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 Inspection Procedures Pre-inspection, during inspection, post-inspection activities Common Observations Final Comments

Introduction to FDA Inspections

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)

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

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

Inspections in the CFR 600.20 – Inspectors 600.21 – Time of inspection 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

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

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

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

Blood and Plasma CSOs Review responsibilities Inspection training 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

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 We don’t inspect all PAS submissions. Pre-license inspections Blood Bank manufacturer - can be a new manufacturer or one previously operating as a unlicensed facility New Source Plasma manufacturer - all SP manufacturers are licensed Testing Laboratory - if applying for a license Pre-approval inspections Additional Source Plasma centers - to a licensed manufacturer Blood Product Irradiation - major manuf. change RBC Immunization - major manuf. change Contract Testing Laboratory - if not previously inspected. The regs allow for a contract test tab to only be registered and not licensed. Many of our b&p facilities have the testing done by an outside lab. If the lab is experience in performing donor testing and has an inspectional history, we will do a compliance check If the lab is not experience (ref. Lab) or there is no inspect history, the lab will be inspected as part of the applicant’s submission.

Inspection Procedures

PAI and PLI Procedures Pre-inspection During inspection Post-inspection Once the desk review is done, we prepare for the inspection. Our preparation methods are basically the same as DMPQ’s with some exceptions. Inspections conducted by B&P cadre who are also the reviewers. We only conduct PLI/PAI inspections (no biennial as lead or product specialist) when available), CBER is the lead and acts as the product specialist. Inspections last 1 to 3 days (do 1-3 facilities in a week) On limited basis – ORA has performed pre-approval inspections at CBER’s direction (not under pilot programs)

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

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

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

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

Scope of Inspections Systems-based Areas reviewed in each system 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

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)

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

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

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

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

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

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

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

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

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

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

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

Common Inspection Observations

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))

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))

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))

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))

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))

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))

Final Comments

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

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 In summary - B&P inspections are very similar to DMPQ inspections Planning, Conducting, Completing B&P review procedures are very similar to other product reviews Desk review, Inspection, CRL, Approval B&P personnel perform the full review (no team) and conduct the inspection as lead(no product specialist)

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

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

References

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

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

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

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 If you have any additional questions - you can reach us at… Or get in contact with me by e-mail Thank you for your time.

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

FDA, Protecting Consumers, Promoting Public Health