上海上海CMCCMC培训培训EnsuringDrugQualityfEnsuringDrugQualityforPublicHealthTheImporPublicHealthTheImplementationlementationOverviewChallenges to Globalization of Drug Manufacturing FDAs Work in ChinaGMP Principles: Issues of the most concern2ChallengesSignificant demand in resources for inspectionsConsequences of globalization, including more foreign manufacturing and clinical trials sitesGreater complexity associated with manufacturingFDA concern about the state of industry compliance and insufficient investment in manufacturing and quality systems3FDA International Efforts4FDA Overseas EffortsLong-Term GoalProducts coming to the U.S. meet U.S. requirements.Strengthened Regulatory CounterpartsIndustry Responsibility: Supply Chain Management at Point of Manufacture, Point of Export, and When Presented for Importation5FDA Overseas Presence Current LocationsChinaIndiaLatin America EuropeMiddle East (2010)6FDAs Work in China7FDA China OfficeIn-Country StaffBeijingChris Hickey, Office DirectorMike Kravchuk, Deputy (device)Brenda Uratani (drug)Irene Chan (food)ShanghaiCharles Ahn (drug inspection)BJ Marciante (device inspection)GuangzhouDennis Doupnik (food inspection)Dennis Hudson (food inspection)8FDA/SFDA Agreement: Key ProvisionsKey Provisions:Registration of designated drugs and devicesJoint Training/Capacity BuildingGreater/More Rapid Information SharingGreater Access to FacilitiesProduct Integrity/Anti-counterfeitingStrengthened FDA, SFDA Collaboration Under Multilateral Auspices9Drugs in China: What Has FDA Done?FDA-SFDA CollaborationInspectionsEngagement of IndustryCapacity-Building10What Is China Doing?Updating Standards, MethodsRevision of China CGMPWorking to Improve Drug Adverse Event ReportingTraining Elite Group of Inspectors Re: International StandardsAttempting to Strengthen Drug Application Review ProcessTaking More Active Role in International Standard-SettingShifting Focus to Conduct More Pre-Approval InspectionsUtilizing Tools to Detect Counterfeiting Supply Chain: Developing Tools and Standards for Tracking/ Tracing11Chinas Role in Drug Development: Challenges for ChinaNeed for Regulatory ReformUniformity of implementation of CGMP across all provincesRegulatory Authorities Working to Strengthen Capacity, Authority, Streamline Reporting StructuresCounterfeits Economically-Motivated Adulteration“Show” and Shadow FactoriesSupply Chain IntegrityBulk ChemicalsExcipient QualityRaw Material Processing Where There is no OversightAdverse Drug Reaction ReportingDifferent Standards for Domestic, Exported ProductsData IntegrityProcess Inspects Firms Generally, Not Capacity to Produce Specific Products12CGMP Requirements & PrinciplesIssues of Most Concern13CGMPC” = currentdynamic and evolve over time“GMP” = Good Manufacturing PracticesMinimal standardsNot “best” practices unless “best” is, in fact, current minimal.14Potential Problems from Non-Compliance with CGMPSuper-potency or SubpotencyImpuritiesContaminationSafety and Efficacy effects15Some Issues of most concernDay-to-day implementation of CGMP Understanding the product and the processCant “test” quality into the productQuality system managementMaterial managementEquipment qualification and useSupply chain management16Day-to-day Implementation of CGMPEliminate variabilityAchieving Process Consistency is of utmost importance to ensure quality of each batch17Process UnderstandingInadequate Development WorkReaction parameters are often too wide and not supported by development workEither extremity of an executed range of parameters is often selected as optimal conditionGaps in knowledge management in progressing from one stage to another stageLack of formalized structure for process development18Quality System19Fundamental Quality Management PrinciplesStrong commitment to drug quality and patient safety Strong “believer” in the value of CGMPUnderstand the importance and impact of quality management, control, and implementation20Firms should not work only to pass an FDA inspectionFirm should operate the facility under quality system21Pharmaceutical Quality SystemThe Quality System is the foundation for the drug manufacturing systemsQuality system model integrates manufacturing systems22Quality SystemCritical Commitment from Top ManagementUnderstand & recognize the value of quality systemStrong commitment on producing safe and effective product- decision to release or reject of batch justified by data and science (responsibility of QA)Clear communication and promotion from top management on importance of quality to all employees and units of operationImplementation and enforcement on quality system23Pharmaceutical Quality System Lifecycle Approach Process performance and product quality monitoring system; Corrective action and preventive action (CAPA) system; Change management system; Management review of process performance and product quality. 24Lifecycle ApproachValidation, maintenance, and continuous improvement of product quality5% pre-approval95% Post-approval25Formal Formal ExperimentalExperimentalDesign Design (DOE)(DOE) Conformance/ Validation StudiesPost-ApprovalProposeProduct Life CycleEvaluationIdentifyIdentify(Critical/ Key (Critical/ Key Attributes/Attributes/Parameters)Parameters) Confirm(Control/ Predict)(Control/ Predict)MonitorMonitor( (CAPACAPAContinuousContinuousImprovementImprovementInnovation)Innovation)RiskRisk Assessment/ Assessment/ MitigationMitigationComparabilityComparabilityProtocolProtocolRiskRisk Assessment/ Assessment/ MitigationMitigationCGMPCGMPAdherenceAdherencePATPATPATPAT26Quality System ICH Q10 Concepts3.1.3 Commercial Manufacturing “The pharmaceutical quality system should assure that the desired product quality is routinely met, suitable process performance is achieved, the set of controls are appropriate, improvement opportunities are identified and evaluated, and the body of knowledge is continually expanded” 27Quality SystemDeviations & investigationsChange controlTrainingAudit/ reviewAnnual product reviewContract agreementDocument control28Investigation & DeviationsAdd Value & Impact QualityLearn from mistakesPrevent recurrences: corrective action & preventive action (CAPA) Build knowledge: variability reduction, continuous improvement in product quality29What is Change Control?Changes are managed by the firm: Evaluates everyday changes to the manufacturing facility, equipment, personnel, improvements, and minor adjustments to the process. All changes must always be done with a written protocol under the change control system including approval by QAHave procedures in place for the execution of the change in an orderly mannerEvaluate the impact of the change Document the change and resultsAdequacy of changes are evaluated by FDA during inspection30TrainingQualified employee to perform the assigned task Strict implementation of the established proceduresSupervision Periodic re-evaluationContinuing education in training31Audit/ Review Annual Product ReviewRegular trending reviews and evaluation of process and product Evaluation of stability, recalls, OOS, product complaints, returnsRisk assessment, mitigation before occurrence of serious consequencesEnsure operation is maintained in an ongoing state of controlKnowledge gained for continuous improvement in product life cycle32Contract AgreementClear contractual agreements on: Responsibilities of each partyEffective communication on all issues that potentially impact drug qualityAdequate qualification, auditing and regular periodic evaluations of contractorsNotification to FDA for changes in contractors33Document ControlsA most critical element to support acceptability of a production batch and GMP complianceNot just a bureaucratic exercise to satisfy FDA REQUIRE ORIGINAL RECORDS as the task (operation) is being performed, not a re-copying of the original. Data must not be alteredProduction: batch recordsQC: testing recordsViolations: Serious Consequences 34Documentation All SOP (especially production batch record) should be in sufficient detail for the operator to carry out the task in a consistent mannerChanges in SOP must be reviewed and approved by QA35Material Management36Material ControlsRaw materialsIntermediatesComponentsAPIManufacturing materialse.g., sterilizing filtersFacility materialse.g., HEPA filters37ICH Q7A: Materials ManagementManufacturers of intermediates and/or API should have a system for evaluating the suppliers of critical materialMaterials should be purchased against an agreed specification, from a suppliers, approved by the quality unit(s)If the supplier of a critical material is not the manufacturer of that material, the name and address of that manufacturer should be known by the intermediate and/or API manufacturer.Changing the source of supply of critical raw materials should be treated according to Section 13, Change Control.38Equipment Management39Qualification of EquipmentIssues especially pertain to:Adequate IQ, OQ, PQ Instruction and training of operation for use of equipmentEstablish regular maintenance, calibration and maintain documentation of these activities40Supply Chain Management41Supply Chain ManagementIdentify critical control points (areas) and implement adequate controls to ensure integrity of the supply of raw materials, component, excipients, API, drug product through procurement, manufacturing and distribution.Tamper resistantSerializationtesting42Regulatory Actions for non-GMP compliant firmsWarning LettersWithholding ApprovalImport Detentions and AlertsSeizuresInjunctionsProsecutionsIMPACT: Product NOT suitable for use.43Thank YouBrenda UrataniBrenda.uratanifda.hhs.gov44结束结束