Considerations for the Development of 
Dried Plasma Products Intended for 
Transfusion 
 
 
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. 
 
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 2019  Contains Nonbinding Recommendations 
 
Table of Contents 
 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 1 
III.  CONSIDERATIONS FOR PRODUCT DEVELOPMENT.......................................... 2 
A.  Considerations Regarding Input Plasma ............................................................ 2 
B.  Manufacturing and Product Quality .................................................................. 3 
C.  Packaging and Reconstitution ............................................................................. 4 
D.  Clinical Studies ...................................................................................................... 4 
E.  Regulatory Pathway for Marketing of Devices for the Manufacturing of 
Dried Plasma  ........................................................................................................ 5 
IV.  EXPEDITED PROGRAMS ............................................................................................. 6 
V.  COMMUNICATION WITH FDA .................................................................................. 6 
VI.  REFERENCES .................................................................................................................. 7 
i  Contains Nonbinding Recommendations 
 
Considerations for the Development of Dried Plasma Products 
Intended for Transfusion 
 
 
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 recommendations intended to assist manufacturers, sponsors, and 
applicants developing dried plasma products intended for transfusion in order to facilitate the 
availability of safe and effective dried plasma1 products in the United States (U.S.).  This 
guidance provides considerations for the successful development and licensing of dried plasma 
products and for the approval of devices used to manufacture dried plasma.  The guidance 
includes recommendations on optimal sources of input plasma;2 manufacturing and product 
quality, including product characterization; packaging and reconstitution; clinical studies; and 
device submissions.  This guidance finalizes the draft guidance of the same title dated October 
2018. 
 
FDAs guidance documents, including this guidance, do not establish legally enforceable 
responsibilities.  Instead, guidances describe the FDAs 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 FDAs guidances means that something is suggested or 
recommended, but not required. 
 
 
II.   BACKGROUND 
 
Plasma is a critical component of early transfusion therapy in the management of traumatic 
hemorrhage (Ref. 1).  Plasma can replenish various coagulation proteins that are consumed 
during the coagulopathy that may accompany traumatic injury (Ref. 2).  Because plasma 
                                                 
1 For the purposes of this guidance, dried plasma means dried (e.g., lyophilized, spray-dried) plasma that is 
intended for transfusion following reconstitution. 
2 For the purposes of this guidance, input plasma describes plasma used as the starting material for the preparation 
of the dried plasma product or used as the input into a device intended for the preparation of a dried plasma product. 
Recommendations regarding use of Plasma (as defined in 21 CFR Part 640, Subpart D) or Source Plasma (as 
defined in 21 CFR 640, Subpart G) as input plasma appear in section III.A of this guidance. 
1  Contains Nonbinding Recommendations 
 
products intended for transfusion such as fresh frozen plasma (FFP), plasma frozen within 24 
hours after phlebotomy (PF24), and plasma frozen within 24 hours after phlebotomy held at  
room temperature up to 24 hours after phlebotomy (PF24RT24) are stored frozen, these products 
need to be thawed prior to transfusion.  This limits or prevents the use of plasma in settings 
where freezers and other support equipment are unavailable (e.g., battlefields, remote locations, 
and other austere settings), and may lead to delayed administration.  Dried plasma (such as 
freeze-dried or spray-dried plasma) offers the potential to address these challenges by providing 
a product that is stable at ambient temperatures, and which can be rapidly reconstituted and 
transfused.  
 
The potential benefits of dried plasma were recognized long ago, and dried plasma products were 
used by U.S. Armed Forces during WWII (Ref. 3).  However, further development and use of 
dried plasma was generally discontinued in the U.S. in large part because of infectious disease 
transmission risks (Ref. 4).  As mitigation of infectious disease transmission risks improved, 
including enhanced testing methods and pathogen reduction technologies, interest in the 
development of dried plasma products reemerged.  More recent clinical studies have 
demonstrated promising efficacy and safety of dried plasma, particularly in military applications, 
and dried plasma products are available for limited use in Germany, South Africa, and France 
(Ref. 3).  
 
 
III.   CONSIDERATIONS FOR PRODUCT DEVELOPMENT 
 
A.  Considerations Regarding Input Plasma 
 
1.  Plasma donors are subject to the donor eligibility requirements set forth in  
21 CFR 630.10 and 630.15. 
 
2.  The dried plasma product should be manufactured from a licensed single donor 
plasma product intended for transfusion or pools of these products.  While Source 
Plasma (21 CFR Part 640, Subpart G) may also be considered in the manufacture 
of dried plasma, it is recommended that manufacturers considering the use of 
Source Plasma discuss this with FDA in advance of product development (section 
V of this document). 
 
3.  Blood and blood components, including plasma, intended for transfusion or for 
use in product manufacturing are subject to the testing requirements for relevant 
transfusion-transmitted infections (RTTI) in 21 CFR 610.40. Manufacture of a 
dried plasma product may occur prior to completion of RTTI testing.  However, 
testing for RTTI must be completed, and the results must be nonreactive, before 
distribution of the finished dried plasma product (21 CFR 630.30).  Manufacturers 
preparing dried plasma from pooled donations should consider additional 
measures to reduce infectious disease transmission risks.  Examples of such 
measures may include viral inactivation or manufacture from input plasma treated 
with an FDA-approved pathogen reduction technology.  
 
2  Contains Nonbinding Recommendations 
 
4.  Development of dried plasma products that can be administered irrespective of 
the ABO group of the recipient offers operational advantages and may decrease 
the risk of transfusion of ABO incompatible units, especially in urgent clinical 
settings. Manufacturers should consider the use of input plasma from AB donors 
or A donors with low anti-B titers.   
 
5.  For products that can be administered irrespective of the ABO group of the 
recipients, FDA recommends documentation of the anti-A and anti-B antibody 
titers of the input plasma (in accordance with the ABO blood groups included in 
the pools), and the methods used for measuring the titer levels.  
 
6.  For development of ABO-group-specific products, early discussion with FDA is 
recommended. 
 
 
B.  Manufacturing and Product Quality 
 
1.  Carefully consider the design, validation, and documentation of the steps involved 
in the manufacturing process, including the controls used to maintain product 
quality.  These steps include input plasma selection (which may include donor 
selection, donation testing, and plasma collection procedures), pathogen reduction 
(if applicable), pre-drying treatment (freezing, for instance), process for thawing 
of frozen input plasma, storage conditions, characterization of antibody titers (if 
applicable), time elapsed prior to drying, and the drying process.  Processing steps 
should be performed under aseptic conditions.  
 
2.  Submit characterization data of the final reconstituted plasma product intended for 
transfusion, including a paired comparison to the input plasma, to demonstrate the 
effects of the manufacturing process on the quality of plasma.  Characterization 
studies should be discussed in advance with FDA and should, in general, assess 
the following properties: 
 
a.  Activities of pro-coagulant and anti-coagulant proteins in the reconstituted 
plasma, including but may not be limited to the following tests: 
 
i.  Prothrombin time (PT) or international normalized ratio (INR) 
ii.  Activated partial thromboplastin time (aPTT) 
iii. Activity of heat-labile proteins (e.g., Factor V, Factor VIII) 
iv. Activity of anticoagulant proteins (e.g., Protein S, Protein C) 
v.  Antigen and activity of large coagulation proteins prone to aggregation 
and degradation (e.g., fibrinogen, von Willebrand factor) 
vi. Markers of coagulation activation (e.g., thrombin-antithrombin 
complexes, fibrin degradation products) 
 
b.  Residual moisture content of the dried plasma product  
c.  pH of the reconstituted plasma 
3  Contains Nonbinding Recommendations 
 
d.  Characterization of particles to determine the impact of the drying process and 
storage conditions, and to assist in establishing the proper reconstitution time. 
 
3.  Develop a written stability testing program to determine the appropriate storage 
conditions and expiration dates (21 CFR 211.166).  If applicable, stability data 
should include information on transport conditions, and on short and long-term 
temperature excursions from labeled storage conditions, including exposure to 
freezing and high temperatures.  
 
4.  The written stability testing program must include testing of dried plasma 
products immediately after reconstitution (21 CFR 211.166(a)(5)) and at the end 
of the proposed timeframe between reconstitution and administration of product. 
Studies should be performed to support the stability of the product at various time 
points following reconstitution. The post-reconstitution stability studies that 
support the expiration date should be described in the labeling. 
 
C.   Packaging and Reconstitution 
 
1.  Although dried plasma products have been effectively lyophilized/dried in glass 
containers, FDA recommends breakage-resistant alternatives supporting 
lyophilization/drying.  One advantage of dried plasma is its ability to be used in 
settings where the use of conventional plasma is not practical (e.g., battlefields, 
remote locations, and other austere settings) and where risks of glass breakage are 
likely to increase. 
 
2.  Given the unique characteristics of dried plasma products (volume, electrolyte 
content, pH), and the possibility of their use in the field or emergency settings, 
FDA suggests that manufacturers consider assembling a packaging kit that 
includes all the materials needed for reconstitution, including the appropriate 
volume of diluent, as well as instructions for reconstitution and use.  Distribution 
of the product as a complete package enhances safety by minimizing 
reconstitution errors and ensures rapid time-to-transfusion, a major advantage of 
dried plasma products. 
 
3.  The time to reconstitute a dried plasma product may vary.  FDA suggests that 
products be able to be fully reconstituted within five minutes given their likely 
use in urgent medical situations.  FDA also suggests the development of dried 
plasma products that may be reconstituted by the simple addition of diluent, or at 
most, with gentle swirling of the product, with no need for special equipment.  
 
D.   Clinical Studies 
 
1.  Clinical studies necessary to support approval will vary depending on the extent 
of in vitro characterization, the indication(s) sought, as well as the degree of 
clinical experience with the product. 
 
4  Contains Nonbinding Recommendations 
 
2.  For indications where conventional plasma (such as FFP or PF24) is unavailable 
or impractical for use, FDA recommends conducting safety and coagulation factor 
recovery studies in healthy subjects, following thorough in vitro product 
characterization.  Autologous plasma may be used, provided the processing is 
conducted in a manner identical to that of the ultimate product, except for 
pooling.  The initial safety cohort should receive one unit of the reconstituted 
dried plasma product, and optimally, subsequent cohorts should be randomized to 
receive additional units of reconstituted dried plasma or conventional plasma (as 
control).  Additional studies may be recommended.  Adverse events must be 
recorded for all enrolled subjects and reported to FDA when required under 21 
CFR Part 312 or 812.  As part of the randomized studies, FDA recommends the 
conduct of coagulation testing, and the determination of factor levels in the 
subjects prior to and following the administration of both conventional plasma 
and reconstituted dried plasma. 
 
3.  To expand the indications for use of dried plasma to situations where 
conventional plasma (such as FFP or PF24) is available, additional adequate and 
well-controlled clinical studies would likely be necessary and should be discussed 
in advance with FDA.  
 
E.   Regulatory Pathway for Marketing of Devices for the Manufacturing of 
Dried Plasma 
 
1.  In general, based on the device risks and the regulatory requirements necessary to 
provide a reasonable assurance of its safety and effectiveness, devices intended 
for the manufacture of dried plasma will likely be considered class III medical 
devices subject to premarket approval (PMA) requirements  
(21 CFR Part 814).3 
 
2.  Manufacturers seeking approval to market a device for the manufacture of dried 
plasma should include, as part of the device for which they are seeking approval, 
the necessary equipment with precise specifications for a blood establishment to 
process the dried plasma product, except for that which is likely to be standard 
equipment in a blood establishment (e.g., sterile connecting devices, storage 
freezers, water baths).  Validation and product characterization data on the dried 
plasma, performed as recommended in this guidance, should be provided using a 
consistent and pre-specified final device configuration.  The category of input 
plasma (e.g., FFP, PF24) unique to the device should be specified.  Data should 
be provided which demonstrate your device consistently produces a plasma 
product that meets established quality specifications.  
 
                                                 
3As additional experience with devices used to manufacture dried plasma is obtained, FDA will consider 
whether reclassification of such devices is appropriate, including whether the de novo pathway is 
appropriate for such devices. 
  
5  Contains Nonbinding Recommendations 
 
3.  Considerations regarding input plasma, manufacturing and product quality, 
packaging, reconstitution, and clinical studies, as described earlier in this 
guidance, also apply to devices used for the manufacture of dried plasma and their 
output.  Submit clinical data to demonstrate that the dried plasma manufactured 
with the device is safe and effective. 
 
 
IV.   EXPEDITED PROGRAMS 
 
There are several expedited programs that may be available to sponsors of dried plasma products 
intended to address unmet medical needs in the treatment of serious or life-threatening 
conditions.  Further information on these programs is available in a separate guidance 
document.4  
 
 
V.   COMMUNICATION WITH FDA 
 
FDA recommends communication with the Office of Blood Research and Review (OBRR) early 
in product development, before submission of an investigational new drug application (IND)  
(21 CFR Part 312) or investigational device exemption (IDE) (21 CFR Part 812) application. 
There are different meeting types that can be used for such discussions, depending on the stage 
of product development and the issues to be considered.  These include Q-subs (pre-submission 
meetings for devices), pre-IND meetings, and, earlier in development, INitial Targeted 
Engagement for Regulatory Advice on CBER producTs (INTERACT) meetings.5  Contact 
OBRR with any questions regarding the appropriate meeting type. 
 
 
   
                                                 
4 Guidance for Industry:  Expedited Programs for Serious Conditions  Drugs and Biologics, May 2014, 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents/expedited-programs-serious-
conditions-drugs-and-biologics  
5 Going forward, INTERACT meetings will serve in place of pre-pre-IND meetings.  For additional information 
about INTERACT meetings, please see https://www.fda.gov/vaccines-blood-biologics/industry-biologics/interact-
meetings-initial-targeted-engagement-regulatory-advice-cber-products 
6  Contains Nonbinding Recommendations 
 
VI.   REFERENCES  
 
1.  Sperry JL, Guyette FX, Brown JB, et al., PAMPer Study Group. Prehospital Plasma during 
Air Medical Transport in Trauma Patients at Risk for Hemorrhagic Shock. N Engl J Med. 
2018 Jul 26;379(4):315-326. 
 
2.  Borgman MA, Spinella PC, Perkins JG, et al., The ratio of blood products transfused affects 
mortality in patients receiving massive transfusions at a combat support hospital. J Trauma. 
2007 Oct; 63(4):805-813.  
 
3.  Pusateri AE, Given MB, Schreiber MA, et al., Dried plasma: state of the science and recent 
developments. Transfusion. 2016 Apr; 56 Suppl 2:S128-139.  
 
4.  Schmidt PJ, The plasma wars: a history, Transfusion, 2012 May; 52 Suppl 1:2S-4S 
 
 
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