Note: This article originally appeared in the September 2021 issue of AABB News
, a member benefit of AABB.
When the Food and Drug Administration’s industry guidance on bacterial risk control strategies for platelets was finalized in late 2019, many blood banks and transfusion services began in earnest to map out how to meet the recommendations by the April 2020 deadline. The agency updated the guidance in December 2020, extending the deadline to October 2021 in light of the ongoing COVID-19 pandemic.1
Blood banks have been struggling with considerations and challenges to developing and implementing policies and practices to ensure the safety of platelets intended for transfusion.
Mitigating Bacterial Contamination
Traditional methods for bacterial testing of platelet products include culture-based and rapid tests. Testing can also be classified as primary (or initial) or secondary. Primary testing is culture-based and performed early. Secondary testing (currently optional) includes additional rapid tests performed closer to the time of transfusion to detect bacterial contamination not revealed by primary testing. 2
The new risk control mitigations outlined in the FDA guidance relate to sampling and culture strategies, secondary rapid testing, and pathogen reduction technology (PRT). Testing can also be broken down to one-step or two-step.3
Single-step strategies include large-volume delayed sampling (LVDS), done no sooner than 36 hours after collection, and PRT. LVDS involves taking larger volumes from each platelet unit and performing aerobic and anaerobic culturing between 36 and 48 hours after collection.
Two-step strategies require a primary culture taken at 24 hours after collection followed by either a rapid (point-of-issue) bacterial test prior to transfusion or a secondary culture at the 3-day mark. Rapid (point of issue) tests, such as the Pan Genera Detection test (Verax Biomedical), are designed to detect a broad spectrum of both aerobic and anaerobic bacteria.
The results from a survey of hospital-based transfusion services suggest that the preferred strategies for meeting the FDA guidance are 5-day pathogen-reduced platelets and large volume delayed sampling at 48 hours for 7-day platelets.4
These preferred strategies were primarily motivated by product availability, reduction of the risk of septic transfusion reactions, and the complexity added by a new or second test.
The Starting Line
The risk control strategy finally implemented by a blood bank to meet the FDA guidance depends in part from where they start. This colors decisions about 5- or 7-day platelets, one- or two-step strategies, and the timeline for implementing the plan. For example, the New York Blood Center (NYBC), includes five centers — four centers collecting Trima (Terumo) platelets and one center producing 100% Amicus (Fresenius Kabi USA) platelets in platelet additive solution (PAS). Two of the Trima centers and the 100% Amicus center are licensed to produce PRT platelets (Intercept, Cerus) and one center is awaiting FDA licensure for PRT platelets. The remaining center — already licensed for Intercept platelets — produces a combination of Trima and Amicus platelets.
According to Donna Strauss, vice president of laboratories at NYBC, the center has used one step testing, sampling the parent bag at 24 hours. Now, to meet FDA guidance, they are holding units for sampling at 48 hours, using aerobic and anaerobic bottles for each split. These are held for 12 hours and released if negative. NYBC is now producing more PRT units as well.
LVDS plays a role in several of the FDA bacterial risk mitigation strategies. Traditionally, apheresis platelets have been universally screened using a culture-based test, sampling the main collection no sooner than 24 hours after collection. Sampling volume was limited to 8 mL, inoculated into an aerobic culture medium.5
In the final guidance, LVDS requires a 16 mL sample larger than the traditional 8 mL sample with delayed sample collection at 24-36 hours after collection of apheresis platelets, according to the FDA. The thinking is that delayed sampling “would allow bacteria already present in the collection to proliferate further, and in conjunction with large volume sampling, would increase the bacterial yield.”6
“Blood Centers will likely implement large-volume, delayed-sampling, so their customers will not have to perform secondary testing,” said Strauss. At NYBC's one center using Amicus and PAS, LVDS is performed at 36 hours to produce 5-day platelets.
All other NYBC centers will perform LVDS sampling at 48 hours to produce 7-day platelets. At these centers, 7-day platelet production looks like this:
• BACT/ALERT (biomerieux) culture of LVDS sample taken at 48 hours post-collection
• 16-20 mL sample inoculated into anaerobic and aerobic bottles for each split
• Products are released at 12 hours post-sample collection, if negative
• Bottles are incubated until 7-day expiration date
• All non-PR products will be LVDS 7-Day products
The American Red Cross (ARC) is temporarily using LVDS testing on all platelet products not pathogen reduced as a bridge to all-PRT platelets, according to Pampee Young, MD, PhD, chief medical officer at ARC. At the time of implementation, platelet inventories have been approximately 40% pathogen-reduced and 60% LVDS. Over a 2-year period, ARC will gradually move to a 100% pathogen-reduced supply. The length of the transition period was selected to allow hospitals adequate time to adjust to these changes and minimize any impact on supply.
To Pathogen Reduce on Not
ARC has opted to move towards a 100% PRT platelet inventory. “This decision involved a balancing of many complex factors,” said Young.
Four NYBC centers also are already using PRT. “We are trying to make as many of those units as possible,” said Strauss. However, NYBC plans to provide a mix of PRT and LVDS units.
Studies have shown that the options outlined in the FDA guidance achieve comparable levels of bacterial risk mitigation. While efficacy against bacterial contamination is key, PRT protects patients in a number of other ways, as well. Pathogen reduction also eliminates a broad spectrum of pathogens threats, including viruses, bacteria, parasites and white blood cells. PRT also provides protection against emerging pathogens and those that are as yet unknown. This proactive approach can help sustain platelet availability during outbreaks.
Unlike other bacterial mitigation strategies, PRT also reduces the risk of transfusion-associated graft-versus-host disease, something other mitigation methods do not address at all. Perhaps just as important, PRT has a positive impact on platelet availability. With bacterial testing, bacteria- positive units must be discarded, along with their co-components. However, all PRT platelet products can still be used. In addition, bacterial testing requires product samples for testing, resulting in lower split rates — fewer products per donation.
“Our analysis and extensive experience with making PRT platelets indicate that the Red Cross will increase output and produce more platelet products with a complete PRT strategy than it would produce using other bacterial mitigation methods or a mix of PRT and other methods,” said Young.
Strauss noted that “depending on the cost of LVDS platelets, pathogen reduction may become a more attractive alternative to hospitals, especially when 7-day platelets are available.”
Bumps in the Road
Despite the progress that many centers have made in moving to meet the new guidance, they still face a number of challenges. These include product loss, time and cost. NYBC estimates that with LVDS TRIMA, products may lose approximately 7% and Amicus products may lose approximately 5%.
“LVDS is a time-consuming, expensive process that results in loss of platelets due to lower split rate and increased outdated products,” said Young. “PR conversion has also resulted in reduced split rates. Both processes have increased generation of low-yield products.”
The shift to later hold times could also translate to longer waiting times for hospitals and transfusion services to receive some products. For example, currently 5-day products are available for transfusion with 3 days left based on hold time. However, delayed testing means that they may receive the product 12-24 hours later.
Regardless of the strategy chosen, meeting the guidance is translating to increased costs for blood centers that now require more equipment, space and staff. In fact, centers are already seeing staff shortages. “Finding staff has been a huge struggle for us,” said Strauss.
More equipment is needed with samples increasing from one to four bottles. More incubators may be needed. Those opting for PRT-only platelets may need to invest in more equipment. More equipment means more space.
There are labeling changes to incorporate, as well. Secondary testing means updating the label to reflect the new expiration date.
Computer systems can also pose problems. Coding can be an issue. “We’ve had some challenges with hospital systems getting the new coding to work. We’ve worked together to sort out these problems,” said Strauss. In addition, some Blood Establishment Computer Systems (BECS) may not be equipped to handle the changes either.
Then there’s licensing. Establishments that distribute platelet products in interstate commerce must have an approved biologics license application (BLA). Those that are currently licensed to manufacture apheresis platelets with a 5-day expiration date and that choose to extend the storage time to a 6 or 7-day expiration date for interstate commerce may require a Prior Approval Supplement. Blood centers must have a license before shipping 7-day products.
The Finish Line
NYBC estimates a 130% increase in the cost of bacterial detection due to testing materials and technologist time (1-2 new technologists). Revenue may also be lost due to additional volume required for LVDS testing. False positives have been associated with anaerobic culturing, leading to more lost product.
A study from 2020 estimated that for an approach using LVDS (for 7-day platelets), the total cost per transfused unit is $735.78. At a rate of 20,000 transfusions per year, LVDS would cost $14.72 million annually. “Per-unit LVDS costs would need to be less than $22.32 to be cheaper per transfusion than all other strategies, less than $32.02 to be cheaper than [secondary bacterial culture] (7-day), and less than $196.19 to be cheaper than PR (5-day),” the researchers noted.7
ARC conducted a detailed analysis based on its real-world experience in manufacturing PRT platelets since 2016. They looked at “every step, from adjusting collections parameters on our apheresis devices to delivering platelets to our hospitals. We included multivariable assessments of splitting, sampling and split points along with detailed time-motion studies of staff performing the necessary activities,” said Young.
Starting in February 2021, ARC began charging an additional $150 for PRT platelet units. Given the additional expenses associated with testing, ARC has added an $83 additional charge per unit.8
AABB has a number of resources to help blood collectors and transfusion services implement bacterial risk control strategies for platelets. Additional information is available on the AABB website
1 U.S. Food and Drug Administration. Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion. Dec 2020. https://www.fda.gov/media/123448/download
2 U.S. Food and Drug Administration, Blood Products Advisory Committee Meeting, November 30 - December 1, 2017. https://www.fda.gov/media/109659/download
3 U.S. Food and Drug Administration. Bacterial Risk Control Strategies for Blood Collection Establishments and Transfusion Services to Enhance the Safety and Availability of Platelets for Transfusion. Dec 2020. https://www.fda.gov/media/123448/download
4 Lu W, Delaney M, Dunbar NM, et al. A national survey of hospital-based transfusion services on their approaches to platelet bacterial risk mitigation in response to the FDA final guidance for
industry. Transfusion. 2020;60:1681-7.
5 Haddad S. Options to Further Reduce the Risk of Bacterial Contamination in Platelets for Transfusion. Presented at Blood Products Advisory Committee Meeting, September 2012. https://www.fda.gov/media/130295/download
6 U.S. Food and Drug Administration, Blood Products Advisory Committee Meeting, November 30 - December 1, 2017. https://www.fda.gov/media/109659/download
7 Kacker S, Katz LM, Ness PM, et al. Financial analysis of large-volume delayed sampling to reduce bacterial contamination of platelets. Transfusion. 2020;60:997-1002.
8 American Red Cross, The American Red Cross Approach to Platelet Safety Implementation Plan for FDA Bacterial Control Strategies, July 15, 2020, https://www.redcrossblood.org/content/dam/redcrossblood/hospital-page-documents/red_cross_approach_to_platelet_safety__rcb__july_15_2020.pdf