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

8. Inspections in the CFR (cont.)
– 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 – )
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 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

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
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.

13. Inspection Procedures

14. 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)

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 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 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

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 , CPG )
FDA cannot review reports of periodic audits
FDA can review records required to be maintained under 211s, and 606s (FD&C Act)
(b), (a), – SOP deviations must be recorded and justified
(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 ( )
Office of Blood Research and Review, CBER ( )
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 ( (b))
Manufacturing records are either not reviewed to identify discrepancies or a thorough investigation, including conclusions and follow-up was not made and recorded ( (c))

34. Records
Records not maintained concurrently with performance of each significant step so that steps can be clearly traced ( (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 ( (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 ( (b)(1)(i))
Deferral records not maintained to ensure they contain current and accurate information ( (b)(1)(ii) & (e))
Phlebotomy site was not prepared thoroughly and carefully by method that gives maximum assurance of sterile container of blood (640.4(f) & (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
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)

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
SOPP 8103: Headquarters Contacts with Regulated Manufacturers during Agency Inspections

46. CBER SOPPs (cont.)
SOPP 8505: Nomination and Approval of CBER Inspectors and Product Specialists Assigned to Conduct Inspections of Biological Products
SOPP 8407: Compliance Status Checks

47. Compliance Programs
– Inspection of Licensed and Unlicensed Blood Banks, Brokers, Reference Laboratories, and Contractors
– Inspection of Source Plasma Establishments, Brokers, Testing Laboratories, and Contractors

48. ORA References Compliance Policy Guidance Manual
Biologics -
Investigations Operations Manual
FMD 86: Establishment Inspection Report Conclusions and Decisions
ORA considers documents on the ORA website to be the most current
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Thank you for your time.

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
Telephone – (301)
Fax – (301)

50. FDA, Protecting Consumers, Promoting Public Health