Transfusion medicine

Quality and compliance

Biological product deviation



Last author update: 29 November 2023
Last staff update: 29 November 2023

Copyright: 2022-2024, PathologyOutlines.com, Inc.

PubMed Search: Biological / blood product deviation

Chinelo P. Onyenekwu, M.D.
Melissa R. George, D.O.
Page views in 2023: 71
Page views in 2024 to date: 82
Cite this page: Onyenekwu CP, George MR. Biological product deviation. PathologyOutlines.com website. https://www.pathologyoutlines.com/topic/transfusionmedbioproductdeviation.html. Accessed April 14th, 2024.
Definition / general
  • Error or deviation from the standard operating procedure (nonconformance) related to the manufacture, storage or distribution of licensed biological products (e.g., blood products)
  • Could potentially affect the safety, purity or potency of the product
  • May include issues regarding the testing, processing, packing, labeling or storage of blood components
Essential features
  • Biological product deviation (BPD) refers to unexpected events in manufacture, storage or distribution that deviate from the standard operating procedure
  • BPD reporting is mandated by the FDA and governed by title 21 of the Code of Federal Regulations (CFR)
  • Events occur after distribution and are categorized according to the phase of manufacture, storage or distribution in which they occur
Terminology
  • Nonconformance
  • Unexpected event
  • Center for Biologics Evaluation and Research (CBER)
  • Center for Drug Evaluation and Research (CDER)
  • Code of Federal Regulations (CFR)
  • U.S. Food and Drug Administration (FDA)
  • Safety means "relative freedom from harmful effect to persons affected, directly or indirectly, by a product when prudently administered, taking into consideration the character of the product in relation to the condition of the recipient at the time" (eCFR: 21 CFR 600.3(p) [Accessed 11 August 2023])
  • Purity is the "relative freedom from extraneous matter in the finished product, whether or not harmful to the recipient or deleterious to the product; purity includes but is not limited to relative freedom from residual moisture or other volatile substances and pyrogenic substances" (eCFR: 21 CFR 600.3(r) [Accessed 11 August 2023])
  • Potency is defined as "specific ability or capacity of the product, as indicated by appropriate laboratory tests or by adequately controlled clinical data obtained through the administration of the product in the manner intended, to effect a given result" (eCFR: 21 CFR 600.3(s) [Accessed 11 August 2023])
Epidemiology
  • Quality control and distribution events constituted 38.0% of the BPD events reported by licensed blood establishments to the FDA and 60.2% of BPD events from unlicensed registered blood establishments in fiscal year 2022
  • 1,785 reports (29.1%) by licensed blood establishments involved blood collection deviations in fiscal year 2022
  • 17.5% of reports from unlicensed registered blood establishments in fiscal year 2022 were due to routine testing deviations
  • Quality control and distribution nonconformances constituted 54.3% of reports from transfusion services in fiscal year 2022
  • Routine testing deviations constituted 28.5% of the reports from transfusion services to the FDA in fiscal year 2022 (FDA: Biological Product and HCT/P Deviation Reports - Annual Summary for Fiscal Year 2022 [Accessed 11 August 2023])
Diagrams / tables

Contributed by Chinelo P. Onyenekwu, M.D. and Melissa R. George, D.O.
BPD reporting overview

Reporting overview

BPD reporting responsibility

Reporting responsibility

BPD reporting process

Reporting process

BPD labeling events

Labeling events

BPD quality control / distribution events

Quality control / distribution events

Basis of BPDs / blood and biologic guidance
Responsibility (who must report)
  • Responsible party is the one that had control over the blood product at the time the nonconformance occurred
  • Control is defined as responsibility for ensuring the safety, purity and potency of a product
  • Control also covers responsibility for maintaining compliance with applicable standards and good manufacturing practices
  • Manufacturing steps contracted out by a blood establishment still fall under the control of the primary blood establishment
  • Manufacturing contractors are not mandated to report BPDs to the FDA
  • Manufacturing performed by contractors must conform to current good manufacturing practice (CGMP) (United States Code: Title 21 - Food and Drugs [Accessed 11 August 2023])
  • Examples of usual contracted manufacturing steps include blood collection, storage, distribution and irradiation
  • Establishments who should report BPDs include
    • Licensed manufacturers of blood products
    • Unlicensed registered blood establishments
    • Transfusion services
  • Establishments that conduct compatibility testing for a transfusion service have control of this step and are in charge of reporting any nonconformance related to this aspect
  • Reference: eCFR: 21 CFR 606.171(a) [Accessed 11 August 2023]
Events to report
  • Any event related to manufacturing, inclusive of testing, processing, labeling, storage, distribution of blood or its components that deviates from current good manufacturing practices, relevant standards and regulations
  • Any manufacturing events that impact the safety, purity or potency of a product
  • Events discovered after product was distributed even if not transfused
  • Usually unforeseen or unexpected events
  • Happen within reporting facility or establishments in contract with the facility
  • Events involving distributed blood or its components
  • References: eCFR: 21 CFR 606.171(b) [Accessed 11 August 2023], eCFR: 21 CFR 600.14 [Accessed 11 August 2023]
Events not required to report
  • When likely impacted products were not distributed
  • Impact donor safety only but do not compromise the safety, purity or potency of the product
  • Information received postdonation that may have prompted donor deferral if available at time of donation
  • Identified before distribution and rectified
  • Report of a delay in reporting a nonconformance
  • Reference: eCFR: 21 CFR 606.171 [Accessed 11 August 2023]
Timing of report (when to report)
Modality for reporting (how and where to report)
Types of events
  • Donor eligibility
    • Occurs during screening and deferral of donors
    • Examples include
      • Donor inappropriately deemed eligible when available information should result in deferral
      • Unacceptable donor temperature
      • Missing responses to high risk questions
      • Inaccurate omission of a donor from deferral list
  • Collection events
    • Take place during collection and are only identified postdistribution
    • Examples include
      • Contaminated or possibly contaminated products
      • Use of expired anticoagulant, collection set or bag
      • Omission of arm preparation
      • Clotted or hemolyzed product
  • Component preparation
    • Happens during preparation or processing
    • Identified after product distribution
    • Examples include
      • Products contaminated during pooling
      • Components prepared outside of stipulated interval following collection
      • Products manufactured outside of specified procedures including
        • Components prepared from whole blood stored at an unsuitable temperature
        • Inaccurate irradiation dosage
        • Wrong filter used in leukoreduction
  • Testing events
    • Arise during testing
    • Identified after product distribution
    • Examples include
      • Testing performed outside of manufacturer's instructions
      • Incomplete testing
      • Omission of testing or the documentation of testing
      • Testing conducted with unacceptable quality control
      • Testing with out of date reagents
      • Mislabeled specimens used in pretransfusion testing with subsequent product distribution based on the results
      • Compatibility testing results are misread and products are distributed off of the interpretation
  • Labeling events
    • Occur during labeling
    • Identified after distributing the products
    • Encompass omitted, inaccurate or misleading information on product labeling, including tie tags, transfusion records, information circular and labels on product container
    • Examples include
      • Inaccurate ABO group, Rh or antigen type, volume, anticoagulant, expiration date
      • Missing information on ABO blood group, Rh type or expiry date
      • Labeling with wrong recipient name or identification
      • Labeling with inaccurate or omitted donor identification
      • Omitted or inaccurate testing information on labels
      • Inaccurate or omitted product name
      • Inaccurate extended expiry date despite product being transfused within the correct dating interval
  • Quality control and distribution
    • Arises during quality control procedures or in the quarantine and distribution of products distributed
    • Examples include
      • Products processed with instruments or reagents with unacceptable quality control
      • Omission or nondocumentation of daily or weekly quality control
      • Improper release from quarantine and distribution of a product not meeting established requirements
      • Omission of quarantine and the distribution of units from an ineligible donor
      • Improper distribution of a product before resolving a discrepancy with manufacturing or testing
      • Distribution of an expired product
      • Shipping or storage of a product at a wrong temperature prior to distribution
      • Lack of documentation on appropriate storage temperature of a product
      • Identification of a donor as a source of transmission transmitted infection
      • Issuance of inaccurate products or units for a particular patient
      • Omission of or nondocumentation of visual check of products before distribution
      • Receipt, acceptance and subsequent identification of a hemolyzed product after distribution
  • Reference: FDA: Biological Product Deviation Reporting for Blood and Plasma Establishments - Guidance for Industry [Accessed 11 August 2023]
Implementation
  • Reporting a BPD involves analysis of the system(s) in which there was a failure that led to an unsuitable product being distributed
  • Includes donor screening, quality control, distribution
Reporting fatalities associated with transfusion
Case reports
Sample assessment & plan
  • The director of a licensed blood establishment received a telephone communication from a client transfusion service regarding leukoreduced red blood cell (LRBC) products supplied to them. The client notified the director that the transfusion service received a batch of leukoreduced red blood cells whose bags were out of date. This nonconformance had been detected by the inventory officer at the transfusion service upon receipt of the supply.
  • Assessment: The director determined this was a blood product deviation affecting quality control / distribution and involving multiple products. The quality assurance (QA) officer at the establishment had needed to go on an emergency family and medical leave, resulting in the role being filled in by other personnel on ad hoc basis each day. The usual automatic alerts for expiry dates and review of supplies were not recognized for 2 days during that period; therefore, multiple blood products and components bags were affected, including leukoreduced red blood cells, fresh frozen plasma and cryoprecipitate collection bags. He effected a recall on all the distributed products processed on those days.
  • Plan: The licensed blood establishment outlined details in the report to the CBER using Form FDA 3486 to highlight
    • Reporting facility information
    • BPD information including date(s) event occurred, date discovered, date reported
    • Description of contributing factors / root cause
    • Details of affected products type, collection and expiration dates, product codes, disposition and notification
    • Follow up and prevention plan
      • Recall affected distributed products / components from all client facilities
      • Implement a central automated alert system for the inventory software for any batch of component collection bags with expiration dates of 3 days or less
      • Commence physical storage of collection bags according to months / years of expiry
      • Implement mandatory inspection of expiry dates on 3 random product units in each dispatch
      • Train and ensure competency of all personnel in QA and inventory / distribution divisions
Board review style question #1
A 68 year old man has a transfusion attribute in the blood bank laboratory information system that all cellular products (packed red blood cells and platelets) for him should be irradiated. He carries a diagnosis of chronic lymphocytic leukemia / small lymphocytic lymphoma and blood bank policy indicates that blood products for patients with hematological malignancies should receive irradiated cellular products. During a particularly busy shift in the blood bank, a unit of packed red blood cells is issued to this patient without having been irradiated. An astute nurse in the infusion room notices that the unit does not have the usual irradiation indicator sticker on it and calls the blood bank. The blood bank requests the unit back, irradiates it and reissues it to the same patient. The temperature indicator on the unit is still acceptable. What are the next steps in handling a potential biological product deviation?

  1. Do not report it to the FDA but do report it to your institutional quality program since the unit was not transfused until after it was irradiated
  2. Do not report it to the institutional quality program or the FDA, since the unit was not transfused until after it was irradiated
  3. Report it to your institutional quality program and to the FDA since an error occurred that was caught after distribution, even though it was caught before transfusion
  4. Report it within your institutional quality program but do not report it to the FDA, since the unit was not transfused until after it was irradiated
Board review style answer #1
C. Report it to your institutional quality program and to the FDA since an error occurred that was caught after distribution, even though it was caught before transfusion. Since the error was not caught until after distribution, it is therefore reportable to both the institutional quality program as well as the FDA, even though there was no patient harm. Answers A, B and D are incorrect because despite a lack of patient harm, the error was not caught until after distribution. Therefore, it is reportable to internal and external quality monitors.

Comment Here

Reference: Biological product deviation
Board review style question #2
On an unusually busy evening shift, a medical laboratory scientist (MLS) in the blood bank is concerned because she witnessed one of the new staff members starting to deviate from the standard operating procedure (SOP) in making an aliquot of pRBC for an infant. The unit had 2 previous aliquots drawn for this same infant over the past 2 days and the new staff member was preparing to draw an aliquot off the source bag in an open fashion, without creating a sterile weld. The unit had 72 hours of shelf life left. The new staff member misremembered that the SOP specifies that it is acceptable to create an open system if the source bag is due to expire within 24 hours and instead thought it was okay for 72 hours. He had previously been covering the day shift where there were more staff members around to ask for help or clarify instructions. The observing medical laboratory scientist intervenes and demonstrates the correct way to access the main unit in a sterile fashion and draw off an aliquot. The new staff member admits that he got a little overconfident and notes that he should have kept the SOP open on the screen in front of him since he has only done this before during training. He takes the time to carefully review the SOP and carefully opens SOPs for all other tasks that evening. He also asks the other staff member to double check a visual inspection on a unit of platelets he is issuing. What is the next most appropriate step?

  1. Reinforce adherence to the standard operating protocol and do not report the error to the FDA, because it was caught before distribution and the product / patient was not harmed
  2. Reinforce adherence to the standard operating protocol and report the error to the FDA because it involved a blood component being prepared for an infant
  3. Report the new staff member to human resources, quarantine every product that he has accessed and report the error to the FDA
  4. Report this error to the internal quality program and to the FDA, as well as any other aliquots made by this staff member, as it is unclear if he ever made this error before
Board review style answer #2
A. Reinforce adherence to the standard operating protocol and do not report the error to the FDA, because it was caught before distribution and the product / patient was not harmed. This reflects a near miss that was caught before the product was distributed. New medical laboratory scientist staff members are more likely to make a few mistakes and this is an opportunity for professional growth. This error was caught before the product was compromised and there was no patient harm. Even if the aliquot had been drawn in an open system, it would have changed the expiration date and potentially wasted product but there would not have been harm to the intended recipient. Answer B is incorrect because there is no difference in how errors are handled / reported based on adult versus pediatric patients. Answers C and D are incorrect because there is no evidence of widespread errors from this particular staff member.

Comment Here

Reference: Biological product deviation
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