Manufacture of Blood Components 
Using a Pathogen Reduction Device in 
Blood Establishments:   
Questions and Answers
 
 
 
Guidance for Industry 
 
 
 
 
 
 
 
 
 
 
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 
November 2021  Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  QUESTIONS AND ANSWERS ....................................................................................... 2 
A.  General Information ............................................................................................. 2 
B.  Manufacture of Pathogen-Reduced Blood Components by Blood 
Establishments....................................................................................................... 3 
C.  Reporting Implementation of Pathogen Reduction in Licensed Blood 
Establishments....................................................................................................... 6 
III.  REFERENCES ................................................................................................................ 10 
APPENDIX .................................................................................................................................. 11 
 
i  Contains Nonbinding Recommendations 
 
 
Manufacture of Blood Components Using a Pathogen Reduction 
Device in Blood Establishments:   
Questions and Answers 
 
 
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 
 
We, FDA, are providing you, blood establishments that collect or process blood and blood 
components, with recommendations for implementing a pathogen reduction device for the 
manufacture of pathogen-reduced blood components.  We have received specific questions from 
blood establishments who have chosen to use the INTERCEPT Blood System for Platelets and 
Plasma and who have questions on implementation of this pathogen reduction device.  As a 
result, we are providing guidance in a question and answer format, addressing the most 
frequently asked questions.  This guidance also provides recommendations to licensed 
manufacturers on reporting the manufacturing changes associated with implementation of a 
pathogen reduction device under Title 21 of the Code of Federal Regulations 601.12 (21 CFR 
601.12). 
 
The recommendations in this guidance apply to blood establishments that intend to manufacture 
pathogen-reduced platelet and plasma products using an FDA approved pathogen reduction 
device.  Currently, the INTERCEPT Blood System has been approved for the manufacture of 
certain pathogen-reduced platelet and plasma products, and the preparation of cryoprecipitated 
fibrinogen complex.  If the product platforms for this FDA approved device change or FDA 
approves another pathogen reduction device with a similar intended use in the future, the Agency 
will consider providing additional recommendations to blood establishments.  
 
This guidance finalizes the draft guidance entitled 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 contents of this document do not have the force and effect of law and are not meant to bind 
the public in any way, unless specifically incorporated into a contract.  This document is 
intended only to provide clarity to the public regarding existing requirements under the law. 
FDA guidance documents, including this guidance, should be viewed only as recommendations, 
1  Contains Nonbinding Recommendations 
 
 
unless specific regulatory or statutory requirements are cited.  The use of the word should in 
FDA guidances means that something is suggested or recommended, but not required. 
 
 
II.  QUESTIONS AND ANSWERS 
 
A.  General Information 
 
1.  After blood establishments implement a pathogen reduction device for 
the manufacture of pathogen-reduced blood components, are they 
required to perform the infectious disease testing required in 21 CFR 
610.40? 
 
Yes.  Under 21 CFR 610.40(a) testing is required of each donation for evidence of 
infection due to relevant transfusion-transmitted infections (RTTI) unless an 
exception applies, or, in accordance with 21 CFR 610.40(a)(2)(iii) and 21 CFR 
610.40(a)(3)(ii), adequate and appropriate alternative procedures have been found 
acceptable for this purpose by FDA.  If identified, we will announce such 
alternative procedures in a guidance document. 
 
2.  After blood establishments implement a pathogen reduction device for 
the manufacture of pathogen-reduced blood components, can they modify 
the donor history questionnaire to remove questions related to risk of 
disease transmission? 
 
No.  You must continue to assess the donors medical history for factors 
associated with an increased risk for, or evidence of, an RTTI, in accordance with 
21 CFR 630.10(e)(1).  We may consider revised recommendations for complying 
with the requirements for assessing a donors medical history in 21 CFR 630.10, 
and would announce such recommendations in a guidance document.  
 
3.  Which blood components can undergo pathogen reduction using the 
INTERCEPT Blood System?  
 
Please refer to the manufacturers instructions (operators manual and processing 
sets package inserts) for information about which specific blood components can 
be pathogen-reduced with this device.   
 
4.  Can pathogen reduction using the INTERCEPT Blood System 
substitute for irradiation of platelets to prevent the risk of transfusion-
associated graft versus host disease (TA-GVHD)? 
 
Yes.  As described in the FDA-approved labeling, the INTERCEPT Blood 
System for Platelets can be used as an alternative to gamma irradiation for 
prevention of transfusion-associated graft versus host disease (TA-GVHD).   
 
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5.  Can pathogen reduction of platelets substitute for bacterial detection 
testing to reduce bacterial contamination in platelets?  
 
Yes.  When used in accordance with the manufacturers instructions, we consider 
use of the INTERCEPT Blood System acceptable to control the risk of bacterial 
contamination in platelets as required in 21 CFR 606.145.   
 
In the future, we may approve or clear other pathogen reduction devices that 
would be acceptable to control the risk of bacterial contamination of platelets. 
 
6.  Can pathogen-reduced plasma undergo fractionation for further 
manufacturing into plasma derivatives? 
 
The impact on product quality of using pathogen-reduced plasma in the 
manufacture of plasma derivatives is not known at this time.  Consignees should 
contact FDA before using pathogen-reduced plasma for further manufacture.   
 
B.  Manufacture of Pathogen-Reduced Blood Components by Blood 
Establishments 
 
1.  Where can blood establishments find information on additional 
specifications for manufacturing pathogen-reduced blood components 
using the INTERCEPT Blood System? 
 
You should refer to the INTERCEPT Blood System manufacturers instructions 
for additional specifications regarding the manufacture of pathogen-reduced 
platelet and plasma products and cryoprecipitated fibrinogen complex. 
 
2.  According to the manufacturers instructions for the INTERCEPT 
Blood System for platelets, platelets must be pathogen-reduced within 24 
hours of collection.  Should the platelets be agitated prior to the pathogen 
reduction process?  
 
Yes.  Under 21 CFR 640.25(a), platelets stored at 20C to 24C must be gently 
agitated continuously during the storage period.  This includes during the storage 
of the platelet products both before and after pathogen reduction. 
 
3.  Can blood establishments prepare Cryoprecipitated AHF from apheresis 
plasma or Whole Blood-derived pooled plasma that was pathogen-
reduced using the INTERCEPT Blood System?  
 
Yes, provided the pathogen-reduced apheresis plasma or Whole Blood-derived 
pooled plasma is placed in the freezer within 8 hours after collection (for Whole 
Blood-derived pools  within 8 hours after collection of the oldest unit in the 
pool) or within the timeframe specified in the directions for use for the blood 
3  Contains Nonbinding Recommendations 
 
 
collecting, processing, and storage system, in accordance with the requirements in 
21 CFR 640.54(a)(2).   
 
Cryoprecipitated AHF prepared from pathogen-reduced apheresis plasma or 
Whole Blood-derived pooled plasma must contain acceptable levels of 
antihemophilic factor and fibrinogen in the final product in accordance with the 
requirements in 21 CFR 640.54(b) and 21 CFR 606.122(n)(2).   
 
4.  How long can Whole Blood-derived plasma be kept at room temperature 
before it is pathogen-reduced using the INTERCEPT Blood System? 
 
The time at room temperature must be determined by the regulations applicable to 
the products you intend to manufacture.  For example, if you intend to 
manufacture pathogen-reduced Fresh Frozen Plasma, you must place the plasma 
in a freezer within 8 hours after collection (21 CFR 640.34(b)).  According to the 
manufacturers instructions for the INTERCEPT Blood System for Plasma, all 
manufacturing steps, including separating plasma from red blood cells, 
performing the pathogen reduction process, and placing the pathogen-reduced 
plasma in the freezer, must be completed within 24 hours after collection.  The 
manufacturers instructions for the INTERCEPT Blood System for Plasma do 
not specify how long Whole Blood-derived plasma can be stored at room 
temperature before it is pathogen-reduced.   
 
5.  The manufacturers instructions for the INTERCEPT Blood System 
state that the red blood cell content of the platelets and plasma before 
pathogen reduction should be < 4.0 x 106 RBC/mL.  Do blood 
establishments need to determine the red blood cell content of each 
platelet and plasma product before they undergo the pathogen reduction 
process?   
 
Yes.  Unless otherwise stated in the manufacturers instructions, you may use 
tools, such as the color comparator provided by the manufacturer, to estimate the 
red blood cell content of the platelets and plasma before pathogen reduction.  
Products that do not meet the standards stated in the manufacturers instructions 
(e.g., contain more than the acceptable red blood cell content) must not undergo 
the pathogen reduction process (21 CFR 606.65(e)).   
 
6.  What other testing should be performed to qualify platelet and plasma 
products before these products are pathogen-reduced using the 
INTERCEPT Blood System? 
 
Blood establishments should refer to the manufacturers instructions of the FDA 
approved pathogen reduction device for input specifications for the manufacture 
of pathogen-reduced platelet and plasma products.  The manufacturers 
instructions will guide what further testing needs to be performed (21 CFR 
606.65(e)). 
4  Contains Nonbinding Recommendations 
 
 
 
7.  Should blood establishments determine platelet retention (i.e., platelet 
yield after pathogen reduction compared to platelet yield before pathogen 
reduction) as part of their validation and quality control testing?  If so, 
what would be an acceptable retention value? 
 
Section 606.140(a) requires that laboratory procedures include the establishment 
of scientifically sound and appropriate specifications, standards and test 
procedures to assure that blood and blood components are safe, pure, potent and 
effective.  Accordingly, to ensure manufacturing consistency, we recommend that 
platelets that have been pathogen-reduced using the INTERCEPT Blood System 
should have at least 80% platelet retention.  We recommend that you use a 
statistically sound sample size and testing procedures that will ensure, with 95% 
confidence, that greater than 95% of the pathogen-reduced platelets will meet this 
specification consistent with previously recommended statistical parameters.  See 
the Appendix of this guidance. 
 
8.  What other quality control procedures are recommended for pathogen-
reduced platelets? 
 
For purposes of the quality control testing required under 21 CFR 640.25, we 
recommend that you consider pathogen-reduced platelets as a distinct product 
from platelets that are not pathogen-reduced.  Quality control testing for 
pathogen-reduced platelet products should be performed separately from quality 
control testing of platelet products that are not pathogen-reduced.   
 
In addition, we recommend that quality control testing be performed separately 
for pathogen-reduced platelets in platelet additive solution and pathogen-reduced 
platelets in 100% plasma.  
 
The quality control testing of the pathogen-reduced platelets should include 
platelet yield and pH using a scientifically valid statistical sampling plan such as 
the binomial distribution (Ref. 1) or hypergeometric distribution (Ref. 2).  The 
samples used for quality control testing can be composed of platelet products 
collected at any blood establishment operating under the same license.  Since the 
Instructions for Use for the INTERCEPT Blood system provide that the starting 
platelet product is leukocyte-reduced platelets, we are not recommending that the 
residual white cell count be performed after the pathogen reduction process (21 
CFR 606.65(e)).  
 
The Appendix of this guidance contains recommendations for platelet quality 
control monitoring after pathogen reduction using the INTERCEPT Blood 
System. 
 
5  Contains Nonbinding Recommendations 
 
 
9.  Where can blood establishments find information about product codes 
for labeling pathogen-reduced blood components? 
 
We recognize the consensus standards prepared by the International Council for 
Commonality in Blood Banking Automation (ICCBBA) as an acceptable format 
to comply with the labeling requirements for blood and blood components in 21 
CFR 606.121.  You may consult ICCBBA for the product names and codes that 
have been assigned to pathogen-reduced blood components. 
 
C.  Reporting Implementation of a Pathogen Reduction Device in Licensed 
Blood Establishments 
 
1.  How should licensed blood establishments submit requests to 
manufacture pathogen-reduced blood components? 
 
An establishment that distributes blood components in interstate commerce must 
have an approved Biologics License Application (BLA), in accordance with 
section 351 of the Public Health Service Act (42 U.S.C. 262).  Licensed blood 
establishments must report major changes to their approved BLAs by submitting a 
Prior Approval Supplement (PAS) in accordance with 21 CFR 601.12(b):  
Changes Requiring Supplement Submission and Approval Prior to Distribution of 
the Product Made Using the Change (Major Changes).  You must not distribute in 
interstate commerce blood components made using a new or changed 
manufacturing process requiring a PAS until you have received FDA approval of 
your PAS (21 CFR 601.12(b)(3)). 
 
We believe a PAS submission is appropriate in the following situations: 
 
a.  You are already licensed to manufacture the blood components you intend 
to pathogen reduce using an FDA approved device. 
 
b.  You are not already licensed to manufacture the blood components you 
intend to pathogen reduce using an FDA approved device.  In accordance 
with 21 CFR 601.12(b)(3)(iv), your submission must include, among other 
things, information about how the blood components are manufactured 
prior to pathogen reduction, e.g., standard operating procedures (SOPs) 
and quality control data. 
 
c.  You may consider submitting a Comparability Protocol as a PAS under 21 
CFR 601.12(e) if you will be implementing the pathogen reduction 
process using the same procedures in multiple locations.  A Comparability 
Protocol is not required, but an approved Comparability Protocol may 
permit a reduced reporting category for implementing the pathogen 
reduction process in multiple locations. 
 
6  Contains Nonbinding Recommendations 
 
 
Questions may be submitted via email to 
CBEROBRRBPBInquiries@fda.hhs.gov. 
 
2.  What should be submitted to FDA under 21 CFR 601.12? 
 
To comply with the requirements in 21 CFR 601.12(b)(3) and 21 CFR 
601.12(f)(1), you must include the following minimum information in your PAS 
submission: 
 
a.   Form FDA 356h, Application to Market a New or Abbreviated New 
Drug or Biologic for Human Use. 
 
b.  A list of the blood components that will be pathogen-reduced. 
 
c.   The address and registration number of the facility/facilities where the 
pathogen-reduced blood components will be manufactured. 
 
d.  A description of the manufacturing process for the pathogen-reduced 
blood components, including the submission of written SOPs that include: 
 
i.  Processes to ensure that blood components selected to undergo the 
pathogen reduction process meet the product specifications 
(guardbands) described in the manufacturers instructions. 
 
ii.  The handling of blood components that were not successfully 
pathogen-reduced, including how process and non-process failures 
will be investigated. 
 
iii. Quality oversight of the manufacturing process. 
 
iv.  Quality control procedures and the sampling plan.  
 
e.   Container labels for the pathogen-reduced blood components. 
 
f.   The Circular of Information for the pathogen-reduced blood components.  
If you are not using the current version of the circular recognized by FDA, 
include your circular in the PAS submission.   
 
g.  The pathogen reduction process validation protocol used and a summary 
of the results, including the results of any process and non-process failure 
investigations. 
 
h.  At least two months of quality control data for each type of platelet or 
cryoprecipitate product that is pathogen-reduced.   
 
For each facility manufacturing pathogen-reduced blood components:  
7  Contains Nonbinding Recommendations 
 
 
 
i.  The platelet yield for pathogen-reduced platelets made at that 
facility.   
 
ii.  The percent platelet retention for pathogen-reduced platelets made 
at that facility. 
 
iii. The antihemophilic factor and fibrinogen content of pathogen-
reduced cryoprecipitate products.  
 
For all facilities performing pathogen reduction operating under the same 
license: 
 
  The pH for pathogen-reduced platelets. 
 
Comparability Protocol submissions under 21 CFR 601.12(e) must also include 
the plan for implementing the process for manufacturing pathogen-reduced blood 
components in multiple manufacturing facilities.  The plan should include a 
description of how you will validate the new processes and how staff will be 
trained. 
 
You should include the following minimum information in your Changes Being 
Effected in 30 Days supplement (21 CFR 601.12(c)) for your approved 
Comparability Protocol: 
 
a.  Form FDA 356h, Application to Market a New or Abbreviated New 
Drug or Biologic for Human Use. 
 
b.  The submission tracking number (STN) for the approved Comparability 
Protocol. 
 
c.  A description of the blood components that will be pathogen-reduced. 
 
d.  The address and registration number of the facility/facilities where the 
pathogen-reduced blood components will be manufactured. 
 
e.  A summary of the validation results, including any process and non-
process failure investigations. 
 
f.  Two months of quality control data for each type of  pathogen-reduced 
platelet and cryoprecipitate product (as described in section II.B. questions 
3 and 8, and section II.C. question 2.h. of this guidance). 
 
Questions regarding your submission may be submitted via email to  
CBEROBRRBPBInquiries@fda.hhs.gov. 
 
8  Contains Nonbinding Recommendations 
 
 
3.  Once a supplement is approved, will the approval apply to all 
manufacturing facilities operating under the blood establishments 
license? 
 
No.  These supplements are considered site-specific approvals.  This means that 
each facility manufacturing pathogen-reduced blood components must be 
individually approved to perform this process.  If you want to manufacture 
pathogen-reduced blood components in multiple facilities, you may consider 
submitting a Comparability Protocol as discussed in section II.C. question 1.c. of 
this guidance.  
   
9  Contains Nonbinding Recommendations 
 
 
III.  REFERENCES 
 
1.  Guidance for Industry and FDA Review Staff:  Collection of Platelets by Automated 
Methods, December 2007, https://www.fda.gov/media/70720/download.  
 
2.  Guidance for Industry:  Pre-Storage Leukocyte Reduction of Whole Blood and Blood 
Components Intended for Transfusion, September 2012, 
https://www.fda.gov/media/84460/download. 
 
 
 
 
 
 
 
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APPENDIX:  FDA RECOMMENDATIONS FOR PLATELET QUALITY CONTROL 
MONITORING AFTER PATHOGEN REDUCTION USING THE INTERCEPT 
BLOOD SYSTEM  
 
 
Recommended  Recommended Criteria for   Recommended 
Specifications  Validation and Quality Control  Confidence 
(For Storage in Platelet Additive Solution  Level/Degree of 
or in 100% Plasma)  Conformity1 
Platelet Yield2    3 x 1011  95%/75%4 
Percent Platelet   80%  95%/95%5 
Retention 
pH3   6.2  95%/95%5 
1.  A binomial statistical sampling plan may be used for both process validation and quality control (Ref. 1).  A 
hypergeometric statistical sampling plan can only be used for quality control (Ref. 2).   
2.  Pathogen-reduced platelets with yields less than 3.0 x 1011 should be appropriately labeled with the actual 
platelet count (Ref. 1). 
3.  At issue or outdate after storage at 20 - 24 C (21 CFR 640.24(d)). 
4.  We recommend 95% confidence that greater than 75% of the components meet the standard. 
5.  We recommend 95% confidence that greater than 95% of the components meet the standard. 
 
 
 
 
 
 
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