Biological Product Deviation Reports

Annual Summary for Fiscal Year 2007

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Table of Contents

1. Executive Summary:
2. BPD Reports Submitted By Blood And Plasma Establishments:
1. Reporting Issues
2. Most Frequent BPD Reports Submitted by Licensed Blood Establishments
3. Most Frequent BPD Reports Submitted by Unlicensed Blood Establishments
4. Most Frequent BPD Reports Submitted by Transfusion Services
5. Most Frequent BPD Reports Submitted by Licensed Plasma Centers
6. Timeliness of BPD Reports
3. BPD Reports Submitted by Manufacturers of Biological Products Other Than Blood and Blood Components (Non-Blood)

   1. Timeliness of BPD Reports

4. HCT/P Deviation Reports Submitted by Manufacturers of 361 HCT/Ps

   1. Timeliness of BPD Reports

5. Attachments
6. References

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I. Executive Summary:

Licensed manufacturers of blood and blood components, including Source Plasma; unlicensed registered blood establishments; and transfusion services who had control over the product when the deviation occurred must submit Biological Product Deviation (BPD) reports to the Center for Biologics Evaluation and Research (CBER) (21 CFR 606.171). Manufacturers of licensed biological products other than blood and blood components (non-blood) who hold the biological product license for and had control over the product when the deviation occurred are also required to submit BPD reports (21 CFR 600.14). In addition, manufacturers of Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/P) regulated under section 361 of the Public Health Service Act are required to submit deviation reports (21 CFR Part 1271.350(b)). Detailed information concerning deviation reporting is available at www.fda.gov/cber/biodev/biodev.htm.

From October 1, 2006 through September 30, 2007 (Fiscal Year 2007 or FY07), CBER's Office of Compliance and Biologics Quality/Division of Inspections and Surveillance entered 43,345 deviation reports into the BPD database:

• We received more than 43,345 reports, but did not capture data for reports that did not meet the reporting threshold. We notified the reporter that a report was not required.
• There was a 12% increase in the number of reports received in FY07 (FY06 - 38,618, FY07 - 43,345) {Table #2}.
  • We received 12% more reports from blood and plasma establishments in FY07 (FY06 - 38,188, FY07 - 42,830).
  • We received 27% more reports from traditional non-blood product manufacturers in FY07, however only 22 reports less than those received in FY05 (FY05 - 385, FY06 - 286, FY07 - 363).
  • We received 8 more reports from HCT/P manufacturers in FY07 (FY06 144, FY07 - 152)
• The number of reporting establishments increased by 6% (1,481 establishments in FY06 and 1,572 establishments in FY07) {Table #2}.
• Unregistered transfusion services typically report few BPDs (66% of those reporting in FY07 submitted 1 or 2 reports) and may file no reports in a given year. Only 13% of the transfusion services submitted more than five reports during FY07.
• The percentage of establishments reporting electronically increased by 5 percentage points (FY06 - 75% {1,118/1,481}, FY07 - 80% {1,256/1,572}. We continue to encourage electronic reporting.
• The reports submitted electronically increased by 19 percentage points (FY06 - 72% {27,701/38,618}, FY07 - 91% {39,270/43,345}) {Table #7}. There was an increase in the percentage of reports submitted electronically from licensed blood establishments (FY06 - 71%, FY07- 94%, and licensed plasma centers (FY06 - 61%, FY07 - 77%).
• Reports of post-donation information (PDI) continue to represent the largest subset of BPD reports submitted by blood and plasma establishments (70%) {Table #8}. Most often (88%), the collection facility becomes aware of disqualifying information during a subsequent donation interview {Table 10}. In 90% of the PDI reports, the donor was aware of the information, but the donor screening process failed to elicit the information {Table #11}. It is unclear why blood establishments are unable to elicit information during the first donor interview, but successfully elicit the information during a subsequent interview. It is clear that the most common PDI relates to travel (40%). Eliciting proper information regarding a donor candidate's travel history is apparently the most problematic part of the donor qualification process. We encourage blood establishments to review their donor screening processes to reduce the frequency of PDI reports. We also encourage those who implement successful strategies to share their information so that others may also fashion promising strategies to reduce PDI in their system.
• We sent 2,314 (5.3%) of the reports to FDA District Offices for follow-up/evaluation as potential recalls {Table #1}. The number of reports identified as potential recall situations increased 13% compared to FY06, but was similar to FY05 activity (FY05 - 2,271{5.9%}, FY06 - 2,046{5.3%}) {Table #2}. However, the percentage of the total reports that we identified as potential recall situations remained the same.
• Of the 2,269 reports blood and plasma establishments submitted, deviations and unexpected events that occur during the donor screening process continue to be the leading cause of potential recall situations (43%) {Table #9}.
• From the previous year, there was an 18% increase in the number of reports licensed blood establishments submitted and 63% increase in the number of reports licensed plasma centers submitted involving donor screening that were potential recall situations. The table below illustrates the most common potential recall reports. It does not include all donor screening reports.

	Licensed Blood Establishments		Licensed Plasma Centers
	FY06	FY07	FY06	FY07
Donor Screening (DS) - total	644	758	128	209
Donor didn't meet acceptance criteria (DS21)	64	26	16	78
Donor record incomplete or incorrect (DS22)	87	233	39	69
Donor gave info, not deferred (DS29)	472	460	47	31

• The number of reports involving traditional non-blood products that we sent to the FDA District Office for follow-up/evaluation as potential recall situations was approximately the same as the previous year (FY06 - 15, FY07 - 11).
• We sent 15 fewer reports involving HCT/Ps to the FDA District Office for follow-up/evaluation as potential recall situations (FY06 - 49, FY07 - 34).

• The number of reports blood and plasma establishments submitted in which they distributed a unit collected from a donor who subsequently tested confirmed positive for a viral marker (on a later donation) more than doubled from the previous year. The majority of this increase in reports involved donors who subsequently tested confirmed positive for Hepatitis B or Hepatitis C.

Some establishments misunderstood the requirement to report such events until the release of our final guidance in October 2006 (Ref. 1). Hence, some began reporting these events in May/June 2007 for the first time. Their data covered roughly half the fiscal year. The observed increase appears to be largely explained by the new reporting pattern¹. The shift warrants review by the industry, those with access to earlier information not reported to FDA, to assess if there is a genuine trend. We will continue to monitor for a possible trend in reports received by FDA. The table below does not include all lookback reports.

Reports Submitted by Blood and Plasma Establishments

	FY05			FY06			FY07
	Blood	Plasma	Total	Blood	Plasma	Total	Blood	Plasma	Total
Lookback; Subsequent unit confirmed positive (MI02) - total	431	64	495	510	98	608	721	646	1,367
HIV (MI0202)	84	8	92	88	13	99	120	81	210
HBV (MI0203)	34	16	50	96	23	90	163	171	344
HCV (MI0204)	293	40	333	309	63	372	315	393	708

• There was a 33% increase, from the previous year, in the number of reports licensed plasma centers submitted involving post donation information related to historic behavior. The table below does not include all post donation information reports.

Reports Submitted by Licensed Plasma Centers

	FY05	FY06	FY07	Percent Change
Post Donation Information; Behavior/History (PD12) - total	3,998	4,826	6,437	FY06 to FY07
Donor had history of male to male sex (PD1214)	42	76	116	↑53%
Donor incarcerated (PD1249)	331	392	551	↑41%
*Donor received tattoo and/or piercing	2,483	3,232	4,528	↑40%
Donor had history of IV drug use (PD1216)	98	116	149	↑28%
Donor traveled to vCJD risk area (PD1242)	244	237	199	↓16%

*includes PD1224, PD1225, PD1226, and PD1231

• The number of reports licensed blood establishments submitted involving donor deferral increased 4fold from the previous year. One firm merged their deferral databases due to reorganizing some functions and identified problems with the deferral process and methods for capturing donors in the deferral file to prevent further donations. This contributed to the increase in reports. These reports identified donors who were either missing or incorrectly identified in the deferral file. The table below does not include all donor deferral reports.
• The number of reports in which the donor should have been deferred due to testing increased from 18 to 40 reports.
• The number of reports in which the donor should have been deferred due to an unacceptable history or behavior increased from 22 to 135 reports.

Reports Submitted by Licensed Blood Establishments

	FY05	FY06	FY07
Donor Deferral (DD) - total	49	47	194
Donor missing or incorrectly identified on deferral list, should have been deferred due to testing (DD31)	10	18	40
Donor missing or incorrectly identified on deferral list, should have been deferred due to history (DD32)	22	22	135

• Allergenic manufacturers submitted 25 more reports in FY07 (FY06 - 149, FY07 - 174). Most of these reports involved product specifications not met - contains precipitate.
• Blood Derivative manufacturers submitted 24 more reports in FY07 (FY06 - 35, FY07 - 59). Most of these reports involved product label incorrect or missing and events associated with process controls.
• Vaccine manufacturers submitted 19 more reports in FY07 (FY06 - 41, FY07 - 60). Most of these reports involved product specifications not met for appearance and stability testing failed.
• Cellular HCT/P manufacturers submitted 33 more reports in FY07 (FY06 -74, FY07 - 107). Most of these reports involved donor testing in which samples used for testing were pooled samples instead of individual samples.
• Non-cellular HCT/P manufacturers submitted 25 fewer reports in FY07 (FY06 -70, FY07 - 45). They submitted fewer reports involving donor eligibility, donor screening and donor testing.
• Manufacturers must submit deviation reports within 45 calendar days of the date of discovery of the reportable event. In FY07, manufacturers submitted 91% of the blood BPD reports, 73% of the non-blood BPD reports, and 75% of the HCT/P deviation reports within 45 days {Tables #27, #30, and #33}. FDA investigators review reporting practices during establishment inspections, and we continue to publicize reporting requirements through professional meetings.

You may submit questions concerning this summary to:

FDA/Center for Biologics Evaluation and Research
Office of Compliance and Biologics Quality
Division of Inspections and Surveillance (HFM650)
1401 Rockville Pike, Suite 200 North
Rockville , Maryland 20852-1448

You may also contact us by email at bp_deviations@fda.hhs.gov, hctp_deviations@fda.hhs.gov, or sharon.ocallaghan@fda.hhs.gov (Sharon O'Callaghan) or by phone at (301) 827 - 6220.

Footnotes

¹Personal communication with industry representatives.

• The number of reports licensed blood establishments submitted involving donor deferral increased 4fold from the previous year. One firm merged their deferral databases due to reorganizing some functions and identified problems with the deferral process and methods for capturing donors in the deferral file to prevent further donations. This contributed to the increase in reports. These reports identified donors who were either missing or incorrectly identified in the deferral file. The table below does not include all donor deferral reports.
• The number of reports in which the donor should have been deferred due to testing increased from 18 to 40 reports.
• The number of reports in which the donor should have been deferred due to an unacceptable history or behavior increased from 22 to 135 reports.

Reports Submitted by Licensed Blood Establishments

• Allergenic manufacturers submitted 25 more reports in FY07 (FY06 - 149, FY07 - 174). Most of these reports involved product specifications not met - contains precipitate.
• Blood Derivative manufacturers submitted 24 more reports in FY07 (FY06 - 35, FY07 - 59). Most of these reports involved product label incorrect or missing and events associated with process controls.
• Vaccine manufacturers submitted 19 more reports in FY07 (FY06 - 41, FY07 - 60). Most of these reports involved product specifications not met for appearance and stability testing failed.
• Cellular HCT/P manufacturers submitted 33 more reports in FY07 (FY06 -74, FY07 - 107). Most of these reports involved donor testing in which samples used for testing were pooled samples instead of individual samples.
• Non-cellular HCT/P manufacturers submitted 25 fewer reports in FY07 (FY06 -70, FY07 - 45). They submitted fewer reports involving donor eligibility, donor screening and donor testing.
• Manufacturers must submit deviation reports within 45 calendar days of the date of discovery of the reportable event. In FY07, manufacturers submitted 91% of the blood BPD reports, 73% of the non-blood BPD reports, and 75% of the HCT/P deviation reports within 45 days {Tables #27, #30, and #33}. FDA investigators review reporting practices during establishment inspections, and we continue to publicize reporting requirements through professional meetings.

You may submit questions concerning this summary to:

FDA/Center for Biologics Evaluation and Research
Office of Compliance and Biologics Quality
Division of Inspections and Surveillance (HFM650)
1401 Rockville Pike, Suite 200 North
Rockville , Maryland 20852-1448

You may also contact us by email at bp_deviations@fda.hhs.gov, hctp_deviations@fda.hhs.gov, or sharon.ocallaghan@fda.hhs.gov (Sharon O'Callaghan) or by phone at (301) 827-6220.

Total Deviation Reports

FY07

Table 1

¹Unlicensed Blood Establishments - unlicensed blood establishments performing manufacturing of blood and blood components that require registration with FDA

²Transfusion Services - blood banks that perform limited blood and blood component manufacturing (e.g. pooling, thawing, compatibility testing), may or may not register with FDA. Generally, we do not classify events reported by transfusion services as recalls because they distribute products within their own facility. In FY07, there was one report submitted by a transfusion service that we identified as a potential recall situation because the transfusion service distributed the product to another facility.

*Number of license holders; one or more establishments operate under one biologics license.

Total Deviation Reports

FY05 - FY07

Table 2

*Number of license holders; one or more establishments operate under one biologics license.

†Reports of events involving products manufactured on or after 5/25/05 {implementation of 21 CFR 1271.350(b)}

Blood & Plasma BPD Reports By Manufacturing System

FY05 - FY07

Table 3

Non-Blood Deviation Reports By Manufacturing System

FY05 - FY07

Licensed Biological Products Other Than Blood and Blood Components

Table 4

Table 4 (continued)

361 HCT/Ps

Table 5

Manufacturing System	Cellular HCT/Ps			Non-Cellular HCT/Ps			Total
	FY05 †	FY06	FY07	FY05 †	FY06	FY07	FY05 †	FY06	FY07
Donor Eligibility	3	2	3	5	30	21	8	32	24
Donor Screening	0	0	0	0	12	8	0	12	8
Donor Testing	0	27	50	0	8	4	0	35	54
Environmental Control	0	0	2	0	1	0	0	1	2
Supplies and Reagents	0	2	5	0	1	1	0	3	6
Recovery	0	2	7	0	0	1	0	2	8
Processing & Processing Controls	0	11	15	0	3	2	0	14	17
Labeling Controls	0	0	0	1	1	1	1	1	1
Storage	0	0	0	0	1	0	0	1	0
Receipt, Pre-Distrib., Shipment & Distrib.	4	30	25	0	13	7	4	43	32
Total	7	74	107	6	70	45	13	144	152

† Reports of events involving products manufactured on or after 5/25/05 (implementation of 21 CFR 1271.350(b))

We implemented the online electronic deviation report form on June 18, 2001. In FY07, 80% of all the facilities filing reports filed at least some reports electronically. The portion of all reports submitted electronically in FY07 increased by 18.9 percentage points from the previous year (FY06 71.7%). We continue to encourage all reporters to use the electronic reporting format.

Deviation Reports Submitted Electronically

Table 6

	#Reporting Est.	Total Reports	# of eBPDR	% eBPDR
Blood/Plasma Manufacturers
Licensed Blood Establishments	214 (91%)	29,356	27,682	94.3%
Unlicensed Blood Establishments	339 (85%)	3,914	3,668	93.7%
Transfusion Services	388 (77%)	1,797	1,586	88.3%
Licensed Plasma Centers	226 (75%)	7,763	5,983	77.1%
Sub-Total	1,167 (81%)	42,830	38,919	90.9%
Non-Blood Manufacturers
Allergenic	7 (100%)	174	151	86.8%
Blood Derivative	10 (63%)	59	33	55.9%
In Vitro Diagnostic	5 (63%)	69	42	60.9%
Vaccine	4 (31%)	60	7	11.7%
351 HCT/P	0	1	0	0.0%
Sub-Total	26 (58%)	363	233	64.2%
361 HCT/P Manufacturers
Cellular HCT/P	43 (73%)	107	86	80.4%
Non-Cellular HCT/P	20 (71%)	45	32	71.1%
Sub-Total	63 (72%)	152	118	77.6%
Total	1,256 (80%)	43,345	39,270	90.6%

Percent of Electronic Deviation Reports

Table 7

† Reports of events involving products manufactured on or after 5/25/05 {implementation of 21 CFR 1271.350(b)}

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II. BPD Reports Submitted By Blood And Plasma Establishments:

Total BPDRs By Manufacturing System

Table 8

• DS - Donor Suitability
• LT - Laboratory Testing
• NA - Not applicable : manufacturing not performed in transfusion service

Potential Recalls By Manufacturing System

Table 9

• DS - Donor Suitability
• LT - Laboratory Testing
• NA - Not applicable: manufacturing not performed in transfusion service

Post donation information (PDI) continues to be the most frequently reported event associated with the manufacturing of blood and plasma products. The most common PDI involved donors providing information concerning travel to malarial endemic areas and travel to an area at potential risk for vCJD. It is unclear why blood establishments are unable to elicit information during the first donor interview, but successfully elicit the information during a subsequent interview. Eliciting proper information regarding a donor candidate's travel history is apparently the most problematic part of the donor qualification process.

We encourage blood establishments to review their donor screening processes to reduce the frequency of PDI reports. We also encourage those who implement successful strategies to share their information so that others may also fashion promising strategies to reduce PDI in their system.

FY07 Reports of Post Donation Information (PDI)

Table 10

Table 11

* Known, e.g., travel outside of U.S., tattoo or body piercing, history of disease, male to male sexual contact, medication

**Not known, e.g., post donation illness, sex partner participated in high risk behavior or tested positive

A. Reporting Issues

In an effort to provide practical and useful information regarding reporting deviations, this section addresses non-reportable events, deviation code selection and product information entry.

Non-Reportable Events

Blood establishments submitted most of the non-reportable reports. The reports did not meet the reporting threshold because the events were either not associated with manufacturing, did not affect the safety, purity or potency of the product, or did not involve distributed products. Examples of non-reportable events include:

• Establishment distributed product collected from a donor who provided post donation information of cold or flu symptoms.
• Establishment distributed product collected from a donor who did not meet suitability criteria related to donor safety only, such as donor's weight, age, donating within 56 days of last donation, or more than 24 pheresis donations within 12 months.
• Establishment distributed product labeled with a shortened expiration date. This includes associated labeling, such as crossmatch tag or transfusion record.
• Hospital staff transfused the wrong patient, transfused the wrong product to a patient, or requested the wrong product from blood bank. Hospital staff errors are not associated with manufacturing.
• Establishment distributed an allogeneic unit when an autologous or directed unit was available.
• Recipient had a transfusion reaction unrelated to an event in manufacturing, such as Transfusion Related Acute Lung Injury (TRALI).
• Establishment distributed products collected from a donor who tested negative on all required assays. The donor then returned and tested reactive or repeat reactive, but not confirmed positive for a viral marker (HIV, HBV or HCV) for which we require or recommend product quarantine or consignee notification (i.e., lookback).
• ABO/Rh and/or antibody screen incorrectly performed on patient, but there were no products distributed based on the incorrect testing.

Deviation Code (BPD Code) Selection

In some cases, the establishment selected the incorrect deviation code to capture the event. When the wrong code is used, our reviewers notify the reporter and enter using the proper code. The most common errors in coding were:

• Donor Screening (DS) vs. Post Donation Information (PD)
  • If the blood establishment does not know the disqualifying information at the time of donation, the event is considered post donation information. If the establishment knows the disqualifying information or the information is available, but does not appropriately defer the donor, the event is a donor screening deviation.
• Routine Testing (RT) vs. Quality Control & Distribution (QC)
  • A patient had a history of an antibody and the blood bank did not screen the unit for the corresponding antigen. The appropriate deviation code is QC9311 (Required testing not performed or documented for: antigen screen), not RT6106 (Testing performed, interpreted, or documented incorrectly for: antigen typing).
  • If compatibility testing is performed incorrectly, (e.g., immediate spin or electronic crossmatch performed instead of full crossmatch), the appropriate deviation code is RT6108 (Testing performed, interpreted, or documented incorrectly for: compatibility testing).
• Blood Collection (BC) vs. Quality Control & Distribution (QC)
  • A blood establishment distributed a unit that was subsequently found to be clotted. The appropriate deviation code is BC4305.
  • A blood establishment discovers a clotted component prior to distribution and discards the product. If any associated products, such as FFP or Platelets, were distributed and determined to be potentially affected, the appropriate deviation code is QC9409.
• Bacterial Detection Testing
  • All events associated with bacterial detection testing should be coded as QC & Distribution; Distribution of product that did not meet specifications; Product with unacceptable (e.g., positive), undocumented, or incomplete product QC (QC9404).
• QC9713 - QC & Distribution; Distribution procedure not performed in accordance with blood bank transfusion service's specifications; Procedure for issuing not performed or documented in accordance with specifications.
  • Do not use QC9713 to report an event associated with not issuing a product appropriately if another deviation code is more specific to the actual event.
    • If the product is issued without identifying that the recipient identification is incorrect or missing, the deviation code should be LA8207, Labeling; Crossmatch tag or tie tag incorrect or missing information; Recipient identification incorrect or missing.
    • If the blood bank does not issue, or incorrectly issues, the product through the computer system and this is the only method of documenting the visual and clerical checks at time of issue, the deviation code should be QC9719, Product not documented or incorrectly documented as issued in the computer.

Product Information

When blood establishments report deviations associated with the distribution of non-blood products, (e.g., Rh Immune Globulin, factor concentrates), the blood deviation codes appropriate for the event should be selected. The product code should be DB00 (Other), and the report should include a description of the specific product.

B. Most Frequent BPD Reports Submitted by Licensed Blood Establishments

Of the 29,356 reports submitted by licensed blood establishments, 22,856 (77.9%) reports involved post donation information.

• The number of these reports increased by 4% (FY06 - 21,954).
• The number of reports in which a donor subsequently provided information regarding travel to a CJD risk area decreased by 16% (FY06 - 4,752).
• The number of reports in which a male donor subsequently provided information of a history of sex with another male increased by 12% (FY06 - 732).
• The number of reports in which a donor subsequently provided information regarding travel to a malaria risk area increased by 7% (FY06 - 7,018).

Most Frequent BPD Reports Post Donation Information

From Licensed Blood Establishments

Table 12

*Includes: tested positive for viral marker either prior to or post donation

Of the 29,356 reports submitted by licensed blood establishments, 1,837 (6.3%) reports involved quality control and distribution deviations and unexpected events.

• The number of these reports increased by 20% (FY06 - 1,534).
• The number of reports involving the release of a product with unacceptable, undocumented, or incomplete product QC increased 24% (FY06 643).
  • There was an increase of 22% (FY06 - 412) in reports specifically related to bacterial detection testing used as a quality control test. The industry implemented a standard for bacterial detection testing in March 2004.
  • There was an increase of 88% (FY06 - 43) in reports involving QC testing for white blood cell count.

Most Frequent BPD Reports Quality Control & Distribution

From Licensed Blood Establishments

Table 13

Of the 29,356 reports submitted by licensed blood establishments, 1,584 (5.4%) reports involved donor screening deviations and unexpected events.

• The number of these reports increased by 33% (FY06 1,189).

• There was a 67% increase in reports involving donor records, which were incomplete, incorrect or not reviewed (FY06 - 263). There was an 82% increase in reports related to the donor history questions (FY06 - 192).
• There was a 74% increase in reports in which the screener did not check the deferral file, i.e., deferral screening not done, or the screener used incorrect donor identification to check the deferral file or (FY06 - 189).

Most Frequent BPD Reports Donor Screening

From Licensed Blood Establishments

Table 14