1. CBER Common Problems on Source Plasma Inspections Judy Ellen Ciaraldi BS, MT(ASCP)SBB, CQA(ASQ) CBER, OBRR, DBA September 16, 2009

2. CBER 2 Outline Common Inspection Observations – SOPs – Records – Personnel – QA Oversight Impact of Inspection Problems – Approvals – Manufacturing Compliance Final Comments

3. CBER Common Inspection Observations

4. CBER 4 Importance of SOPs Describe best techniques, procedures and policies for manufacturing product Effectively communicate management’s expectation of employees’ performance of established procedures Available as reference for less experienced employees Should be readily available and presented in a manner that is easily understood 43 FR 45016, 9/29/78

5. CBER 5 SOPs Observations Center personnel do not always follow written SOPs for the manufacture of blood components for further manufacturing - examples – Donor screening and medical staff accept unsuitable donor – Physician substitute does not explain all hazards of collection or immunization – Donor personnel do not use screening equipment as directed in operator’s manual – Phlebotomists do not prepare venipuncture site properly – Donors collected at greater volume than allowed by nomogram – Donor reactions not properly followed-up

6. CBER 6 Importance of Records Describe how product was manufactured Record the history in order to allow for a meaningful review Identify who performed steps in order to identify deficiencies and substandard practices that need to be corrected Reviewed to ensure manufacturing was performed according to SOPs 40 FR 53539, 11/18/75

7. CBER 7 Records Observations Documentation is not always as detailed as necessary to provide a complete history of the work performed – examples – Not identify person performing test and date performed – Missing test results or interpretation – Missing donor’s responses to questions – Do not contain critical timeframes for procedures – Equipment maintenance missing – No evidence that records were reviewed to identify deficiencies

8. CBER 8 Personnel Training Personnel should have sufficient mix of training, education and experience to perform the job adequately Training must be done on a continuing basis; single training at hire with no subsequent training is not sufficient Personnel must remain familiar with cGMP requirements Training requirement also applies to supervisors 43 FR 45035, 9/29/78

9. CBER 9 Personnel Observations Personnel responsible for manufacturing steps performed on blood components do not have training and experience necessary to assure a thorough understanding and competent performance of their assigned functions – examples – Quality staff do not identify discrepancies – Medical director approved larger IRBC dose – Donor screeners do not perform proper arm check – Staff in all areas do not follow SOPs – Performance evaluation checklists do not include all critical steps

10. CBER 10 QA Oversight Assure appropriate actions were implemented and completed satisfactorily Ensure controls were implemented during manufacturing to assure product quality Review results to assure product quality standards were met Prevent release of unacceptable product QA responsibilities must be described in writing 43 FR 45032, 9/29/78

11. CBER 11 QA Observations Quality review of records do not detect all incidents of missing or incorrect information to ensure records contain a complete and accurate history and are consistent with SOPs – examples – Records show that errors remain undetected despite several layers of review – Thorough investigation, including conclusions and follow- up not done and recorded – Equipment used without appropriate quality control – Unsuitable donors continue to donate – Unacceptable employee performance not detected or corrected

12. CBER 12 Other Inspection Problems Incomplete SOPs – examples – Do not contain procedures for proper documentation – Do not contain actions to take for unacceptable or unexpected results or performance Requested information not provided to inspector in timely manner – Was record not created? – Was record unacceptable? – Was record misfiled? – Prohibits inspector from conducting effective inspection

13. CBER Impact of Inspection Problems

14. CBER 14 Approvals take longer Approvals are delayed when Form FDA-483 is issued after pre-approval/pre-license inspection Inspections for BLAs and supplements require written response to 483 observations – Inspections are a continuation of desk review – Response needed to complete review – Complete response may eliminate need to conduct another inspection of the center (re-inspection)

15. CBER 15 Approvals take longer (cont.) In order to respond completely, you must provide evidence that your manufacturing operations are consistent with cGMPs (601.2) – Investigate the deficiency, make corrections and submit evidence of corrective actions – Compile and submit information not available during inspection – Compile and submit supportive data to explain why there was no corrective action CSO inspectors review responses to 483 observations – CSO inspectors communicate with applicant if responses are incomplete or not clear

16. CBER 16 Manufacturing not in compliance Unsuitable donors are donating Donor’s safety is affected Unacceptable product is collected Unacceptable product will be distributed Recipient’s treatment and safety could be affected – Product that is not safe, pure or potent may not effectively treat patient and could harm patient Re-inspection may be necessary for violative observations

17. CBER 17 Final Comments During inspections, FDA will identify deficiencies in manufacturing FDA cannot be your consultant and tell you specifically how to correct problems, but.. FDA will explain the concern about the deficiencies FDA will explain FDA regulations and policies FDA wants you to be in compliance

18. CBER 18 Final Comments (cont.) Ensure your operations are in compliance before you submit the BLA or supplement and continue to ensure this both before and after the inspection Problems are rarely isolated incidents – Activities in plasma center are interrelated – All areas in the center contribute to the problem – Investigations and corrective actions should include all areas You are ultimately responsible for the compliance of the manufacturing operations at the center