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CBER Pre-License and Pre-Approval Inspections

CBER Pre-License and Pre-Approval Inspections. Judy Ellen Ciaraldi BS, MT(ASCP)SBB, CQA(ASQ) CBER, OBRR, DBA September 15, 2009. Outline. Introduction to Pre-License & Pre-Approval Inspections Purpose Comparing ORA and CBER inspections Submissions requiring PLIs and PAIs

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CBER Pre-License and Pre-Approval Inspections

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  1. CBER Pre-License and Pre-Approval Inspections Judy Ellen Ciaraldi BS, MT(ASCP)SBB, CQA(ASQ) CBER, OBRR, DBA September 15, 2009

  2. Outline • Introduction to Pre-License & Pre-Approval Inspections • Purpose • Comparing ORA and CBER inspections • Submissions requiring PLIs and PAIs • Inspection Procedures • Pre-inspection, during inspection, post-inspection activities • Common Observations • Final Comments

  3. Introduction to FDA Inspections

  4. Definitions • CSO – Consumer Safety Officer • PAI – Pre-approval Inspection • PLI – Pre-license Inspection • Audit – conducted by manufacturer (individual who is not directly responsible) to assure quality system is effective and in compliance with established quality system requirements; corrective actions taken when necessary and re-audits done (61 FR 52656, 10/7/96) • Inspect/Inspection – onsite evaluation of a facility (conducted under the authority of the Acts) to determine whether operations are in compliance with GMPs and commitments made in the BLA (63 FR 60141, 11/6/98)

  5. Purpose of FDA Inspection • Statutory obligation in FD&C and PHS Acts • Check for compliance with FD&C Act and PHS Act • Check for compliance with applicable sections of the CFR • Check for compliance to commitments made in the BLA or supplement

  6. Purpose of FDA Inspections (cont.) • Continuation of the desk review of a BLA or supplement • BLA approval is based on facility inspection and examination of the product and determination that establishment and product meet standards in the application and requirements in applicable regulations (601.20(a & d)) • Approval based on acceptable compliance check • Compliance check based on inspectional history • Inspection done to establish inspectional history

  7. Inspections in the CFR • 600.20 – Inspectors • Officers of FDA having special knowledge of manufacturing methods and controls • 600.21 – Time of inspection • After establishment is in operation and is manufacturing complete product to be licensed • 600.22 – Duties of inspector • Call active head stating objectives of the visit • Interrogate personnel as necessary

  8. Inspections in the CFR (cont.) • 600.22 – Duties of inspector (cont.) • Examine details of manufacturing site used in any part of manufacturing • Investigate fully all methods used to manufacture product to be licensed • Observe procedures used in actual operation • Bring any fault observed during inspection that may affect product to attention of manufacturer • Inspect and copy as needed any required records • Make appropriate recommendations of actions needed regarding licensure

  9. FDA Inspections • Conducted by Office of Regulatory Affairs (ORA) and CBER • What is the same with CBER PLIs and PAIs and routine ORA inspections? • Overall purpose of inspection • Team leader’s responsibilities • General inspection process • Resources used for inspection determinations • Inspectors have credentials identifying them as being approved to conduct inspections

  10. FDA Inspections (cont.) • What is different between CBER PLIs and PAIs and routine ORA inspections? • PLIs and PAIs are announced • PLIs and PAIs only occur before approval; routine ORA inspections occur after approval (every 2 years – 600.21) • PLI/PAI inspection team is composed of product CBER specialist/reviewer; CBER CSO is inspection team leader; ORA investigators often accompany CBER CSOs on PLIs and PAIs • Applicant must respond to 483 observations for PLIs and PAIs in order to receive approval • ORA investigator has a nifty badge

  11. Blood and Plasma CSOs • Review responsibilities • Scientific reviewer • Product specialist • Regulatory Project Manager • Lead investigator on PAIs and PLIs • Inspection training • Food and Drug and Biologics law courses • Blood banking and plasmapheresis inspection courses • Interviewing techniques • Field training during PLIs and PAIs

  12. Submissions that need PLIs and PAIs • Inspections done when there is no inspectional history of manufacturing site or process • Pre-license inspections • Manufacturing sites included in BLA • Examples: Blood Bank, Source Plasma center • Pre-approval inspections • Additional Source Plasma centers under approved BLA • Supplement for blood product irradiation • Supplement for RBC immunization program • Contract donor testing lab with no inspectional history • Other supplements based on new technologies or complexity of change and impact on product

  13. Inspection Procedures

  14. PAI and PLI Procedures • Pre-inspection • During inspection • Post-inspection

  15. Pre-Inspection Activities • CSO reviewer places inspection in queue after desk review completed • CSO inspectors volunteer for inspections • Review submission with CSO reviewer • Plan inspection travel (1-2 inspections/week, ~ 3 days/inspection) • Contact authorized official and discuss activities that will be observed (~ 1 month) • Communicate with ORA inspector

  16. Inspection Activities • Present credentials and issue Form FDA 482 - Notice of Inspection, to most senior official • Obtain general information about operations • Walk-through of facility manufacturing areas • Review written manufacturing procedures and records • Visual observation of manufacturing operations • Closeout discussion • May include Form FDA 483 – Inspectional Observations

  17. General Information Collected During the Inspection • Confirm and complete information in submission • Other centers owned/operated by applicant • Organization chart (corporate, center) • Date center began operations or process • Operating hours • Type of product and donor programs • Consignee information

  18. General information Collected During the Inspection (cont.) • Number of units and/or donors collected to date • Collection equipment used • Center medical director information • Contractor information (back-ups?) • Incidence of positive infectious disease tests • Description of quality oversight of operations • Description of SOP change control process

  19. Scope of Inspections • Systems-based • Quality assurance • Donor suitability • Product testing • Quarantine and inventory management • Production and processing • Areas reviewed in each system • SOPs • Training/Personnel • Facilities • Equipment calibration and maintenance • Records

  20. Review SOPs and Records • Donor selection and deferral • Donation procedures • Medical oversight • Product processing, component preparation • Testing and test results (including QC) • Quarantine, storage and distribution • Donor and patient adverse reactions (including workup of disease transmission)

  21. Review SOPs and Records (cont.) • Lookback and retrieval of unsuitable products • Donor re-entry • Documentation pertaining to computer system • Equipment testing and maintenance • Employee training and proficiency testing • Detecting deviations, investigations and corrective actions • Quality oversight

  22. Review of Quality Oversight • Compliance Policy Guide: FDA Access to Results of Quality Assurance Program Audits and Inspections (Sec. 130.300, CPG 7151.02) • http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm073841.htm • FDA cannot review reports of periodic audits • FDA can review records required to be maintained under 211s, and 606s (FD&C Act) • 211.100(b), 211.160(a), 211.192 – SOP deviations must be recorded and justified • 606.100(c) – review records and investigate discrepancies

  23. Visual Observations • Donor screening and deferral • Including medical staff activities • Blood product collection • Product processing, component preparation • Equipment usage • Testing (ABO/Rh, infectious disease, QC) • Labeling • Documentation, data entry

  24. Visual Observations (cont.) • Physical facility – adequate space for • Private setting to determine donor suitability (606.40(a)(1)) • Product storage and quarantine of units pending testing or not suitable for release (606.40(a)(3-6)) • Safe and sanitary disposal of unsuitable units (606.40(d)(2)) • Other specific activities requested in submission • RBC immunization

  25. Closeout Discussion • Inspectors usually summarize observations at end of each day • Do not discuss whether observations will be on 483 • Form FDA-483 – Inspectional Observations, issued to most senior official • Notification of significant objectionable conditions related to products and/or processes • Inspector’s judgment that practices observed cause (or could cause) release of adulterated products

  26. Closeout Discussion (cont.) • Non-reportable observations (discussion items) • Deviations from Acts or regulations which are of questionable significance • Practices that deviate from guidance documents • No written record of these issued to senior official • Reviewed during next inspection • Open discussion; ask for clarifications and basis for concern • Respond to 483 observations in writing to CBER

  27. Resources for Inspection Decisions • Requirements in FD&C and PHS Acts • CFR (including cGMP regulations) • Operator’s manuals and package inserts • Compliance Programs • Compliance Policy Guides • Investigations Operations Manual • Guidance documents and blood memoranda

  28. Conflicts during FDA Inspections • Discuss issues with inspection team leader • Responding to 483 observations • Response does not always mean a correction is needed • Submit information to support your current procedures • Contact • Office of Compliance and Biologics Quality, CBER (301-827-6220) • Office of Blood Research and Review, CBER (301-827-3524) • CBER will generally not interfere with ongoing inspection

  29. Post-Inspection Activities • Activities performed with input from full team • Write Establishment Inspection Report (EIR) and assemble exhibits • Review applicant’s response to 483 observations • Response fully addresses all 483 observations • Includes evidence of corrective action or data to support why no change was made • Concerns discussed with applicant • May need additional information submitted

  30. Post-Inspection Activities (cont.) • Prepare review and Inspection Closeout Memo • Review of responses to 483 observations • Recommendation for final action • Inspection documents sent to Office of Compliance and Biologics Quality • Quality review of inspection packet • Classify inspection and prepare Endorsement Memo • Send a copy of the EIR to applicant • Return original inspection packet to CSO inspector • Inspection packet given to CSO reviewer who proceeds with approval

  31. Inspection Classification • No Action Indicated (NAI) • Form FDA-483 was not issued to applicant • EIR still prepared • Voluntary Action Indicated (VAI) • Form FDA-483 was issued to applicant • Applicant must respond to 483 observations • Usually no enforcement action taken • Official Action Indicated (OAI) • Enforcement action taken • May prevent approval of BLA or supplement • Manufacturer has opportunity to correct

  32. Common Inspection Observations

  33. SOPs • Written SOPs are not always followed (606.100(b)) • Written SOPs do not include all steps to be followed (606.100(b)) • Manufacturing records are either not reviewed to identify discrepancies or a thorough investigation, including conclusions and follow-up was not made and recorded (606.100(c))

  34. Records • Records not maintained concurrently with performance of each significant step so that steps can be clearly traced (606.160(a)(1)) • Records do not identify person performing test, show dates of entry, test results or interpretation and are not as detailed as necessary to provide a complete history of work performed (606.160(a)(1))

  35. Equipment and Supplies • Equipment used in collection, storage, processing, manufacturing of blood components is not observed, standardized or calibrated on a regularly scheduled basis to assure it will perform in a manner for which it was designed (606.60(a)) • Supplies and reagents are not used in a manner consistent with manufacturer’s instructions (606.65(e))

  36. Personnel & Training • Personnel responsible for manufacturing steps performed on blood components do not have training and experience necessary to assure a thorough understanding and a competent performance of their assigned functions (606.20(b))

  37. Donor Management • Records not maintained for donor selection, including medical interview, examination and informed consent (606.160(b)(1)(i)) • Deferral records not maintained to ensure they contain current and accurate information (606.160(b)(1)(ii) & 606.160(e)) • Phlebotomy site was not prepared thoroughly and carefully by method that gives maximum assurance of sterile container of blood (640.4(f) & 640.64(e))

  38. Donor Management (cont.) • Donor previously deferred for positive infectious disease test was re-entered by method that was not acceptable to FDA (610.41(b)) • Donor deferred for positive infectious disease test was not notified of the supplemental test results (630.6(b)(3))

  39. Final Comments

  40. Reasons for Delays • Submission not adequate • Incomplete information • SOPs, labels need revisions • Center was not ready for inspection • Collection or manufacturing has not started • Internal pre-inspection audit identified significant issues that need correction • Form FDA-483 issued • Response to 483 observations delayed • Response to 483 observations incomplete

  41. Reduce Delays • Send in BLA or supplement after • Write SOPs • Train personnel • Begin operations • Ensure staff and operations are following SOPs and are in compliance with FDA requirements and your policies • Review submission before sending • Complete – includes all applicable elements and forms • Procedures consistent with regulations and other standards

  42. Reduce Delays (cont.) • If issued a Form FDA-483 • Follow corrective and preventative action procedures • Evaluate effectiveness of corrections • Provide a complete explanation of change • Include evidence of change and other supportive information • Provide data or information to support why no change was made • Call Blood and Plasma Branch CSOs with questions about submission, inspections and responses to 483 observations

  43. Blood and Plasma Inspections • Number of PLIs and PAIs conducted • 2007 – 29 • 2008 – 40 • 2009 (as of 9/1/09) – 30

  44. References

  45. CBER SOPPs • SOPP 8410: Determining When Pre-License/Pre-Approval Inspections are Necessary • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm073506.htm • SOPP 8103: Headquarters Contacts with Regulated Manufacturers during Agency Inspections • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm079461.htm

  46. CBER SOPPs (cont.) • SOPP 8505: Nomination and Approval of CBER Inspectors and Product Specialists Assigned to Conduct Inspections of Biological Products • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm073045.htm • SOPP 8407: Compliance Status Checks • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ProceduresSOPPs/ucm073498.htm

  47. Compliance Programs • 7342.001 – Inspection of Licensed and Unlicensed Blood Banks, Brokers, Reference Laboratories, and Contractors • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/CompliancePrograms/ucm095226.htm • 7342.002 – Inspection of Source Plasma Establishments, Brokers, Testing Laboratories, and Contractors • http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/ComplianceActivities/Enforcement/CompliancePrograms/ucm095234.htm

  48. ORA References • Compliance Policy Guidance Manual • Biologics - http://www.fda.gov/ICECI/ComplianceManuals/CompliancePolicyGuidanceManual/ucm116336.htm • Investigations Operations Manual • http://www.fda.gov/ICECI/Inspections/IOM/default.htm • FMD 86: Establishment Inspection Report Conclusions and Decisions • http://www.fda.gov/ICECI/Inspections/FieldManagementDirectives/ucm061430.htm • ORA considers documents on the ORA website to be the most current

  49. Contact Information • Blood and Plasma Branch CSOs • CBER mailing address Director, Division of Blood Applications, OBRR, CBER, FDA HFM-370 c/o Document Control Center, HFM-99 1401 Rockville Pike, Suite 200N Rockville, MD 20852-1448 • Telephone – (301) 827-3543 • Fax – (301) 827-3534

  50. FDA, Protecting Consumers, Promoting Public Health

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