CGMP for Blood and Blood Components: 3rd Party Disclosures

Bacterial Risk Control Strategies for
Blood Collection Establishments and
Transfusion Services to Enhance the
Safety and Availability of Platelets for
Transfusion
Draft Guidance for Industry
This guidance document is for comment purposes only.
Submit one set of either electronic or written comments on this draft guidance by the date
provided in the Federal Register notice announcing the availability of the draft guidance.
Submit electronic comments to https://www.regulations.gov/. Submit written comments to the
Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm.
1061, Rockville, MD 20852. You should identify all comments with the docket number listed in
the notice of availability that publishes in the Federal Register.
Additional copies of this guidance are available from the Office of Communication, Outreach
and Development (OCOD), 10903 New Hampshire Ave., Bldg. 71, Rm. 3128, Silver Spring,
MD 20993-0002, or by calling 1-800-835-4709 or 240-402-8010, or email ocod@fda.hhs.gov, or
from the Internet at
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guid
ances/default.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers or email
address listed above.

U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
December 2018

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Table of Contents

I.

INTRODUCTION............................................................................................................. 1

II.

BACKGROUND ............................................................................................................... 1

III.

RECOMMENDATIONS FOR THE CONTROL OF BACTERIAL
CONTAMINATION OF PLATELETS.......................................................................... 3
A.
B.
C.
D.
E.
F.
G.

IV.

General Considerations ........................................................................................ 3
Primary Culture Testing ...................................................................................... 4
5-Day Platelet Storage .......................................................................................... 4
7-Day Platelet Storage .......................................................................................... 5
Post-Storage Pooled Platelets ............................................................................... 7
Single Units of WBD Platelets .............................................................................. 7
Labeling ................................................................................................................. 7

REPORTING IMPLEMENTATION OF MANUFACTURING AND LABELING
CHANGES ......................................................................................................................... 8
A.
B.

Prior Approval Supplement (PAS)...................................................................... 8
Annual Report ..................................................................................................... 10

V.

TRANSFUSION SERVICES—REGISTRATION AND BLOOD PRODUCT
LISTING .......................................................................................................................... 11

VI.

IMPLEMENTATION .................................................................................................... 11

VII.

REFERENCES ................................................................................................................ 12

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Bacterial Risk Control Strategies for Blood Collection
Establishments and Transfusion Services to Enhance the Safety and
Availability of Platelets for Transfusion
Draft Guidance for Industry
This draft guidance, when finalized, will represent the current thinking of the Food and Drug
Administration (FDA or Agency) on this topic. It does not establish any rights for any person
and is not binding on FDA or the public. You can use an alternative approach if it satisfies the
requirements of the applicable statutes and regulations. To discuss an alternative approach,
contact the FDA staff responsible for this guidance as listed on the title page.

I.

INTRODUCTION

We, FDA, are issuing this guidance document to provide you, blood collection establishments
and transfusion services, with recommendations to control the risk of bacterial contamination of
room temperature stored platelets intended for transfusion. The recommendations in this
guidance apply to all platelet products, including platelets manufactured by automated methods
(apheresis platelets), whole blood derived (WBD) platelets, pooled platelets (pre-storage and
post-storage) and platelets stored in additive solutions.
Additionally, this guidance provides licensed blood establishments with recommendations on
how to report implementation of manufacturing and labeling changes under 21 CFR 601.12.
This draft guidance replaces the draft guidance of the same title dated March 2016.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested or
recommended, but not required.

II.

BACKGROUND

Room temperature stored platelets are associated with a higher risk of sepsis and related fatality
than any other transfusable blood component. The risk of bacterial contamination of platelets is
a leading risk of infection from blood transfusion. Bacterial residual risk per transfused unit on
the day of transfusion is 1/2300 (Ref. 1), and fatal transfusion reactions from undetected

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contaminated platelet collections continue to occur (Ref. 2). This risk has persisted despite
numerous interventions, including the widely used method of primary culture to test platelets
prior to transfusion (Refs. 3, 4, 5, 6).
The reported rates of septic transfusion reactions from platelets vary from 1/100,000 by passive
surveillance to 1/10,000 by active surveillance when testing with primary culture alone (Refs. 1,
7). Surveillance data on platelets stored up to 5 days have shown that 95-100% of platelet
transfusion-related septic reactions (Refs. 3, 4, 8) and 100% of associated fatalities have occurred
with transfusion of day 4 and day 5 stored platelets (Ref. 8).
FDA has established regulations to address the control of bacterial contamination of platelets.
Under 21 CFR 606.145(a), blood establishments and transfusion services must assure that the
risk of bacterial contamination of platelets is adequately controlled using FDA approved or
cleared devices, or other adequate and appropriate methods found acceptable for this purpose by
FDA.
Currently, this risk can be controlled by bacterial testing or pathogen reduction methods.
Bacterial testing includes the use of culture-based or rapid detection tests. 1 While primary testing
is typically performed by culture and within 24 hours of collection, secondary testing is
performed at later times of storage prior to transfusion. Pathogen reduction is performed shortly
after platelet collection.
Under 21 CFR 610.53(b), the dating period for platelets with a storage temperature between 20
and 24 degrees Celsius is 5 days from the date of collection, unless a different dating period is
specified in the instructions for use by the blood collection, processing and storage system
approved or cleared for such use by FDA. Accordingly, implementation of the recommendations
in this guidance on extension of platelet dating beyond day 5 is contingent on the use of cleared
or approved and suitably labeled platelet storage containers, bacterial detection tests and
pathogen reduction devices. 2 The current maximum dating period (expiration date) for platelets
in the United States (U.S.) is up to 7 days in the cleared storage containers.
Most recently, FDA convened a Blood Products Advisory Committee (BPAC) meeting in July
2018 (Ref. 9) to discuss bacterial contamination of platelets and strategies to control the risk. At
this meeting, BPAC considered the scientific evidence and operational considerations of all
available strategies to control the risk of bacterial contamination of platelets with 5-day and 7day dating, including bacterial testing strategies using culture-based devices, rapid bacterial

1

Bacterial tests are labeled as a “safety measure” when clinical studies have shown benefit for detection of bacterial
contamination not revealed by previous bacterial testing or have analytical sensitivity at least equivalent to a
previously cleared “safety measure” device or qualify by other methods found acceptable to FDA.

2

Currently, storage systems that ensure platelet efficacy past 5 days of storage, and up to 7 days of storage, of
platelets treated by pathogen reduction technology (PRT) are not available. Extended dating past 5 days based on
pathogen reduction of apheresis platelets may not be implemented until such technologies are approved for use in
this blood component (21 CFR 606.65(e)).

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detection devices, and the implementation of pathogen reduction technology. The data presented
and BPAC’s discussion at the July 2018 meeting provided the foundation for the
recommendations in this guidance.

III.

RECOMMENDATIONS FOR THE CONTROL OF BACTERIAL
CONTAMINATION OF PLATELETS

Table 1 summarizes recommended strategies for 5-day platelet storage and 7-day platelet
storage.
Table 1. Summary Table of FDA’s Recommendations
Recommendations to control the risk of bacterial contamination in platelets
Dating

Method

Applicable components

5-day storage

Primary culture + secondary culture (no earlier
than Day 3)

•
•
•
•

Apheresis
Pre-storage pools
Apheresis
Pre-storage pools

Pathogen Reduction Technology

•

Apheresis 3

Primary culture + secondary culture (no earlier
than Day 4)

•

Apheresis

Primary culture + secondary rapid testing

•

Apheresis

Large volume delayed sampling 4

•

Apheresis

Primary culture + secondary rapid testing

7-day storage

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A.

General Considerations
1.

Use FDA-cleared or approved bacterial detection tests, pathogen reduction
devices, and platelet storage containers.

2.

Bacterial detection testing, pathogen reduction, and the use of platelet storage
containers must be performed consistent with the instructions for use of the
device (21 CFR 606.65(e)).

3

This strategy could apply to other platelet products in the future if appropriately labeled devices become available.
The instructions for use of the culture-based device currently labeled as a “safety measure” require a primary
culture and secondary test to extend dating of platelets. Therefore, the large volume, delayed sampling strategy
cannot be implemented until appropriately labeled devices are available.
4

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3.

B.

Blood collection establishments and transfusion services should have in place
measures to promptly alert the collection establishment or transfusion service
if a distributed platelet product is subsequently identified as positive for
bacterial contamination.
Primary Culture Testing

This section provides general information pertaining to recommendations for primary
culture testing. Primary culture testing is used as one of several strategies discussed in
this guidance.
Culture-based primary testing should be performed no sooner than 24 hours after
collection. Testing should include methods to identify both aerobic and anaerobic
organisms. To maximize the sensitivity of the culture, we recommend use of the upper
limit of the sample volume range permitted by the device’s instructions for each of the
aerobic and anaerobic cultures. If you opt to sample a volume larger than the upper
limit of the volume range described in the device’s instructions for use for one culture,
we recommend that the amount of the sample that is in excess of the upper limit volume
recommended for use be inoculated into additional culture.
If the instructions for use of the bacterial detection device specify a minimum incubation
period, you should release platelet products consistent with the incubation period
specified. If the instructions for use of the bacterial detection device do not specify a
minimum incubation period, we recommend a minimum incubation period of 12 hours.
C.

5-Day Platelet Storage

The following strategies apply to platelets with 5-day storage:
1.

Primary culture followed by secondary culture performed no earlier
than Day 3

This strategy applies to apheresis platelets and pre-storage pools and includes the
following steps:
•
•

Initial primary culture (see section III.B of this guidance).
Secondary culture on Day 3 or Day 4.

Secondary culture:
To maximize the sensitivity of the culture, we recommend use of the upper limit
of the sample volume range permitted by the device’s instructions for use, taken
from the main collection, and inoculating the sample into an aerobic media. Use
of an anaerobic culture, in addition to the aerobic culture, should be considered.

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If the instructions for use of the bacterial detection device specify a minimum
incubation period, you should release platelet products consistent with the
incubation period specified. If the instructions for use of the bacterial detection
device do not specify a minimum incubation period, we recommend that you
establish a minimum incubation time period in your Standard Operating
Procedures (SOPs).
2.

Primary culture, followed by secondary rapid testing

This strategy applies to apheresis platelets and pre-storage pools, and includes
the following steps:
•
•
3.

Initial primary culture (see section III.B. of this guidance).
Secondary testing with a rapid test.
Pathogen reduction

This strategy applies to apheresis platelets. 5,6 Platelets that have been treated by
pathogen reduction need no further measures because pathogen reduction
technology adequately controls the risk of bacterial contamination of platelets
D.

7-Day Platelet Storage

Storage may be extended beyond 5 days if:
•
•

The platelets are stored in a container cleared or approved by FDA for 7-day
storage, and
Individual platelet units are subsequently tested for bacterial detection using a
bacterial detection device cleared by FDA and labeled for use as a “safety
measure.” 7

The following strategies are recommended for storage of platelets of up to 7 days:
1.

Primary culture, followed by a secondary culture with a device
labeled as a “safety measure” performed no earlier than Day 4

This strategy applies to apheresis platelets, and includes the following steps:

5

This strategy could apply to other platelet products in the future if appropriately labeled pathogen reduction
devices and storage systems become available.
6
See footnote 2.
7
See footnote 1.

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Initial primary culture (see section III.B. of this guidance).
Secondary culture no earlier than Day 4, using a device labeled as a
“safety measure.”

Secondary culture:
To maximize the sensitivity of the culture, we recommend use of the upper limit
of the sample volume range permitted by the device’s instructions for use,
inoculated into both an aerobic culture and an anaerobic culture.
If the instructions for use of the bacterial detection device specify a minimum
incubation period, you should release platelet products consistent with the
incubation period specified. If the instructions for use of the bacterial detection
device do not specify a minimum incubation period, we recommend a minimum
incubation period of 12 hours.
2.

Primary culture, followed by a secondary rapid test labeled as a
“safety measure”

This strategy applies to apheresis platelets, and includes the following steps:
•
•

Initial primary culture (see section III.B of this guidance).
Secondary testing with a rapid test labeled as a “safety measure.”
Large volume delayed sampling 8

3.

This strategy applies to apheresis platelets, and includes the following steps:
•

A single culture performed using a culture-based bacterial detection device
no sooner than 48 hours after collection with a sampling volume of at least
16 mL, inoculated evenly into an aerobic culture and an anaerobic culture.

•

Each apheresis unit should be sampled for culture. If the apheresis
product is split, each split product should be sampled.

•

If the instructions for use of the bacterial detection device specify a
minimum incubation period, you should release platelet products
consistent with the incubation period specified. If the instructions for use
of the bacterial detection device do not specify a minimum incubation
period, we recommend a minimum incubation period of 12 hours.

8

The instructions for use of the culture-based device currently labeled as a “safety measure” require a primary
culture and secondary test to extend dating. Therefore, the large volume, delayed sampling strategy cannot be
implemented until appropriately labeled devices are available.

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E.

Post-Storage Pooled Platelets

Transfusion services should perform a rapid bacterial detection test prior to transfusion
on pools of WBD platelets if the constituent single units were not previously tested.
Post-storage pooled platelets expire 4 hours from the time of preparation
(21 CFR 606.122(l)(2)).
F.

Single Units of WBD Platelets

Single units of WBD platelets may be stored for 5 days. For single units of WBD
platelets that have not been previously tested and are not intended for pooling, testing
should be performed according to either or both of the following strategies:

G.

1.

Sample no sooner than 24 hours after collection, the largest practical
volume within the range permitted by the device’s instructions for use and
inoculate into a culture. Use of an aerobic and an anaerobic culture may be
considered; and/or

2.

Perform testing with a rapid test.

Labeling
1.

Labels on the Container
a. The container labels must comply with 21 CFR 606.121 and
21 CFR 610.60. Blood collection establishments and transfusion services,
as appropriate, must also follow the general requirements for labeling
operations described in 21 CFR 606.120.
b. The container labels must include the expiration date and time, if
applicable, of the product based on bacterial detection testing (21 CFR
606.121(c)(4)(i)).
c. If secondary testing of platelets is performed consistent with this guidance,
and the expiration date is extended to 6 or 7 days based on the bacterial
testing performed, the blood establishment or transfusion service that
performed the secondary testing must update the container label to reflect
the new expiration date (21 CFR 606.121(c)(4)(i)).

2.

Circular of Information

You must update your Circular of Information to include appropriate
statements regarding bacterial detection testing or pathogen reduction (21 CFR
606.122).

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IV.

REPORTING IMPLEMENTATION OF MANUFACTURING AND LABELING
CHANGES

An establishment that distributes platelet products in interstate commerce must have an approved
BLA, in accordance with section 351 of the Public Health Service Act.
Licensed establishments must report changes to their approved biologics license applications
(BLA) in accordance with 21 CFR 601.12. The information below is intended to assist you in
determining which reporting mechanism is appropriate for a change to your approved BLA, as it
applies to the bacterial testing of platelet products and the manufacture of apheresis platelets
with a 6 or 7-day dating period. 9 You should prominently label each submission with the
reporting category under which you are reporting your change, for example, “Prior Approval
Supplement,” or “Annual Report.”
A.

Prior Approval Supplement (PAS)
1.

Changes requiring supplement submission and approval prior to
distribution of the product made using the change (21 CFR 601.12(b)).

Under 21 CFR 601.12(b), changes that have a substantial potential to have an
adverse effect on the identity, strength, quality, purity, or potency of the product
as they may relate to the safety or effectiveness of the product must be reported
to FDA in a Prior Approval Supplement (PAS). You must not distribute in
interstate commerce blood components made using a new or changed
manufacturing process requiring a PAS until you have received our approval of
your PAS (21 CFR 601.12(b)(3)).
We believe a PAS submission is appropriate in the following situations:
a. You are currently licensed to manufacture apheresis platelets with a 5day expiration date and you choose to extend the storage time to a 6-day
or 7-day expiration date and distribute these products in interstate
commerce.
2.

To comply with the requirements in 21 CFR 601.12(b)(3), you must
include the following minimum information in your PAS submission:

9

FDA’s recommendations for the implementation of pathogen reduction are addressed in the guidance document
titled, “Implementation of Pathogen Reduction Technology in the Manufacture of Blood Components in Blood
Establishments: Questions and Answers; Draft Guidance for Industry,” dated December 2017. The draft guidance,
when finalized, will represent FDA’s current thinking on this topic.

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a. Form FDA 356h, “Application to Market a New or Abbreviated New
Drug or Biologic for Human Use.”
b. List of the platelet products involved.
c. Address and registration number of the manufacturing facility/facilities.
d. A detailed description of the manufacturing process. We recommend
the submission of written standard operating procedures (SOPs) that
include:
i. Component manufacturing (if these SOPs were previously
approved by FDA, include the reference number under which
they were reviewed).
ii. Bacterial detection testing, including the name of the devices(s)
used for bacterial detection, when the platelet product is sampled
and when the product will be released.
iii. How to label the platelet product based on the results of the
bacterial detection testing and the timeframe after which the
negative results are no longer valid.
iv. Measures to alert the consignee that a distributed platelet product
has tested positive for bacterial contamination.
v. Quarantine and disposition of unsuitable products.
vi. Investigation of units with positive test results.
vii. A communication plan to notify your consignees the type of
storage container the platelets are stored in, for example, a
storage container approved for 5-day storage or for 7-day
storage and when the bacterial detection testing was performed.
e. The name, address and registration number, if available, of any
contractors who are performing bacterial detection testing of platelet
products for you.
f. Validation plan for the bacterial detection testing method and a
summary of the validation data.
g. Two consecutive months of quality control data for the pH at
expiration or on the date the product is issued for each platelet product
type that will have the expiration date extended based on bacterial
detection testing.
h. Labeling – include the following in your supplement:

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i. Container Labels: A container label for each platelet product,
unless previously approved by FDA, that includes the
expiration date and time, if applicable, of the platelet product
based on bacterial detection testing.
ii. Circular of Information.
3.

B.

You may also consider submitting a Comparability Protocol as a PAS
under 21 CFR 601.12(e). A Comparability Protocol is not required, but an
approved Comparability Protocol may justify a reduced reporting category
for manufacturing apheresis platelets with a 6-day or 7-day expiration date
in multiple locations. In addition to the content listed in section IV.A. of
the guidance, Comparability Protocol (21 CFR 601.12(e)) submissions
must also include the plan for implementing the bacterial detection testing
at multiple manufacturing sites. The plan should include a description of
how you will validate the new procedures.

Annual Report

Under 21 CFR 601.12(d), changes in the product, production process, quality controls,
equipment, facilities, or responsible personnel that have a minimal potential to have an
adverse effect on the identity, strength, quality, purity, or potency of the product as they
may relate to the safety or effectiveness of the product must be documented in an annual
report submitted each year within 60 days of the anniversary date of approval of the
BLA.
We believe the following changes may be submitted in an Annual Report 10 noting the
date the process was implemented:
1.

Implementation of bacterial detection testing as described in this
guidance without modification and the expiration date of apheresis,
single units of WBD platelets, and pre-storage pooled WBD platelets
remains at 5 days.

2.

You or your contractor change from one type of FDA cleared bacterial
detection device to another type of FDA-cleared bacterial detection
device.

NOTE: For assistance in reporting your changes, see FDA’s “Changes to an Approved
Application: Biological Products: Human Blood and Blood Components Intended for
Transfusion or for Further Manufacture; Guidance for Industry” dated December 2014.

10

See 21 CFR 601.12(a)(3).

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The December 2014 guidance represents FDA’s current thinking on this topic and can be
found on FDA’s website at:
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformatio
n/Guidances/default.htmn/Guidances/Blood/ucm354559.htm.

V.

TRANSFUSION SERVICES—REGISTRATION AND BLOOD PRODUCT
LISTING

Except as provided in 21 CFR 607.65, all owners and operators of blood establishments that
engage in the manufacture of blood products must register with FDA and list the blood
products they manufacture, pursuant to section 510 of the Federal Food, Drug, and Cosmetic
Act and the implementing regulations under 21 CFR 607.7. The implementation of a bacterial
detection device that is used to re-label a platelet product with a 6 or 7-day expiration date,
thereby extending the dating of the platelet product, is a manufacturing procedure requiring
registration and blood product listing, as described in 21 CFR 607.3(d). Transfusion services
that implement secondary testing on platelets with a 5-day expiration date are not required to
register and list because they are not extending the dating period of platelets.
If you are a transfusion service that is currently exempt from registration and blood product
listing under the provisions of 21 CFR 607.65(f), and you implement a bacterial detection test
to determine the suitability of platelet products to be released on day 6 or day 7 after
collection, you are no longer considered exempt because you are engaging in blood product
manufacturing under 21 CFR 607.3(d). You must therefore register your blood establishment
with FDA and list the blood products you manufacture, pursuant to 21 CFR 607.7. Indicate
that you are performing bacterial detection testing on platelet products by selecting “Bacterial
Testing” as a process for the platelet products.
Instructions on how to register electronically with FDA can be found on FDA’s website at:
https://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Est
ablishmentRegistration/BloodEstablishmentRegistration/default.htm.
VI.

IMPLEMENTATION

We recommend that you implement the recommendations contained in this guidance within 12
months after the final guidance is issued.

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VII.

REFERENCES

1. Jacobs MR, Smith D, Heaton WA, et al., Detection of bacterial contamination in prestorage
culture-negative apheresis platelets on day of issue with the Pan Genera Detection test,
Transfusion, 2011; 51(12): 2573-2582.
2. Fatalities Reported to FDA Following Blood Collection and Transfusion Annual Summary.
https://www.fda.gov/BiologicsBloodVaccines/SafetyAvailability/ReportaProblem/Transfusio
nDonationFatalities/default.htm.
3. Hong H, Xiao W, Lazarus HM, et al., Detection of septic transfusion reactions to platelet
transfusions by active and passive surveillance, Blood, 2016; 127(4): 496-502.
4. Benjamin RJ, Transfusion-related sepsis: a silent epidemic, Blood, 2016; 127(4): 380-381.
5. Fuller AK, Uglik KM, Savage WJ, et al., Bacterial culture reduces but does not eliminate the
risk of septic transfusion reactions to single-donor platelets, Transfusion, 2009; 49(12): 25882593.
6. Horth R, Jones J, Kim J, et al; Fatal sepsis associated with bacterial contamination of
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