug Development David A. Moyer VP, Regulatory Compliance Programs Fulcrum Pharma Developments, Inc. PDA SciTech Summit Orlando, Florida March 10, 2004
3 How do Regulators View Network Prepared Submissions? Submission sponsor bears ultimate responsibility - no difference!Expectation is to have an integrated approach to quality even though many quality systems are involved –Preclinical Supplier must meet GLPCRO(s) must meet GCPDrug Substance and Drug Product CMOs must meet GMPElectronic data must meet appropriate 21 CFR Part 11 security and retrieval requirements
4 Quality System Foundation It is essential to have a quality system in place at the core of a drug development program that complements, but does not interfere with the suppliers’ programs.
5 Components of the Core Program Project Quality PlansVendor qualification and approval systemDocument control and record retention policyRegulatory inspections policyStaff training programProgram management proceduresStandardized audit plans for major development activitiesProcedures for electronic records management, including secure data sharing with clients
6 Standard Operating Procedures Quality PyramidQualSystemProjectQuality PlanProject PlanStandard Operating Procedures
7 Standard Operating Procedures Quality PolicyDocument Control (Internal & External)Employee TrainingProject Plan and Protocol DevelopmentSupplier Evaluation and ApprovalIT SecurityData QAGeneration of Regulatory Documentation
8 Quality Policy Generation and execution of Project Quality Plan (PQP) Performance of supplier audits and assessments in accordance with PQPConduction of internal audits on an annual basisStatement of quality and ethical standardsStatement and standards for suppliersReview and approval of deliverablesPolicy for data access to regulatory authorities and third party consultantsCommitment to ensure internal and external (supplier) compliance with applicable regulations
9 Document Control Essential Elements A set of procedures to guide internal generation of critical documentation to satisfy regulatory guidelinesA system for integrating internally and externally generated documents to ensure consistency while still protecting supplier proprietary informationAlso covered by Supplier and Quality Agreements in most cases
10 Planning for Quality Begins with development of project plan Gain complete understanding of project objectives from:Sponsor project informationInformation in Master Service and Quality AgreementsSupplier capabilities and performance historyRisk Assessment Using M.I.R.Si.e. Capturing the Issues
11 Issues: Capturing and Providing Context Message, Issue, Response, SupportPrepared based on team input and documented in tablesMIRS supports planning and communication based on identifying objectives and issues at the beginning and then regularly reviewing and updatingMIRS tables are a useful and simple way of structuring and recording project informationMIRS tables are a communication tool and support preparation of documents
12 M.I.R.S. to Define, Capture and Communicate Information MessageIssueResponse/RationaleSupportWhat do we want or need to say and what can we say?What stands in the way of the message?How do we overcome the issue? / What reasoning supports our message?Where are the data?
13 The MIRS Knowledge Process MessageIssuesResponse/RationaleSupportClaimsFeatures and benefitsAdvantagesInterpretationsConclusionsChallengesRisksComparisonsConflictingResultsQuestionsNew StudiesRefutationScientific precedentRe-analysisExpert opinionDesigns/dataCompleted/ongoing studiesPublicationsGuidelinesPrecedents
14 M.I.R.S. Example Message Issues Response/ Rationale Support Final purification step is controlled, resulting in consistent production of polymorph A, which is stable and doesn’t change in drug substance or drug product. Optimized purification procedure leads to the highest quality.Why was polymorph A the selected form?Would polymorph B alter the outcome of bio-availability?Polymorph A is the most stable form.Current recrystalliz-ation process ensures consistent formation of polymorph A.Lab data (thermo-dynamic and stability data)LIMS data (Polymorph B, which is specified, has not been seen since the current method of synthesis was established).
15 Project Quality PlanProject Quality Plan is a fully integrated subset of the Project Plan. It defines:Quality expectations for each drug development projectProcesses and activities to be completed to ensure quality expectations are achieved at the internal project management level and by suppliersRationale for specifying internal review criteria and external supplier assessment methodology
16 Building Supplier Relationships Supplier EvaluationCulture and goalsStrategic fitOverall expertiseServices providedSupplier QualificationSpecific expertise and previous experienceGeneral capabilities e.g. facilities equipment, staff and workloadOrganization structure, staff turnover and affiliationFinancial stabilityProject management, communication and reportingMasterServiceAgreementSupplier AuditAudit of Quality systemsTailored project audits
17 Planning Onsite Audits SUPPLIERTASKS ALLOCATEDAREATARGET AUDIT DATESEXPECTED DURATIONCMO 1QC testing of API and Drug ProductDrug Product ReleasePackaging, Labeling & DistributionSupply of CTM TabletsGMPDecember 20032 days onsiteCRO1Study Monitor / Drug Safety Follow-upGCPFebruary 20041 day onsite
18 Issue and Resolution Log SUPPLIERDATE OF AUDITSIGNIFICANT ISSUESRESOLUTION DETAILSCMO1December 10-11, 2003Frequent problems with dissolution testingPackaging area material control concernReview methods transfer package/run comparative testsSend auditor to monitor packagingCRO1February 12, 2004No significant issues identifiedNot Applicable
19 Risk Management and the New FDA “The CGMP regulations for drugs have not been updated in 25 years Continuous quality improvement in manufacturing hasn’t been the subject of as much attention in the pharmaceutical industry FDA’s broad-based program is working on developing new guidance based on the latest science of risk management and quality assurance.”Quotes by Mark B. McClellan, M.D., Ph.D.FDA’s Strategic Action Plan – August 2003
20 Process Analytical Technology The goal of PAT is to understand and control the manufacturing process, i.e., quality cannot be tested into products; it should be built-in or should be by design.Fantastic solution to promote innovation given appropriate resources, but what risk management/quality improvement options are available to “little pharma” and companies with existing products?
21 Risk Management for the “Little Guy” Hazard Analysis at Critical Control Points (HACCP)An Old Tool with a New Purpose
22 Back to the Future – Ahead to the Past HACCP is a tried and tested methodology for monitoring and managing processesUsed by the FDA to protect US food supply since the 1970sSince December 1995, FDA requirement for seafood producers to use HACCP principles - estimated to prevent ,000 seafood poisonings/year HACCP is: Simple by designProactive in practiceEasily incorporated into pharmaceutical compliance programs
23 Steps for Building the HACCP Plan Define potential hazards (hazard analysis)Identify measurable critical control pointsDetermine critical limits for control pointsEstablish control point monitoring proceduresDevelop corrective action strategies for critical control point deviationsDesign effective documentation systemVerify effectiveness of plan - periodically
24 Preliminary Steps for Development of Hazard Analysis Plan Establish a HACCP Team, including Manufacturing, Quality, Engineering, Validation, Development and the LaboratoryDevelop Master Scope Document describing the process or processes to be coveredCreate Process Flow Diagram(s)Group similar/equivalent processes together for consistency
25 STEP I - Conduct a Hazard Analysis If you have a formal Corrective Action/Preventive Action (CAPA) Program - just harvest the dataWhat are the hazards? Equipment FailuresCritical Utility FailuresProcess FailuresComputer Automation FailuresDocumentation System FailuresOperator/Analyst ErrorsTraining System ShortfallsTesting and Measurement Shortfalls
26 STEP II - Identify the Critical Control Points (CCPs) A GMP-compliant company has a head start on Step II. Most CCPs for equipment, process, utilities, and computer automation are (should be!) documented in validation filesChallenge is to study CAPA data to learn about the most variable component – PEOPLEWhat do you look for? Repetitive errors:Batch recordsProcess stepsPieces of equipmentTest proceduresDetermine root cause of errors – this identifies CCPs
27 Step III - Establish Critical Limits for Each Critical Control Point Like Step II, most CCP limits for equipment, process, utilities, and computer automation are established and documented in validation filesCreativity needed to cover the rest of your operation - examples of miscellaneous control limits based on deviations from normal trends:Control ParameterSource of Control LimitCheck PointCalibration DeviationsCalibration DatabaseCalibration LogYield FluctuationsAnnual Batch Record ReviewBatch ReviewRaw Material VariationsVendor Quality ProgramQC Insp & ReleaseMechanical FailuresPreventive Maintenance PgmMaintenance LogTraining FailureCAPA Program
28 Step IV - Establish Monitoring Procedures (1) "If you can't describe what you are doing as a process, you don't know what you're doing"– W. Edwards DemingStep IV ties all the GMP control systems together and creates a very powerful proactive toolMonitoring procedures are standard activities done routinely - by an employee or by mechanical means (including computer controls) - that measure the process at a given CCP and create a record for future use
29 Step IV - Establish Monitoring Procedures (2) Elements of the process:Requires input from cross-functional teamIntervals of measurement determined by considering potential corrective action responsesTeam must determine impact of a "critical HACCP finding", i.e., does process need to stop?Format for reporting findings to a centralized point must be established
30 Worksheet for Determining Monitoring Procedures HACCP PLAN DEVELOPMENT FORM: MONITORING PROCEDURES AND FREQUENCYProcess or System Category:Process Step/CCPCritical LimitsMonitoring Procedures(Who, What, When, How)
31 Step V - Establish Corrective Actions (1) CAPA program and HACCP come together at Step V by which time the team has determined the:Critical Control Points (CCPs)Critical Limits for each Control PointMeans of Measuring Performance at the CCPs Step V requires team to answer:Has the cause of a deviation been identified and eliminated?Will the CCP be under control after corrective action has been taken?Have measures to prevent recurrence of the deviation been established?Do corrective action procedures ensure that no product which is injurious to health or otherwise adulterated because of the deviation enters commerce?
32 Step V - Establish Corrective Actions (2) Tools for getting the job done: Meaningful statistical feedback from CAPA ProgramRoot cause analysis techniquesResponsible employees trained in the principles of cGMP
33 STEP VI - Establish Record Keeping Procedures Comprehensive list of all CCPs monitored plus electronic and/or paper raw data collection filesQuarterly summary of findings by type of hazardList of batches potentially affected by CCP deviationsReports formal root cause analysis evaluations
34 STEP VII - Establish Verification Procedures HACCP process built on foundation and principles of total quality systemObjective is continuous process improvementOnly achievable by becoming master of every step in your process – no one else can/should know it betterThe verification process confirms that HACCP plan is working and involves:Validation of initial phase in which plan is tested and reviewed to determine that CCPs are effective and relevant to a well-controlled processOngoing verification to ensure that monitoring activities provide necessary data without negatively impacting the processAnnual reassessment (and modification, if necessary) of HACCP plan to ensure continued relevance of CCPs
35 SummaryFDA quality expectations for drug development are the same for “big” and “small” pharma irrespective of outsourcing used.The organization responsible for management of a drug development project must have a core quality program that serves as a foundation for applying quality principles across the project.Supplier selection and management are key components of drug development project quality.M.I.R.S. and HACCP are two simple risk management tools that can be applied to any size project.
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