Presented by Karen Dosanjh Quality Director Blood Systems The ABCs of BPDs

Disclosure I have no relevant financial relationships to disclose.

Learning Objectives Describe a scenarios that would be reportable as a BPD. Recognize when patient lookback is required. Apply root cause analysis tools to process improvement.

FDA Guidance: BPD Reporting for Blood and Plasma Establishments Who Must Report? All establishments involved in the manufacture of blood and blood components, including: -licensed manufacturers, -unlicensed registered establishments, -transfusion services. licensed manufacturers of blood and blood components, including Source Plasma; unlicensed registered blood establishments; and transfusion services.

FDA Guidance: BPD Reporting for Blood and Plasma Establishments Who Must Report? Per 21 CFR 606.171,  the manufacturer that had control over the product when the deviation from current good manufacturing practice, applicable regulations, applicable standards, or established specifications or an unexpected or unforeseeable event that may affect the safety, purity, or potency… We define "control" in 21 CFR 606.3(l ) as having responsibility for maintaining the continued safety, purity and potency of the product and for compliance with applicable product and establishment standards, and for compliance with current good manufacturing practice (CGMP).

FDA Guidance: BPD Reporting for Blood and Plasma Establishments Who Must Report? Contract Manufacturing: Viral Marker or Compatibility Testing Irradiation Blood Collection Storage Distribution Occasionally, a blood establishment establishes a contract with another entity to perform some or all of the manufacture of a product. If you contract out any manufacturing step, for the purposes of 21 CFR 606.171(a), that step is performed under your control. Under the CFR, you must establish, maintain, and follow a procedure for receiving information from that contract manufacturing facility on all deviations, complaints, and adverse events that may affect your products.

FDA Guidance: BPD Reporting for Blood and Plasma Establishments What Must Be Reported? Event Represents a deviation from current good manufacturing practice, applicable regulations, applicable standards, or established specifications that may affect the safety, purity, or potency of that product; or Represents an unexpected or unforeseeable event that may affect the safety, purity, or potency of that product; Occurs in your facility or a facility under contract with you; Involves a distributed blood or blood component. Deviation could be an unacceptable thawing temperature when preparing a special order component. Deviation could be out of range mini physical value for hematocrit or temperature. Unexpected or unforeseeable event could be Post Donation Information, or sample collection error for a sample that was used to perform compatibility testing, or faulty supply reported by the supply vendor that could not be detected by incoming supplies qualification process.

FDA Guidance: BPD Reporting for Blood and Plasma Establishments Flow Chart Questions (1) Was the event associated with “manufacturing” or holding or distribution as they are described in the regulation? (2a) Was there a deviation that may affect the safety, purity, or potency of a product? (2b) Was there an unexpected or unforeseeable event that may affect the safety, purity, or potency of a product? (3) Did it occur in your facility or in a facility under contract with you? (4) Did you have control over the product when the event occurred? (5) Was the product distributed? These are questions that correspond to a BPD flow chart in the guidance for blood establishments to aid in the determination of reportability.

FDA Guidance: BPD Reporting for Blood and Plasma Establishments Items of significance in the guidance (PDI): Report post donation information if you would have deferred the donor had you known the information at the time of donation and the safety, purity, or potency of the product could be affected. PDI is also reportable if the medical evaluation reasonably suggests that the safety, purity, or potency of the product could be affected , or the information is insufficient to conclude that the safety, purity, or potency of the product is not affected. These are questions that correspond to a BPD flow chart in the guidance for blood establishments to aid in the determination of reportability.

FDA Guidance: BPD Reporting for Blood and Plasma Establishments What Is NOT Reported? When you did not distribute potentially affected products, regardless of the event. When you determined, prior to distributing the product, that the event did not actually affect the safety, purity, or potency of the product. When you detected the event and prior to distribution, made the appropriate corrections. When the event was related to donor safety only and did not have the potential to affect the safety, purity, or potency of the product. If your report would simply state that you were late in reporting the event to us. Also not reportable are donor conditions that CBER has determined do not affect SPP is (e.g. – Cancer, Multiple Sclerosis, Lupus, Endoscopy, etc.) Some of these conditions are indicated in the guidance document. While the above examples would not be reportable under 21 CFR 606.171, the events may constitute deviations from the regulations, which we would assess during inspection.

Error Examples – Reportable or Not Reportable?

Error Examples – Reportable or Not Reportable?

PDI Examples – Reportable or Not Reportable?

PDI Examples – Reportable or Not Reportable?

PDI Examples – Reportable or Not Reportable?

PDI Examples – Reportable or Not Reportable?

Lookback per 21 CFR 610 Initially reactive viral marker test results require donor lookback. (NR) Confirmed positive viral marker test results for HCV and HIV also require patient lookback. (RE) NAT reactive test results for HCV and HIV require donor and patient lookback. (RE) NAT reactive test results for other infectious diseases may require donor and patient lookback. (RE) Under 21 CFR 610.46, 610.47, and 610.48, you must perform lookback for HIV-1 and/or HCV. Initially reactive test results are not reportable in and of themselves – do not require BPD Reporting. Confirmed positive viral marker test results ARE reportable to the FDA – do require BPD Reporting. NAT reactive test results ARE reportable for repeat donors – do require BPD Reporting.

FDA Guidance: BPD Reporting for Blood and Plasma Establishments What Must Be Reported? Facility information Date of Discovery BPD Reporting Code Description of the event Investigation/RCA findings and Corrective Actions Only distributed components from the impacted or affected donation(s). BPD Reporting to the FDA must occur as soon as possible but no later than 45 days from the date of discovery. Event specific coding – by process: Donor Suitability - PDI Donor Suitability - Donor Screening and Deferral Collection Component Preparation Testing Labeling Quality Control & Distribution Clear and concise description of the event with pertinent dates. Investigation/RCA findings – Requirements for reportable deviations indicate that you must evaluate and investigate, as appropriate, unexplained discrepancies and failures to meet specifications, and to maintain complaint records, including records of investigations and follow-up (21 CFR 606.100, 211.192 and 211.198). We recommend that your procedures for the investigation of any unexplained discrepancy or the failure of a lot or unit to meet any of its specifications include provisions for: a timely investigation; an appropriate corrective action plan to prevent recurrence; procedures to gain control of unsuitable products in a timely manner; appropriate disposition of all affected products (in-date and expired); for deviations and discrepancies associated with donor suitability, an assessment of the donor's suitability to serve as a donor in the future. If you have a concurrent Red Cell and Plasma product from the impacted donation, and only the Red Cell shipped, that is the only component that must be reported in the BPD report.

FDA Guidance: BPD Reporting for Blood and Plasma Establishments BPD Reporting Codes Donor Suitability – PDI Donor Suitability – Donor Screening and Deferral Collection Component Preparation Testing Labeling Quality Control & Distribution Event specific coding – by process: Donor Suitability - PDI Donor Suitability - Donor Screening and Deferral Collection Component Preparation Testing Labeling Quality Control & Distribution There is also one other category named Miscellaneous, which captures confirmed positive viral market tests which are reportable, including NAT.

BPD Reporting Codes – Which Code Fits Best? On a subsequent visit, a donor reported using needles to take drugs not prescribed by their physician 3 years ago. During the same visit, the donor reported having had a tattoo prior to his last donation. PD-12-16 IV Drug Use Not Prescribed by a Doctor PD-12-53 Multiple High Risk Behaviors/Contact The correct BPD Reporting Code is PD-12-53. Two high risk events indicated here, one requiring only temporary deferral and the other requiring indefinite deferral. This BPD was originally coded with the event resulting in the indefinite deferral, however the correct code is for multiple high risk behaviors regardless of deferral length.

BPD Reporting Codes – Which Code Fits Best? An underweight FFP product was received in the manufacturing lab for quarantine and subsequently discarded. During the investigation, it was determined that the apheresis kit may have been prematurely raised resulting in a changed collection status from a closed system to an open system. Companion platelet products had shipped prior to discovery of the information with a 5 day expiration date, and not the 24 hour open system expiration date. QC-94-12 Product identified as unsuitable due to a collection deviation or unexpected event LA-81-06 Expiration date or time extended or missing The correct BPD Reporting Code is QC-94-12 Product identified as unsuitable due to a collection deviation or unexpected event (event discovered prior to distribution, but failed to quarantine product; includes collection time extended, discrepant, or not documented, potential air contamination, unit or associated unit was clotted or hemolyzed). The expiration date was not necessarily extended, the deviation that occurred during product collection resulted in an unsuitably labeled product.

BPD Reporting Codes – Which Code Fits Best? A red blood cell product was returned by a consignee because the product was labeled as A negative and the consignee typed the product as A positive. Reference Laboratory testing resulted in a typing of A positive, supporting a partial D antigen. This is a known limitation of the commercial reagents currently available. LA-81-02 ABO and/or Rh incorrect or missing RT-61-04 Testing performed, interpreted, or documented incorrectly – ABO and/or Rh The correct BPD Reporting Code is RT-61-04 Since this is an unexpected testing error that caused the labeling error, the event would be captured as RT-61-04.

BPD Reporting Codes – Which Code Fits Best? On a subsequent visit, Collection staff discovered that a male donor who presented and donated at 3 prior visits had the incorrect sex identified in the donor identification profile in the BECS. As a result, the electronic donor questionnaire launched to the donor on each of these previous visits excluded the male gender questions (unanswered). DS-22-02 Donor record incomplete or incorrect – Donor identification DS-22-03 Donor record incomplete or incorrect - Donor history questions The correct BPD Reporting Code is DS-22-03 Donor record incomplete or incorrect – Donor history questions. This code includes the abbreviated questionnaire used instead of the full-length questionnaire; response to educational materials/AIDs questions not documented; incorrect gender specific questions asked.

Investigation/Root Cause Analysis and Corrective Action Investigation and root cause analysis of an unexplained discrepancy or failure of a lot of unit to meet specification must be robust. Determination of the root cause may be achieved through the use of a root cause analysis tool. Investigation/RCA findings – Requirements for reportable deviations indicate that you must evaluate and investigate, as appropriate, unexplained discrepancies and failures to meet specifications, and to maintain complaint records, including records of investigations and follow-up (21 CFR 606.100, 211.192 and 211.198). We recommend that your procedures for the investigation of any unexplained discrepancy or the failure of a lot or unit to meet any of its specifications include provisions for: a timely investigation; an appropriate corrective action plan to prevent recurrence; procedures to gain control of unsuitable products in a timely manner; appropriate disposition of all affected products (in-date and expired); for deviations and discrepancies associated with donor suitability, an assessment of the donor's suitability to serve as a donor in the future.

Root Cause The root cause of an event is the most basic cause from which the event, desirable or undesirable, originates from.

Root Cause Analysis Tools 5 Whys Cause and Effect Diagram Ishikawa (Fishbone) Diagram Flowcharts Pareto Charts Histograms

Root Cause Analysis Do’s and Don’ts Don’t use judgments. Don’t state your opinion. Don’t state your emotions. DO visualize the problem using tools. DO consider the data you will need to collect. DO think about the past: Has this happened before? What was done in the past? DO analyze the data objectively. DO implement process improvement & prevention.

Questions? Kdosanjh@bloodsystems.org Reference: FDA Guidance for Industry: Biological Product Deviation Reporting for Blood and Plasma Establishments, dated October 2006