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1、FDA Manufacturing Facility Inspection ProgramsJim Li, Ph.D. MBAJune 29, 2010Presentation Overview w Types of inspections 检查类型w Pre-approval inspection (PAI) process 药品批准前检查程序w FDAs Expectations in CGMP Compliance FDA 对CGMP合规性方面的预期和要求w Cases 案例2Types of GMP InspectionsGMP检查类型3Type of Inspection 检查类型S
2、urveillance Inspections常规 GMP 监测检查For-Cause Inspections 原因引起的GMP检查 Pre-approval Inspections药品批准前GMP检查4System Based Inspection 系统GMP检查5Surveillance Inspections 常规 GMP 监测检查Full Inspection 全面检查 A broad and deep evaluation of the firms CGMP compliance Conducted when Little or no information is known The
3、re is doubt about the CMGP compliance in the firm Follow up to previous regulatory actions. At least four systems, one must be Quality System 6Surveillance Inspections 常规 GMP 监测检查Abbreviated Inspection 简略检查An update evaluation of a firms CGMPConducted when a firm has a record of satisfactory CGMP co
4、mpliance no significant recall (召回), product defect (缺陷) or incidents (事故) little shift in the manufacturing profiles within last two yearsAt least two systems, one must be Quality SystemOptional systems are rotated in next Inspections. For a contract lab, two systems may be considered a Full Inspec
5、tion7Surveillance Inspections 常规 GMP 监测检查Post-Approval Inspection 批准后检查 Audit for changes in the production and control practices that occur after approval Confirm that the approved applications have been appropriately supplemented to reflect those changes Cover approved products regardless of wheth
6、er or not these products were covered under the pre- approval program8Significant Problems Found in Post-Approval Audit 批准后检查中发现的一些主要问题Scale up not documented/validated prior to commercial distributionLack of data supporting processes and controls, and changes theretoLack of controls and recordsInad
7、equate, or lack of, validationInadequate change control proceduresUnauthorized process changesInadequate stability data, unfulfilled stability testing commitments, Unreported stability test failures9Significant Problems Found in Post-Approval Audit 批准后检查中发现的一些主要问题Unfulfilled application commitmentsU
8、nreported/unapproved changes in manufacturing or testing/QA proceduresImproperly reported or *fraudulent (欺骗)* changesNon-permitted change to new suppliers, testing, or contract laboratoriesUsing unapproved suppliers, testing, or contract laboratories10For-Cause Inspection 原因引起的GMP检查Evaluate correct
9、ive actions after a regulatory action Cover areas found deficient and subjected to corrective actions Focus on systems for determination on overall compliance Firm is expected to address all of its operations in its corrective action plan, not just the deficiencies in the FDA-483 Full Inspection is
10、used for a compliance inspection, especially if Abbreviated Inspection was used during the violative inspection In addition, For-cause inspection may be conducted under following situations Field Alert Reports (FARs) industry complaints recalls indicators of defective products etc. 11Pre-Approval In
11、spection 批准前GMP检查Inspection conducted before approval of a NDA/ANDA and CMC supplement to assureThe objectives determine the scope of inspection coverageAt least 1 objective will be addressed during a PAI1.Readiness for commercial manufacturing2.Conformance (相符) to application3.Data integrity audit1
12、2Pre-Approval Inspection (PAI)药品批准前检查13A Statutory Requirement 联邦法的要求FDA may approve a NDA/ANDA if, among other requirements, 21 U.S.C. 355(d)(3) and 355(j)(4)(A)14“the methods used in, and the facilities and controls used for, the manufacture, processing, packing, and testing of the drug are found
13、adequate, and ensure and preserve its identity, strength, quality, and purity”.Priority PAI 首要PAIPriority PAI criteria:1. Firm first time in an application2. First application filed by applicant for DP3. First ANDA for an approved drug4. Product containing a NME5. Product content assay has narrow ra
14、nge, or requires titrated dosing6. Product or API manufactured by a substantially different process7. API deviation is high risk (from animal tissue) or intended use changed8. Numerous submissions/changes9. Profile class status not updated in last 2 years (3 years for testing lab, 4 years for packag
15、ing investigating failures, deviations, complaints, and adverse events; conducting recalls; and for reporting this information to FDA?30Readiness for Commercial Manufacturing 商业生产准备就绪Examples: Development studies and knowledge about manufacturing operation vulnerabilities, including raw material var
16、iability. Studies conducted to establish process controls or parameters directly related to the critical quality attributes. Studies of “worst case” or boundary conditions to establish “proven acceptable ranges” or studies involving design of experiment or multivariate analysis modeling. Protocols, execution of the studies, and reliability of the data and conclusions. Scale-up studies. High l
