Alternative Procedures for the 
Manufacture of Cold-Stored Platelets 
Intended for the Treatment of Active 
Bleeding when Conventional Platelets 
Are Not Available or Their Use Is Not 
Practical 
 
 
Guidance for Industry 
 
This guidance is for immediate implementation.
 
 
This guidance is being implemented in accordance with 21 CFR 10.115(g)(2) without prior 
public comment because the Food and Drug Administration has determined that prior public 
participation for this guidance is not feasible or appropriate.  This guidance document is being 
implemented immediately, but it remains subject to comment in accordance with the Agencys 
good guidance practices. 
 
Comments may be submitted at any time for Agency consideration.  Submit written comments to 
the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 Fishers Lane, 
Rm. 1061, Rockville, MD 20852.  Submit electronic comments to https://www.regulations.gov.  
All comments should be identified 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/vaccines-blood-biologics/guidance-compliance-
regulatory-information-biologics/biologics-guidances. 
 
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 
June 2023 Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 2 
A.  Platelet Transfusions ............................................................................................ 2 
B.  Regulatory History of CSP ................................................................................... 2 
C.  Available Data on Quality and Use of CSP ........................................................ 3 
D.  The Need for Additional Studies on CSP ............................................................ 4 
E.  Regulatory Considerations ................................................................................... 5 
III.  NOTICE OF EXCEPTIONS OR ALTERNATIVES .................................................... 6 
IV.  RECOMMENDATIONS AND CONSIDERATIONS FOR THE MANUFACTURE 
OF COLD-STORED PLATELETS ................................................................................ 7 
A.  Manufacture of Apheresis CSP and Storage Conditions .................................. 7 
B.  Control of Bacterial Contamination of Platelets ................................................ 7 
C.  Process Validation ................................................................................................. 8 
D.  Quality Control Testing ........................................................................................ 8 
E.  Container Labels ................................................................................................... 8 
F.  Circular of Information ........................................................................................ 9 
V.  REPORTING IMPLEMENTATION OF MANUFACTURING AND LABELING 
CHANGES ......................................................................................................................... 9 
VI.  REFERENCES ................................................................................................................ 11 
i  Contains Nonbinding Recommendations 
 
 
Alternative Procedures for Cold-Stored Platelets  
Intended for the Treatment of Active Bleeding when Conventional 
Platelets Are Not Available or Their Use Is Not Practical 
 
Guidance for Industry 
 
 
This guidance represents 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 
 
FDA (we) is issuing this guidance to provide a notice of exceptions and alternatives to certain 
requirements in Title 21 of the Code of Federal Regulations (CFR) regarding blood and blood 
components.  This notice is being issued under 21 CFR 640.120(b) to respond to a public health 
need and address the urgent and immediate need for platelets for the treatment of active bleeding 
when conventional platelets are not available, or their use is not practical.  Maintaining platelet 
availability in the face of logistical challenges (e.g., in military, prehospital, or austere settings) 
or other threats to blood availability (e.g., mass casualty events or public health emergencies) is 
critical to assure that platelets are available to patients with active bleeding.  
 
Additionally, the guidance provides recommendations to blood establishments for the 
manufacture and labeling of cold-stored platelets (CSP).  The guidance also discusses the need 
for additional data on the efficacy of CSP, in particular, to address whether their use is supported 
when conventional platelets are available, and their use is practical.   
 
For the purposes of this guidance, conventional platelets include all platelets (as defined in 21 
CFR 640.20) intended for transfusion and stored at 20 to 24C.  Conventional platelets are also 
referred to as room-temperature platelets (RTP).  Platelets stored continuously at 1 to 6C within 
a specified time after collection are referred to in this guidance as CSP.  
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys 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 Agency guidances means that something is suggested or recommended, but 
not required.  
 
 
   
1  Contains Nonbinding Recommendations 
 
 
II.  BACKGROUND 
 
A.  Platelet Transfusions  
 
Platelets have a critical role in normal hemostasis and control of bleeding.  Platelet 
transfusions are used to treat patients with thrombocytopenia, dysfunctional platelet 
disorders (congenital, metabolic, or medication-induced), or active platelet-related 
bleeding, or for patients at serious risk of bleeding (i.e., prophylactic use) (Ref. 1). 
Platelets for transfusion may be manufactured from whole blood collections or collected 
by plateletpheresis (21 CFR 640.20(b)).  In the United States (U.S.), most plateletsare 
collected by plateletpheresis and stored continuously at 20 to 24C (see 21 CFR 
640.24(d)(1)).  The dating period (expiration date) for platelets with a storage 
temperature between 20 and 24C 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 (21 CFR 610.53(b)).  In the 
U.S., the current maximum dating period for platelets with a storage temperature between 
20 and 24C is up to 7 days in the FDA-cleared or approved storage containers.  Thus, 
platelets may be stored at 20 to 24C for a period of up to 7 days, depending on the 
bacterial risk control strategy (Ref. 2), and the blood collection, processing and storage 
system approved or cleared for such use by FDA (21 CFR 610.53(b)).  Despite efforts to 
maintain an adequate inventory of platelets stored at room temperature, in circumstances 
involving logistical challenges or other threats to blood availability, there remains an 
unmet need for platelets for the treatment of active bleeding in both pre-hospital and 
hospital settings.  At the November 2019 meeting of the Blood Products Advisory 
Committee (BPAC), presenters and public comments described rural and military settings 
where platelets were not available for treatment of acute bleeding, as well as logistical 
challenges in mainting platelet availability in the pre-hospital setting, including short 
potential storage duration, and need for agitation (Ref. 3).  Considering the hemostatic 
properties and potential logistical advantages of CSP that could address these challenges, 
there is a renewed interest in clinical use of CSP (see section II.C. of this guidance).  
 
B.  Regulatory History of CSP 
 
Regulatory standards for platelets established in 1975 (40 FR 4304) included cold storage 
of platelets at 1 to 6C, with a dating period of 72 hours.1  Although CSP were commonly 
used in the 1970s, investigators at that time observed that room-temperature storage of 
platelets resulted in higher recovery and longer survival in circulation in transfused 
patients (Refs. 4-6).  In subsequent decades, given the predominant use of prophylactic 
platelet transfusion to maintain adequate circulating platelets  and reduce the risk of 
spontaneous bleeding in patients who develop thrombocytopenia following chemotherapy 
or hematopoietic stem cell transplantation, platelets were stored almost exclusively at 20 
to 24C. 
 
 
1 See Additional Standards for Platelet Concentrate (Human), and Whole Blood (Human), January 29, 1975; 40 FR 
4300, at 4304; https://archives.federalregister.gov/issue_slice/1975/1/29/4298-4308.pdf#page=3. 
2  Contains Nonbinding Recommendations 
 
 
The dating period of platelets stored outside 20 to 24C is defined as specified in the 
instructions for use by the blood collection, processing and storage system approved or 
cleared for such use by FDA (21 CFR 610.53(b)).  Additionally, supplies and reagents 
used in the collection, processing, compatability testing, storage, and distribution of 
blood and blood components must be used in a manner consistent with instructions 
provided by the manufacturer (21 CFR 606.65(e)).  However, currently, there are no 
blood collection, processing and storage systems cleared or approved by FDA for storage 
of platelets at temperatures other than 20 to 24C.  Consequently, the manufacture of 
CSP by blood establishments is contingent upon issuance of exceptions or alternative 
procedures to 21 CFR 610.53(b), 21 CFR 606.65(e).  Further, exceptions or alternatives 
to the quality control testing requirements requirements in 21 CFR 640.25(b)(1) and 21 
CFR 640.25(b)(3) are necessary to assure the availability of platelets, as discussed in 
more detail in section II.E. of this guidance.  FDA has issued alternative procedures in 
response to requests from individual blood establishments under 21 CFR 640.120(a) to 
manufacture CSP (Ref. 7).   
 
C.  Available Data on Quality and Use of CSP 
 
While use of RTP became standard practice, researchers continued to perform in vitro 
studies to assess the effects of cold storage on platelet viability, activation, metabolism, 
and hemostatic function (Refs. 8-10).  These studies demonstrated that CSP have 
different physiologic properties compared to RTP (Refs. 10-13).  In summary, CSP have 
an activated profile, and, in some studies, CSP have demonstrated greater aggregation 
responses to agonists, higher clot strength in viscoelastic testing, and improved adhesion 
under flow when compared to RTP of similar storage age, especially beyond 5 days of 
storage (Refs. 14-19).  CSP may be more prone to aggregate formation during storage 
compared to RTP, and aggregation may be influenced by use of platelet additive 
solution, method of platelet preparation, and bedside filtration (Refs. 20-22).  Studies 
have also shown that cold storage inhibits growth of several bacterial strains in platelets 
(Ref. 23). 
 
The in vitro data prompted renewed interest in the use of CSP, especially in settings of 
trauma and massive bleeding (Refs. 24-26), because CSP potentially have longer dating 
periods than RTP and do not require the use of continuous agitation during storage (21 
CFR 640.25(a)).  Although the in vitro results suggest that CSP may have better 
preservation of hemostatic activity when compared to RTP with similar storage duration, 
well-controlled clinical studies examining their use remain limited (Ref. 27).  Studies 
published in the 1970s demonstrated that CSP prepared from whole blood showed 
improved pH and aggregability following up to 72 hours of storage, but their circulation 
and recovery in vivo were impaired compared to similarly prepared RTP (Ref. 6).  In 
thrombocytopenic patients and in healthy volunteer subjects pre-treated with aspirin, 
some studies found that CSP demonstrated better correction of bleeding time (Refs. 6 and 
28), while another study found either no measurable improvement, or only transient 
improvement, in bleeding time with CSP transfusion, whereas fresh platelets or RTP 
were largely able to correct bleeding times (Ref. 4).  More recent studies have confirmed 
the reduction in circulatory recovery and survival of CSP compared to RTP (Ref. 29), 
3  Contains Nonbinding Recommendations 
 
 
with a continuous decline in platelet recovery from 5 to 20 days of storage, and with 
platelet survival reaching its lowest level at 10 days (Ref. 30). 
 
To assess the efficacy of CSP in the treatment of bleeding, investigators in Norway 
conducted a two-stage pilot study in patients undergoing complex cardiac surgery 
comparing apheresis CSP to similarly prepared RTP (Ref. 31).  The first stage of the trial 
compared CSP to RTP in a two-armed randomized study, with 25 subjects per arm, and 
both components stored up to 7 days in platelet additive solution (PAS).  In the first 
stage, there was no significant difference in the median chest drain output between the 
study arms.  In the second stage, a single-arm study was performed in 15 subjects with 
CSP stored 8 to 14 days, and similar median chest drain output was observed.  No 
significant differences were observed between CSP and RTP in other outcomes such as 
number of transfused units of red cells, plasma, and platelets, platelet function testing, 
thromboembolic events, intensive care unit stay, and mortality.  The authors concluded 
that the pilot trial supported the feasibility of CSP stored for up to 14 days.  In a different 
study of CSP and RTP transfused to healthy volunteers after receiving anti-platelet 
medications (clopidogrel and acetylsalicylic acid (ASA)) (Ref. 32), CSP showed 
differences in in vitro testing when compared to RTP.  Although both CSP and RTP 
showed an immediate ASA-reversing effect after transfusion, the effect was shorter-lived 
in recipients of CSP compared to RTP.  Clopidogrel-reversing effects were not observed 
for either CSP or RTP, similar to other recent reports (Ref. 33).  The U.S. Department of 
Defense (DoD) also reported on CSP use in the military, with 48 patients transfused with 
CSP stored for up to 10 days (Ref. 34).  
 
The in vitro and clinical data on CSP were the topic of a November 2019 BPAC meeting 
(Ref. 35).  During this meeting, presenters shared most of the clinical and in vitro data 
summarized above with the committee.  In addition, investigators shared their clinical 
experience with use of CSP under a variance that allowed for 3 day storage, including an 
obervational study comparing trauma patients transfused with RTP to those transfused 
with CSP (20 subjects per arm).  These investigators described that while laboratory 
measures and clinical outcomes appeared similar between the groups, there were high 
rates of wastage with CSP, largely owing to expiration, and, to a lesser extent, aggregate 
formation.  Researchers from DoD also shared an observational study of 161 patients 
tranfused with only RTP compared to 94 patients transfused with CSP and RTP, and one 
patient transfused with only CSP, when the CSP had been stored for up to 14 days.  This 
comparison found no significant differences in rates of thromboembolic events, sepsis, or 
mortality when adjusting for injury severity.  
 
D.  The Need for Additional Studies on CSP 
 
At the November 2019 meeting of the BPAC (Ref. 35), the committee also recognized 
the need for additional data to support indications for use of CSP where conventional 
platelets are an available alternative.  FDA is also not aware of well-controlled clinical 
studies supporting use of CSP for prevention of bleeding (prophylactic transfusion).  An 
adaptive trial design in the setting of cardiac surgery, previously described in published 
literature (Ref. 36), was proposed and discussed at BPAC (Ref. 35) and is currently 
4  Contains Nonbinding Recommendations 
 
 
underway.  (See, e.g., Ref. 37; the ongoing nature of this study has also been disclosed on 
participating sites websites.)  Additional studies of CSP manufactured using different 
procedures and devices, for example CSP prepared from platelets manufactured using 
pathogen-reduction devices or CSP prepared from Whole-Blood-derived platelets, would 
provide additional information.  Sponsors and investigators planning such studies to 
support regulatory submissions for CSP are encouraged to contact FDA to discuss 
applicable regulatory pathways.  
 
FDA also expects that the use of CSP manufactured under the alternative procedures and 
recommendations described in this guidance will generate real-world evidence to further 
inform regulatory decision-making on the storage conditions and dating periods for 
devices used in the manufacture of CSP.  The use of standardized product labeling for 
CSP using the International Society of Blood Transfusion (ISBT) format (as 
recommended in section IV.E. of this guidance) has the potential to facilitate future data 
collection using surveillance infrastructure such as the FDA/CBER Biologics 
Effectiveness and Safety Initiative (BEST).   
 
FDA will continue to assess the available data on the use of CSP to determine whether 
changes to the alternative procedures and recommendations described in this guidance 
are appropriate.   
 
E.  Regulatory Considerations 
 
Under 21 CFR 640.120(b), to respond to a public health need, the Director of CBER may 
issue a notice of exception or alternative to any requirement in subchapter F of chapter I 
of title 21 of the CFR (21 CFR parts 600-680) regarding blood, blood components, or 
blood products, if a variance under this section is necessary to assure that blood, blood 
components, or blood products will be available in a specified location or locations to 
address an urgent and immediate need for blood, blood components, or blood products or 
to provide for appropriate donor screening and testing. 
 
A variance under 21 CFR 640.120(b) is necessary to assure that platelets will be available 
to treat active bleeding when conventional platelets are not available, or their use is not 
practical, to address the urgent and immediate need for platelets.  Accordingly, section 
III. of this guidance provides a notice of exceptions or alternatives under 21 CFR 
640.120(b) to the following regulations:  
 
  Section 21 CFR 610.53(b), which defines the dating period for platelets stored at 
temperatures other than 20 to 24oC as specified in the instructions for use of the 
blood collection, processing, and storage system approved or cleared for such use 
by FDA, and 
 
  section 21 CFR 606.65(e) which specifies that supplies and reagents used in the 
collection, processing, compatability testing, storage, and distribution of blood 
and blood components must be used in a manner consistent with instructions 
provided by the manufacturer.  This means that blood establishments must follow 
5  Contains Nonbinding Recommendations 
 
 
the instructions for use provided by the device manufacturer for the blood 
collection, processing, and storage system.   
 
Exceptions or alternatives to these requirements are necessary for the manufacture of CSP 
because the blood collection, processing and storage systems currently cleared or approved by 
FDA are not intended for platelet storage at temperatures other than 20 to 24C.  
  
In addition, section III. of this guidance provides a notice of exceptions or alternatives to certain 
quality control testing requirements for the manufacture of CSP, specifically: 
 
  section 21 CFR 640.25(b)(1), regarding testing for platelet count at the end of the 
storage period, and 
 
  section 21 CFR 640.25(b)(3), regarding measurement of actual plasma volume at the 
end of the storage period. 
 
The platelet count and plasma volume of platelets are routinely measured at the time of 
collection to determine collection yields.  A platelet count and plasma volume of CSP at the end 
of storage may not provide meaningful information due to aggregates formed during storage 
(Ref. 20) and FDA anticipates that requiring such testing would limit the availability of CSP.  
Exceptions or alternatives to these requirements are necessary to assure the availability of 
platelets. 
 
 
III.  NOTICE OF EXCEPTIONS OR ALTERNATIVES 
 
To address the urgent and immediate need for platelets in the U.S., the Director of CBER is 
issuing the following exceptions and alternatives under 21 CFR 640.120(b):   
 
  Sections 21 CFR 610.53(b) and 21 CFR 606.65(e):  The Director of CBER is issuing 
alternative procedures to 21 CFR 610.53(b) and 21 CFR 606.65(e) to permit the storage 
of apheresis platelets at 1 to 6C for up to 14 days from the date of collection, when such 
apheresis platelets are intended for the treatment of active bleeding when conventional 
platelets are not available or their use is not practical.   
 
  Sections 21 CFR 640.25(b)(1) and 21 CFR 640.25(b)(3):  The Director of CBER is issuing 
exceptions to the requirements in 21 CFR 640.25(b)(1) and 21 CFR 640.25(b)(3), regarding 
testing for platelet count and measurement of actual plasma volume, for the manufacture of 
apheresis platelets stored at 1 to 6C for up to 14 days from the date of collection, and 
intended to treat active bleeding when conventional platelets are not available or their use 
is not practical. 
 
Blood establishments may adopt the above-listed exceptions and alternatives without submitting 
a request to FDA under 21 CFR 640.120(a).  Licensed establishments must report changes to 
their approved application in accordance with 21 CFR 601.12 as discussed in section V. of this 
guidance.  
6  Contains Nonbinding Recommendations 
 
 
 
IV.  RECOMMENDATIONS AND CONSIDERATIONS FOR THE MANUFACTURE 
OF COLD-STORED PLATELETS 
 
Blood establishments that manufacture CSP must comply with all requirements that apply to 
platelets collected by automated methods, except for the alternative procedures and exceptions 
under 21 CFR 640.120(b) described in section III. of this guidance.  Notably, collection of 
apheresis platelets and further processing (such as leukocyte reduction or pathogen reduction) 
must be performed in accordance with the device manufacturers instructions for use (21 CFR 
606.65(e)), except for their instructions for the platelet storage temperature and dating period.    
 
A.  Manufacture of Apheresis CSP and Storage Conditions 
 
1.  Blood establishments should prepare CSP from apheresis platelets 
suspended in 100% plasma or an FDA-approved PAS.  
 
2.  Blood establishments must place CSP that have not been treated with an 
FDA-approved pathogen reduction device at 1 to 6C no later than 4 hours 
from the end of collection to assure that the risk of bacterial contamination 
is adequately controlled (21 CFR 606.145(a)), see section IV.B. of this 
guidance.  
 
3.  Blood establishments should place pathogen-reduced apheresis CSP in 
cold storage at 1 to 6C no later than 4 hours after completion of the 
pathogen reduction process. 
 
4.  Blood establishments must continuously store CSP at a temperature of 1 to 
6C (21 CFR 640.24(d)(2)), must maintain CSP at a temperature of 1 to 
10C during shipment (21 CFR 600.15(a)), and should not return CSP 
placed in room-temperature conditions back into cold-stored inventory or 
relabel CSP as RTP.  
 
5.  For CSP stored at a temperature of 1 to 6C for a period of up to 14 days, 
agitation is optional (21 CFR 640.25(a)). 
 
B.  Control of Bacterial Contamination of Platelets  
 
1.  Cold storage of apheresis platelets as described in this guidance is an 
adequate and appropriate method to assure that the risk of bacterial 
contamination is adequately controlled (21 CFR 606.145(a)).  However, 
blood establishments may consider implementing additional measures 
described in the FDA guidance, titled Bacterial Risk Control Strategies 
for Blood Collection Establishments and Transfusion Services to Enhance 
the Safety and Availability of Platelets for Transfusion (Ref. 2).    
   
7  Contains Nonbinding Recommendations 
 
 
2.  Blood establishments must not release CSP, or any other component 
prepared from the same collection procedure, for transfusion if the 
platelets are identified as bacterially contaminated (21 CFR 606.145 (b) 
and (c)).  
 
C.  Process Validation 
 
1.  Blood establishments must conduct process validation to assure that a 
specific process will consistently produce a product meeting its pre-
determined specifications and quality characteristics (21 CFR 211.100).  
We recommend that blood establishments validate the CSP manufacturing 
process using a binomial distribution statistical sampling plan to 
demonstrate with 95% confidence that greater than 75% of the platelets 
stored at 1-6 C maintain a pH not less than 6.2 at the end of the storage 
period of up to 14 days.  The blood establishment should test 
consecutively manufactured platelet components at each manufacturing 
location at the end of the storage period.  Testing approaches consistent 
with this recommendation include: 
 
  test 11 platelet components with no failures, or 
  test 18 platelet components with 1 allowable failure, or 
  test 24 platelet components with 2 allowable failures  
 
Note that you may combine platelet components prepared from all 
approved collection types (e.g., single/doubles/triples) and collection 
devices.  
 
D.  Quality Control Testing  
 
Blood establishments must conduct monthly pH quality control (QC) testing on CSP, and 
that testing must be performed in accordance with the QC statistical sampling plan as 
described in the firms written procedures (21 CFR 640.25 (b)(2), 21 CFR 211.160(b), 
and 21 CFR 211.165(c)).  The number of CSP components included in the overall 
monthly QC testing plan should represent the proportion of CSP in the total platelet 
inventory.  For example, if 20% of your total platelet inventory is CSP, you should 
include that proportion of CSP in your monthly QC platelet testing plan.  
 
E.  Container Labels  
 
1.  Blood establishments must label CSP in accordance with 21 CFR 606.121.   
 
2.  We recommend the use of a uniform container label for CSP.  In 
particular, we recommend you use the International Society of Blood 
Transfusion (ISBT) 128 format specified in the U.S. Industry Consensus 
Standard for the Uniform Labeling of Blood and Blood Components 
Using ISBT 128 for container labels.  
8  Contains Nonbinding Recommendations 
 
 
 
F.  Circular of Information 
 
Blood establishments must provide adequate directions for use of CSP in the Circular of 
Information (21 CFR 606.122).  We recommend including the following statements and 
information:   
 
a.  CSP are intended for the treatment of active bleeding when conventional 
platelets are not available, or their use is not practical. 
 
b.  CSP must be stored continuously at 1-6C to control the risk of bacterial 
contamination for up to 14 days (section IV.B. of this guidance).  
 
c.  Transfusion services should establish procedures for examining CSP for 
visible aggregates before transfusion. 
 
 
V.  REPORTING IMPLEMENTATION OF MANUFACTURING AND LABELING 
CHANGES 
 
Blood establishments that manufacture licensed blood components must report changes to their 
approved Biologics License Application in accordance with 21 CFR 601.12.  
 
For establishments already licensed to manufacture apheresis platelets or Whole Blood-derived 
platelets, the manufacture of CSP is considered to have a moderate potential to adversely affect 
the identity, strength, quality, purity, or potency of the product as it may relate to the safety or 
effectiveness of the product.  Therefore, you must report this change to your approved 
application to FDA as a Supplement - CBE30 in accordance with 21 CFR 601.12(c). 
 
We recommend that you include the following in your CBE30 submission:  
 
a.  Form FDA 356h, Application to Market a New or Abbreviated New Drug or 
Biologic for Human Use.  
 
b.  Cover letter describing the contents of the supplement and a description of the 
CSP manufacturing process. 
 
c.  Address and registration number(s) of the facility/facilities that will manufacture 
CSP, including quality control testing and storage at 1-6 C.  
 
d.  Standard operating procedures, if changes to previously approved procedures 
have been made or new procedures created to describe the manufacturing process 
for CSP.  
 
e.  Summary of results of the validation study performed at each manufacturing 
facility to show that a pH of  6.2 is maintained throughout the storage period.   
9  Contains Nonbinding Recommendations 
 
 
 
f.  Container labels.  
 
g.  Amended Circular of Information. 
 
Unlicensed blood establishments are not required to report this change to FDA. 
 
 
   
10  Contains Nonbinding Recommendations 
 
 
VI.  REFERENCES 
 
1.  AABB, ABC, ARC, ASBP.  Circular of Information for the Use of Human Blood and 
Blood Components; 2021. 
2.  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; 2019.  Available from:  
https://www.fda.gov/media/123448/download. 
3.  121st Meeting of the Blood Products Advisory Committee - Meeting Transcript; 2019. 
Available from:  https://www.fda.gov/media/134477/download. 
4.  Slichter, SJ and LA Harker, Preparation and storage of platelet concentrates. 
Transfusion; 1976.  16(1): p. 8-12. 
5.  Murphy, S and FH Gardner, Effect of storage temperature on maintenance of platelet 
viability--deleterious effect of refrigerated storage.  N. Engl. J. Med.; 1969.  280(20): p. 
1094-1098. 
6.  Becker, GA, et al., Studies of platelet concentrates stored at 22 C and 4 C.  Transfusion; 
1973.  13(2): p. 61-68. 
7.  U.S. Food and Drug Administration.  Exceptions and Alternative Procedures Approved 
Under 21 CFR 640.120:  Available from:  https://www.fda.gov/vaccines-blood-
biologics/regulation-blood-supply/exceptions-and-alternative-procedures-approved-
under-21-cfr-640120 . 
8.  Pidcoke, HF, et al., Refrigerated platelets for the treatment of acute bleeding:  a review 
of the literature and reexamination of current standards.  Shock; 2014.  41 Suppl 1: p. 
51-53. 
9.  Reddoch-Cardenas, KM, et al., Cold-stored platelets:  A product with function optimized 
for hemorrhage control.  Transfus. Apher. Sci.; 2019.  58(1): p. 16-22. 
10.  Getz, TM, Physiology of cold-stored platelets.  Transfus. Apher.  Sci.; 2019.  58(1): p. 
12-15. 
11.  Rumjantseva, V and KM Hoffmeister, Novel and unexpected clearance mechanisms for 
cold platelets.  Transfus. Apher. Sci.; 2010.  42(1): p. 63-70. 
12.  Hoffmeister, KM, et al., The Clearance Mechanism of Chilled Blood Platelets.  Cell; 
2003.  112(1): p. 87-97. 
13.  Kattlove, HE and B Alexander, The effect of cold on platelets.  I. Cold-induced platelet 
aggregation.  Blood; 1971.  38(1): p. 39-48. 
11  Contains Nonbinding Recommendations 
 
 
14.  Reddoch, KM, et al., Hemostatic function of apheresis platelets stored at 4 degrees C and 
22 degrees C.  Shock; 2014.  41 Suppl 1: p. 54-61. 
15.  Nair, PM, et al., Platelets stored at 4 degrees C contribute to superior clot properties 
compared to current standard-of-care through fibrin-crosslinking.  Br. J. Haematol.; 
2017.  178(1): p. 119-129. 
16.  Nair, PM, et al., Effect of cold storage on shear-induced platelet aggregation and clot 
strength.  J Trauma Acute Care Surg; 2014.  77(3 Suppl 2): p. S88-93. 
17.  Braathen, H, et al., In vitro quality and platelet function of cold and delayed cold storage 
of apheresis platelet concentrates in platelet additive solution for 21 days.  Transfusion; 
2019.  59(8): p. 2652-2661. 
18.  Johnson, L, et al., Refrigeration of apheresis platelets in platelet additive solution (PAS-
E) supports in vitro platelet quality to maximize the shelf-life.  Transfusion; 2021.  
61(S1): p. S58-S67. 
19.  Irene, M, et al., Cold storage of platelets in additive solution: the impact of residual 
plasma in apheresis platelet concentrates.  Haematologica; 2019.  104(1): p. 207-214. 
20.  Getz, TM, et al., Storage of platelets at 4C in platelet additive solutions prevents 
aggregate formation and preserves platelet functional responses.  Transfusion; 2016. 
56(6): p. 1320-1328. 
21.  Li, VJ, et al., Effect of bedside filtration on aggregates from cold-stored whole blood-
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