Feature Story

FDA Tightens Rule, Targets Transfusion Services

April 2001
Katharine A. Downes, MD

The New Rule

Beginning next month, on May 7, licensed manufacturers, unlicensed registered blood establishments, and transfusion services will be required to report biological product deviations to the Food and Drug Administration if such a deviation occurred when the product was under their control and was subsequently distributed. The report must be filed as soon as possible but no later than 45 days from the date of discovery of the possible deviation.

"Biological product deviations," or BPD, formerly known as "errors and accidents," are "events which may affect the safety, purity, or potency of a distributed biological product and which represent either a deviation from current Good Manufacturing Practice (cGMP), applicable regulations, applicable standards, or established specifications, or are unforeseen or unexpected."

Although licensed manufacturers are now required to report to the FDA "errors and accidents in manufacturing that may affect the safety, purity, or potency of a product," (21 Code of Federal Regulations §600.14), transfusion services, to date, have reported such incidents only on a voluntary basis. Expansion of the reporting requirement to include unlicensed registered blood establishments and transfusion services appears to be driven by the FDA’s observation that product recalls by unlicensed blood establishments due to biological product deviations in manufacturing are not now being voluntarily reported to the FDA.

The complexities of this new reporting requirement specific to transfusion services are reviewed below.

New reporting requirement
The final rule for reporting BPD, published by the FDA in the Nov. 7, 2000 Federal Register, is an amendment of a current regulation (21 CFR §600.14) and the introduction of a new regulation (21 CFR §606.171). Code of Federal Regulations §600.14, formerly titled "Reporting of errors," has been replaced by a new regulatory section titled "Reporting of biological product deviations by licensed manufacturers." The manufacturer that holds the biological product license and has control of the product when the deviation occurs must report the biological product deviation under 21 CFR §600.14. Unlicensed registered blood establishments and transfusion services that had control of the product when the deviation occurred must report biological product deviations under the new section 21 CFR §606.171, titled "Reporting of product deviations by licensed manufacturers, unlicensed registered blood establishments and transfusion services."

Transfusion services must report any event and relevant information associated with the manufacturing (including testing, processing, packing, labeling, storage, and distribution) of licensed and unlicensed blood or blood components if the event represents a biological product deviation.

Under this rule, the entity (licensed manufacturers, unlicensed blood establishments, or transfusion services) that has control of a product when a deviation occurs is responsible for reporting to the FDA the biological product deviation, but only for products that have been distributed or released to patients. Control is defined in the final rule as being responsible "for maintaining the continued safety, purity, and potency of the product and for compliance with applicable product and establishment standards, and for compliance with cGMP."

When a product is distributed, released, or issued, it is no longer under the control of the transfusion service. The FDA elected to require deviation reporting only for released products because such deviations involve blood products that might be transfused to patients. These released products, therefore, present the greatest risk to public health. If a deviation is discovered but the blood product is still under the control of the transfusion service, the service does not need to file a biological product deviation report with the FDA. The transfusion service must, however, investigate and, if necessary, remedy the deviation as required by cGMP regulations that apply to transfusion services (§606.100[c], 21 CFR §606.100[c]).

Again, it is the responsibility of the establishment that has control of a product when a deviation occurs to report a BPD. For example, a hospital transfusion service pools 24 units of cryoprecipitate and then affixes an incorrect, extended expiration date to the pooled product. The product is then issued to a patient. The transfusion service would need to file a biological product deviation report with the FDA for the following reasons:

• The mislabeling of the product with an incorrect expiration date affects the safety, purity, and potency of the product.
• The pooled cryoprecipitate did not meet cGMP and was distributed to the patient.
• The transfusion service had control of the product when the deviation occurred and the product was released to the patient.

Even if the product was not transfused to the patient and was returned to the transfusion service and reprocessed and reworked and the date corrected, the transfusion service is still required to report the deviation to the FDA because the product was distributed with a deviation. If, however, the transfusion service issued a component irradiated by a blood manufacturer and subsequently was notified that the product was inadequately radiated, then the blood manufacturer would be responsible for filing the deviation report with the FDA.

Biological product deviation reports will be subject to public disclosure under the provisions of the 1966 Freedom of Information Act. The act established a presumption that records in the possession of agencies and departments of the executive branch of the U.S. government are accessible to the people. The act also set standards as to which records must be disclosed and which may be withheld from the public.

Prior to the act, it was up to an individual to establish a right to examine government records. Under the act, the burden of proof rests with the government, which must justify why it will not disclose certain documents. While deviation reports filed by a transfusion service will be subject to public disclosure under the act, the FDA "will appropriately purge all nondisclosable information prior to the release of the reports" (65[216] Federal Register 66624).

Implications for transfusion services
Transfusion services will have to prepare or revise their standard operating procedures to incorporate the specifics of the new BPD reporting requirement and then review the new or revised SOP with the staff who will file the deviation reports. Transfusion services will need to devote time to staff training and implementing the new SOP.

The FDA deviation report form asks for, but does not require, an establishment tracking number or internal tracking number for the deviation. Transfusion services now must comply with parts 606 and 640 (21CFR part 640), which require a transfusion service to keep "records of errors and accidents, transfusion reaction reports and complaints, with a record of investigation and follow-up." While the FDA does not require an internal or establishment tracking number on deviation reports, transfusion services without such a tracking system might consider developing one before May 7.

Filing a deviation report
To file a deviation report, transfusion services must use form FDA-3486, a standardized report form that one will be able to file by mail or electronically by May 7. As mentioned earlier, the reporting establishment must file the report as soon as possible but no later than 45 days from the date of discovery of information that reasonably suggests a reportable event occurred.

The biological product deviation report form seeks information about the reporting facility, biological product deviation, and unit or product. An establishment must include on form FDA-3486 the following information about the deviation: dates for the discovery and report of the deviation, a description of contributing factors or root cause analysis, and followup of the deviation. Transfusion services should not include in the narrative portion of the report donor, patient, or employee identification or other confidential information.

The FDA has developed a series of six-character codes to categorize deviations. The first two characters, which are letters, identify the system in which there was a failure that resulted in an unsuitable product being distributed. These codes are: DS-donor screening, PD-post donation information, DD-donor deferral, BC-blood collection, CP-component preparation, VT-viral testing, RT-routine testing, LA-labeling, QC-quality control and distribution, MI-miscellaneous.

The code topics consist of many deviations from standards, standard operating procedures, and regulations that may affect the safety, purity, or potency of a product. The FDAdeveloped these codes using previously submitted error and accident reports. The agency hopes that using BPD codes will streamline the process of analyzing deviation trends and facilitate data analysis.

Transfusion services must categorize a deviation by assigning a specific code to a reportable event when submitting the report to the FDA. (A complete list of codes can be found at www.fda.gov/cber.) Transfusion services, however, should not use the code topics to determine whether to report an event to the FDA. Transfusion services instead should have a process that determines which events are reportable and that is consistent with the regulation "Biological product deviation reporting for blood and plasma establishments."

A biological product deviation report should not be used to report fatalities associated with the collection or transfusion of blood products. Fatalities must be reported to the FDA in accordance with 21 CFR §606.170.

Transfusion-associated fatalities may be reported to the FDACenter for Biologics Evaluation and Research 24 hours per day, seven days per week via voice mail: 301-827-6220, e-mail: fatalities2@cber.fda.gov, or fax: 301-827-6748. Transfusing facilities must file a written report within seven days for fatalities (required by 21CFR §606.170[b]) and send the report to the Center for Biologics Evaluation and Research Director, Office of Compliance and Biologics Quality, Attn: Fatality Program Manager (HFM-650), 1401 Rockville Pike, Rockville, MD 20852-1448.

The most current information about the BPD requirement can be downloaded from the Web at www.fda.gov/cber/biodev/biodev.htm. The Web site offers a copy of the final rule, titled "Deviations in manufacturing; final rule 11/7/2000," the biological product deviation report form, and form instructions. Also available on the site are deviation codes, blood product codes, and nonblood product codes.

If you need additional information or have questions or concerns related to biological product deviation reporting, contact CBER/OCBQ Division of Inspections and Surveillance Program Surveillance Branch at 301-827-6220 or at bp_deviations@cber.fda.gov.

Dr. Downes is the transfusion medicine fellow at the program administered jointly by the American Red Cross, University Hospitals of Cleveland, and Cleveland (Ohio) Clinic Foundation. She is a member of the CAPTransfusion Medicine Resource Committee.