Guidance for Industry 
and FDA Review Staff
 
 
Collection of Platelets by Automated 
Methods
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Additional copies of this guidance are available from the Office of Communication, Training and 
Manufacturers Assistance (HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-
1448, or by calling 1-800-835-4709 or 301-827-1800, or from the Internet at 
http://www.fda.gov/cber/guidelines.htm. 
 
For questions on the content of this guidance, contact the Division of Blood Applications, Office 
of Blood Research and Review at 301-827-3524. 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Biologics Evaluation and Research 
December 2007  Contains Nonbinding Recommendations 
 
 
Table of Contents 
 
 
I.  INTRODUCTION.............................................................................................................1 
II.  DISCUSSION....................................................................................................................2 
A.  Background...........................................................................................................2 
B.  Definitions..............................................................................................................3 
III.  DONOR SELECTION AND MANAGEMENT............................................................5 
A.  Donor Selection.....................................................................................................5 
B.  Donor Management..............................................................................................6 
1.  Platelet Count....................................................................................................6 
2.  Donation Frequency..........................................................................................6 
3.  RBC Loss Prior to a Collection of Platelets, Pheresis......................................6 
4.  Total Plasma Volume Loss Per Collection Procedure......................................7 
IV.  INFORMATION PROVIDED TO THE DONOR........................................................7 
V.  COMPONENT COLLECTION......................................................................................7 
VI.  VALIDATION OF THE COLLECTION PROCESS...................................................8 
A.  Equipment Installation Qualification.................................................................9 
B.  Validation Protocol...............................................................................................9 
C.  Process Performance Qualification (Operator).................................................9 
D.  Product Performance Qualification for Component Collection Process.......10 
E.  Re-Qualification/Re-Validation.........................................................................14 
VII.  QUALITY ASSURANCE AND MONITORING........................................................14 
A.  Standard Operating Procedures (SOPs) and Recordkeeping........................14 
1.  Requirements for SOPs...................................................................................14 
2.  Additional Provisions Applicable to SOPs.....................................................14 
3.  Recordkeeping................................................................................................17 
B.  Donor Monitoring...............................................................................................17 
1.  Platelet Counts................................................................................................17 
2.  Adverse Reactions in Donors..........................................................................17
C.  Component Testing.............................................................................................18 
1.  Component Specification Check.....................................................................18 
2.  QC Monitoring................................................................................................19 
D.  Equipment/Supplies............................................................................................20 
E.  Operator Training..............................................................................................20 
F.  Quality Monitoring.............................................................................................21 
VIII.  PROCESSING AND TESTING....................................................................................21 
A.  Processing............................................................................................................21 
B.  Communicable Disease Testing.........................................................................21 
C.  Expiration Date...................................................................................................21 
i  Contains Nonbinding Recommendations 
 
IX.  LABELING.....................................................................................................................22 
X.  REPORTING CHANGES TO AN APPROVED BIOLOGICS LICENSE 
  APPLICATION (BLA)...................................................................................................22 
A.  Prior Approval Supplement (PAS):  Changes Requiring Supplement 
Submission and Approval Prior to Distribution of the Product Made Using 
the Change (Major Changes) (21 CFR 601.12(b))...........................................22 
B.  Changes Being Effected in 30 Days (CBE-30) Supplement:  Changes 
Requiring Supplement Submission at Least 30 Days Prior to Distribution of 
the Product Made Using the Change (21 CFR 601.12(c))...............................24 
C.  Submission Inclusion Documents......................................................................24 
D.  Submission of Platelets, Pheresis Sample(s) to CBER.....................................27 
E.  Shipping Platelets, Pheresis Sample(s) to CBER.............................................27 
XI.  CONTACT INFORMATION........................................................................................28 
XII.  REFERENCES................................................................................................................30 
ii  Contains Nonbinding Recommendations 
 
Guidance for Industry and FDA Review Staff 
 
Collection of Platelets by Automated Methods 
 
 
This guidance represents the Food and Drug Administrations (FDAs) current thinking on this 
topic.  It does not create or confer any rights for or on any person and does not operate to bind 
FDA or the public.  You can use an alternative approach if the approach satisfies the 
requirements of the applicable statutes and regulations.  If you want to discuss an alternative 
approach, contact the appropriate FDA staff.  If you cannot identify the appropriate FDA staff, 
call the appropriate number listed on the title page of this guidance. 
 
 
I.  INTRODUCTION 
 
This guidance provides you, blood establishments, and FDA staff with revised recommendations 
for the collection of Platelets by automated methods (plateletpheresis).  This guidance is intended 
to help you ensure donor safety and the safety, purity, and potency of Platelets collected by an 
automated blood cell separator device.  For the purpose of this document, Platelets collected by 
automated methods and resuspended in plasma will be referred to by the product name 
Platelets, Pheresis.  We consider the recommendations in this guidance document to provide 
appropriate criteria for a biologics license application or supplement for manufacturing Platelets, 
Pheresis, and provide guidance on preparing a manufacturing supplement for Platelets, Pheresis 
under Title 21 Code of Federal Regulations 601.12 
(21 CFR 601.12). 
 
This guidance applies only to the following Platelets, Pheresis components: 
 
  Platelets, Pheresis (single, double, and triple collections); 
  Platelets, Pheresis Leukocytes Reduced (single, double, and triple collections); and 
  Platelets, Pheresis or Platelets, Pheresis Leukocytes Reduced collected concurrently with 
Plasma, Red Blood Cells (RBCs), and/or Source Plasma.1  
 
This guidance replaces FDAs Revised Guideline for the Collection of Platelets, Pheresis dated 
October 1988.  Also, this guidance finalizes the draft guidance, Guidance for Industry and FDA 
Review Staff:  Collection of Platelets by Automated Methods dated September 2005. 
 
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.  
                                                 
1 This guidance does not apply to plateletpheresis components collected concurrently during apheresis granulocyte 
collection procedures or plasma reduced apheresis platelets, which are not currently licensed products, or to platelets 
prepared from plasmapheresis as described in 21 CFR 640.22(b). 
 
1  Contains Nonbinding Recommendations 
 
The use of the word should in FDAs guidances means that something is suggested or 
recommended, but not required. 
 
If you have any questions about the effect of any portion of this guidance on a regulatory 
requirement, contact the Center for Biologics Evaluation and Research (CBER), Office of Blood 
Research and Review, Division of Blood Applications, at 301-827-3524. 
 
 
II.  DISCUSSION 
 
A.  Background 
 
Plateletpheresis is the routine collection of platelets using an automated blood cell 
separator device, which results in the product Platelets, Pheresis manufactured from a 
high yield of platelets from a single donor.  Transfusion of Platelets, Pheresis is effective 
for treating patients with platelet related insufficiencies, while limiting the recipients 
exposure to platelets from multiple donors.  In recent years, many improvements have 
been made in automated blood cell separator device technology, platelet storage stability, 
and blood cell counting methods, including: 
 
  collection process efficiency; 
  storage container characteristics; and 
  accuracy of methods for determining a donors pre-donation platelet count and 
component yields. 
 
Automated blood cell separator devices are now capable of various plateletpheresis 
collection procedures including but not limited to the following: 
 
  collection of double and triple platelet components obtained during a single 
procedure; 
  use of in-process leukocyte reduction (Ref. 1); 
  collection of concurrent plasma components (Ref. 2); and  
  collection of concurrent RBC components (Ref. 3). 
 
This document includes the following recommendations: 
 
  Published research indicates that there is poor recovery of viable platelets stored at a 
pH of less than 6.2 (Refs. 4 and 5).  Therefore, your process validation and quality 
control (QC) testing for Platelets, Pheresis should assure a pH at or above 6.2, to rule 
out a pH less than 6.2 on the date the product is issued or on the date the product 
expires (outdates). Note that we recommend that you adopt a stricter pH standard than 
that currently specified in 21 CFR 640.25(b)(2). 
  You should include additional deferral criteria for donors of Platelets, Pheresis who 
have taken certain medications (see section III.A.) (Refs. 6, 7, and 8). 
2  Contains Nonbinding Recommendations 
 
  To protect the safety of the donor, seven days should elapse after collection of a 
double or triple Platelets, Pheresis before the donor is eligible to donate Platelets, 
Pheresis again.  In addition, first-time donors without a pre-donation platelet count 
should not undergo collection of a triple Platelets, Pheresis. 
  Because of similarities between plateletpheresis and Source Plasma donation, you 
should follow the donor weight provisions for Source Plasma donors under  
21 CFR 640.63(c)(6) (see Section III.A.). 
  QC testing, as prescribed in 21 CFR 640.25(b)(1) through (3) requires that, each 
month, four units prepared from different donors be tested at the end of the storage 
period for platelet count, pH of not less than 6.0 when measured at the storage 
temperature of the unit, and volume.  In addition, 21 CFR 211.160(b) requires that 
laboratory controls include the establishment of scientifically sound and appropriate 
specifications, standards, sampling plans, and test procedures designed to assure that 
components, drug product containers, closures, in-process materials, labeling, and 
drug products conform to appropriate standards of identity, strength, quality, and 
purity. 
 
We also note that bacterial contamination of blood components and associated 
transfusion risks is a continuing problem (Refs. 9 and 10).  Bacterial contamination 
testing is a necessary part of process validation and quality assurance monitoring for 
Platelets, Pheresis. 
 
B.  Definitions 
 
For purposes of the terms used in this guidance, the following definitions apply: 
 
Actual platelet yield  The total platelet yield in the component, calculated by 
multiplying the platelet count of the sample times the volume of the component (platelet 
count x component volume = actual platelet yield). 
 
Apheresis  Automated blood collection in which a device continuously or intermittently 
removes a small volume of whole blood, separates the components, collects certain 
components, and returns to the donor the uncollected remainder. 
 
Automated blood cell separator  A device that uses a centrifugal or filtration 
separation principle to automatically withdraw whole blood from a donor, separate the 
whole blood into blood components, and return to the donor the remainder of the whole 
blood and blood components.  The automated blood cell separator device is intended for 
routine collection of blood and blood components for transfusion or further 
manufacturing use. 
 
Bacterial contamination testing  Testing conducted to determine whether a product 
contains viable contaminating bacteria.  
 
Component  A part of a single donors blood, such as platelets, separated from whole 
blood by physical or mechanical means.  For Platelets, Pheresis, a component is a 
3  Contains Nonbinding Recommendations 
 
transfusable product that may result from a single collection (resulting in one 
component), a double collection (resulting in two Platelets, Pheresis components), or a 
triple collection (resulting in three Platelets, Pheresis components). 
 
Concurrent component  When a blood component, such as Platelets, is being collected 
during an apheresis procedure, a concurrent component is a different blood component 
(i.e., Plasma, RBCs) collected at the same time. 
 
Dedicated donation  Platelets, Pheresis donated for a specific recipient. 
 
Devices cleared or approved  Describes a device that has been cleared or approved by 
FDA pursuant to a 510(k) Premarket Notification (cleared device) or Premarket Approval 
Application (approved device).  (See Title 21, United States Code, section 360c; Federal 
Food, Drug, and Cosmetic Act (FDCA), section 515  Premarket Approval; and, FDCA, 
section 510(k)). 
 
Donation frequency  Interval between a donors collection procedures. 
 
Process validation  Establishing documented evidence which provides a high degree of 
assurance that a specific process will consistently produce a product meeting its pre-
determined specifications and quality characteristics.  
 
Qualification  A part of process validation that establishes confidence that a 
manufacturing device is capable of operating consistently (equipment installation 
qualification) and can be performed effectively and reproducibly (process performance 
qualification), and that the finished product meets all of the release requirements for 
functionality and safety (product performance qualification). 
 
Residual White Blood Cell (WBC) count  The number of WBCs remaining in a 
Leukocytes Reduced component, calculated by multiplying the WBC count from a 
sample of the component times the volume of the component.  In this document: 
 
  references to residual WBC count testing apply when the Platelets, Pheresis will be 
labeled as Leukocytes Reduced. 
  references to percent platelet retention apply to leukocyte reduction by filtration, 
provided there is access to a pre-filtration sample. 
 
Rolling 12-month period  Continual assessment of a donor over a 12-month period.  
This is not a set 12-month period (i.e., calendar year). 
 
Target platelet yield  The intended platelet yield programmed into an automated blood 
cell separator device, which may be based on the donors platelet count and other factors. 
 
Tolerance values  Minimum and maximum values (i.e., container volume; platelet 
concentration) described by the manufacturer as being acceptable.  These values may also 
be described as specifications. 
4  Contains Nonbinding Recommendations 
 
 
Weight/volume conversion  The total weight of the component minus the tare weight 
of the empty container divided by the specific gravity of the component equals volume of 
the component. 
 
 
III.  DONOR SELECTION AND MANAGEMENT 
 
A.  Donor Selection 
 
Under 21 CFR 640.21(c), plateletpheresis donors must meet donor suitability criteria 
described in the biologics license application or supplement.  These typically conform to 
donor suitability requirements (21 CFR 640.3) and recommendations applicable to 
donors of Whole Blood.  In addition, we recommend: 
 
  donor weight of at least 110 pounds (currently required for Source Plasma donors 
under 21 CFR 640.63(c)(6)) 
  Prior to the first donation, collect a sample for a platelet count.  
  If you cannot test a sample for a platelet count prior to the first donation (for example, 
because the donor presents at a mobile collection site), you should collect a pre-
donation sample and evaluate the donors platelet count after the first collection. 
 
You should not collect Platelets, Pheresis from donors who have ingested platelet 
inhibitory drugs recently enough to adversely affect platelet function in the product, or 
the safety of the donor.  These recommendations include, but may not be limited to: 
 
  Aspirin (ASA)/ASA-containing drugs/Feldene  two full medication free days prior 
to donation (Refs. 6 and 7) 
  Plavix (Clopidogrel) and Ticlid (Ticlopidine)  14 full medication free days prior to 
donation (Ref. 8).  
 
When the drugs listed in this section are taken for a specific medical condition, donors 
should not discontinue taking drugs prescribed or recommended by their physicians in 
order to be eligible2 to donate Platelets, Pheresis.  However, we do not necessarily 
recommend deferral of such donors for all blood products, if the donors are in good 
health, and establishments may make eligibility determinations for donations of other 
products. 
                                                 
2 We are using the terms eligible and eligibility in this guidance to refer to the donor suitability requirements 
described in 21 CFR 640.3 and 640.21(c). 
5  Contains Nonbinding Recommendations 
 
B.  Donor Management 
 
1.  Platelet Count 
 
  You should collect a pre-donation sample from the donor for a platelet count.  
The device operator should enter that platelet count, or the one obtained 
immediately following initiation of the collection procedure, to more 
accurately set the target platelet yield parameters for each collection of 
Platelets, Pheresis.  These steps should be consistent with the automated 
blood cell separator device manufacturers directions for use. 
 
  For any collection facility that cannot test a pre-donation sample for a platelet 
count (for example, a mobile collection site), you may use an average of 
previous historic platelet counts (as specified by the device manufacturer), or 
a default platelet count (either as recommended by the automated blood cell 
separator device manufacturer, or determined by using blood center specific 
values), to set the target platelet yield.  You should not collect a triple 
Platelets, Pheresis from first-time donors who do not have a pre-donation 
platelet count available either prior to or immediately following initiation of 
the collection procedure.  Concurrent components may be drawn if the donor 
meets eligibility requirements for those components.  
 
  You should defer from donation donors whose platelet counts are less than 
150,000 platelets/uL until a subsequent pre-donation platelet count indicates 
that the donors platelet count is at least 150,000 platelets/uL. 
 
2.  Donation Frequency 
 
To protect the safety of the donor: 
 
  a donor should undergo no more than 24 Platelet, Pheresis collections in a 
rolling 12-month period. 
  the interval between each collection of Platelets, Pheresis should be at least 
two days with no more than two procedures in a seven-day period. 
  the interval between collection of a double or triple Platelets, Pheresis and any 
subsequent collection of Platelets, Pheresis should be at least seven days. 
  the automated blood cell separator device should be set with a post-donation 
platelet count target of no less than 100,000 platelets/uL.  
 
3.  RBC Loss Prior to a Collection of Platelets, Pheresis 
 
To protect the donor from significant RBC loss, we recommend that: 
 
  you not allow a donor who has donated a unit of Whole Blood, a single unit 
of Red Blood Cells by apheresis, or a single unit of Red Blood Cells by 
apheresis concurrent with Platelets, Pheresis or Plasma in the previous 8 
6  Contains Nonbinding Recommendations 
 
weeks to donate Platelets, Pheresis, unless the extracorporeal red blood cell 
volume during the Platelets, Pheresis collection is expected to be less than 
100 mL (Ref 3). 
 
  you not perform any collection procedure on a donor who has donated two 
units of Red Blood Cells by apheresis within the previous 16 weeks (Ref. 3). 
 
4.  Total Plasma Volume Loss Per Collection Procedure 
 
The total plasma volume (excluding anticoagulant) of all blood components 
retained per collection of Platelets, Pheresis should not exceed: 
 
  500 mL (600 mL for donors weighing 175 lbs or greater), or 
  the volume described in the labeling for the automated blood cell separator 
device (this volume may be more or less than the 500 mL or 600 mL volume 
stated in the above bullet). 
 
 
IV.  INFORMATION PROVIDED TO THE DONOR 
 
Under 21 CFR 640.22(c), the collection procedure must be as described in the biologics license 
application or supplement.  As part of the collection procedure, Platelets, Pheresis donors should 
receive information about the collection procedure and its associated risks.  You should provide 
Platelets, Pheresis donors with the same information that is provided to a Whole Blood donor3,  
plus the following information specific to the platelet collection: 
 
  a description of the procedure for collection of Platelets, Pheresis and its associated risks. 
  information about potential side effects of the procedure including possible effects as a 
result of solutions and/or treatment to reduce side effects such as treatment with a calcium 
replacement.  Examples of side effects include anticoagulant effects (tingling and/or 
nausea), hypovolemia (decreased blood volume), fainting, and any other side effect as 
described by the automated blood cell separator device manufacturer. 
  information indicating that there are limitations to the number and types of components that 
can be donated per year. 
 
 
V.  COMPONENT COLLECTION 
 
Improvements in collection of Platelets, Pheresis have enabled blood establishments to obtain 
from a single collection procedure one, two, or three Platelets, Pheresis component(s) (and 
concurrent collection of Plasma, Source Plasma and/or RBC components). 
 
                                                 
3 Refer to FDA regulations and guidance developed by FDA on this topic and available on the FDA website.  
http://www.fda.gov/cber/blood/bldpubs.htm 
7  Contains Nonbinding Recommendations 
 
Under 21 CFR 640.22(c), the collection procedure must be as described in the biologics license 
application or supplement.  In addition, the phlebotomy must be performed by a single 
uninterrupted venipuncture with minimal damage to, and minimal manipulation of, the donor's 
tissue (21 CFR 640.22(d)).  A sterile connecting device may be used as described in the 
manufacturers directions for the apheresis collection set.  The automated blood cell separator 
device must perform in the manner for which it was designed (21 CFR 606.60(a)).  Accordingly, 
your collection procedures should be consistent with the Operators Manual, directions for use, 
and/or manufacturers specifications.  Specifications identified by the manufacturer may include, 
but not be limited to, the donors platelet count, weight, height or hematocrit; the 
minimum/maximum volume of the storage container; platelet concentration per uL in the storage 
container, or actual platelet yield.  In addition, supplies and reagents must be used in a manner 
consistent with instructions provided by the manufacturer (21 CFR 606.65(e)). 
 
 
VI.  VALIDATION OF THE COLLECTION PROCESS 
 
The Current Good Manufacturing Practice (CGMP) regulations described in 21 CFR Parts 210 
and 211 contain the minimum requirements for methods to be used in, and the facilities or 
controls to be used for, the manufacture, processing, packing or holding of a drug to assure that 
the drug meets the requirements of the FDCA as to safety, and has the identity and strength and 
meets the quality and purity characteristics that it purports or is represented to possess 
(21 CFR 210.1(a)).  These CGMP regulations also apply to Whole Blood and blood components 
(21 CFR 210.2(a), 211.1(b)) and supplement the CGMP regulations for blood and blood 
components contained in 21 CFR Part 606.  As an element of CGMP, process validation 
establishes documented evidence which provides a high degree of assurance that a specific 
process will consistently produce a product meeting its pre-determined specifications and 
quality characteristics (Ref. 11).4  We recommend that establishing documentation of process 
validation include, but not be limited to, validation protocol development, installation 
qualification, process operator performance qualification, and product performance component 
qualification (Ref. 11). 
  
Each device intended for the routine collection of Platelets, Pheresis must be cleared or 
approved by FDA for this purpose (see 21 CFR 864.9245).  You should conduct validation of 
the collection process using each type of device used in your establishment prior to 
implementing routine collections. 
 
In addition, your validation efforts should include the following manufacturing steps: 
 
  cell counting  
  pH measurement:  we recommend that a pH meter or gas analyzer be routinely used rather 
than pH (nitrazine) paper. 
  component weighing 
                                                 
4 The requirement for process control is set forth in general terms in 21 CFR 211.100. 
8  Contains Nonbinding Recommendations 
 
  sterile connecting method (Ref. 12) 
  storage 
  shipping 
 
A.  Equipment Installation Qualification 
 
21 CFR 606.60(a) requires that equipment be observed, standardized and calibrated on a 
regularly scheduled basis as prescribed in the Standard Operating Procedures Manual  
and must perform in the manner for which it was designed.  Upon initial installation, the 
automated blood cell separator device should be qualified as described in the Operators 
Manual or manufacturers directions for use. 
 
B.  Validation Protocol 
 
An integral element of the performance and documentation of process validation is the 
development of a validation protocol.  You should refer to FDAs Guideline on General 
Principles of Process Validation (Ref. 11) as an outline for developing your validation 
protocol.  The validation protocol should include at least the following: 
 
  a description of the equipment to be used 
  minimum/maximum acceptable values for the Platelets, Pheresis collection and/or 
component as specified by the automated blood cell separator device manufacturer  
-  total volume (after removal of samples for hematological testing and bacterial 
contamination testing), including per component (container) from double and 
triple collections 
-  actual platelet yield 
-  residual WBC count (if Leukocytes Reduced) for the collection and components 
(if multiple components are collected), and percent platelet retention when 
applicable 
-  concurrent component volume (Plasma or RBC), if applicable 
-  pH measurement 
  manufacturers specifications or recommendations for processing parameters (i.e., 
actual platelet yield and concentration, weight or volume collected) 
  description of supplies used in the collection (e.g., collection/storage containers, 
anticoagulants, etc.) 
  failure investigation criteria   
  personnel training criteria 
  standard operating procedures for performing each element of the collection process 
  documentation of the validation protocol criteria (all of the above)   
     
C.  Process Performance Qualification (Operator) 
 
Each person engaged in the collection of Platelets, Pheresis must have adequate 
education, training, or experience to assure competent use of the automated blood cell 
separator devices involved (21 CFR 211.25(a)).  Establishments must maintain 
applicable proficiency test results (21 CFR 606.160(b)(5)(v)).   
9  Contains Nonbinding Recommendations 
 
 
We recommend that personnel training include the successful, consecutive, performance 
under supervision of an appropriate number of procedures, as defined by your facility.  
These procedures should result in the collection of Platelets, Pheresis meeting relevant 
component specifications. 
 
D.  Product Performance Qualification for Component Collection Process 
 
Various mechanical and biological factors may influence the plateletpheresis collection 
process (i.e., the optical qualities of a donors plasma, the donors platelet count and 
platelet size, vascular access, and procedure duration) (Ref. 14).  The objective of 
collection performance qualification is to verify that the automated blood cell separator 
device performs according to the manufacturers claims when used, and through 
appropriate testing establishes confidence that the finished product produced by the 
specified process meets all release requirements for functionality and safety (Ref. 11).  
All components collected during the validation process can be released for transfusion 
provided that they meet minimum specifications as defined by the manufacturer, are 
labeled appropriately, and are otherwise suitable.   
 
Process performance qualification should include testing for the actual platelet yield, pH, 
and volume; residual WBC count and percent platelet retention (for Leukocytes Reduced 
components) (See Table 1).  We recommend that you assess the following at each 
collection site: 
 
  actual platelet yield (platelet count multiplied by the volume): 
o  determine actual platelet yield at collection. 
o  follow the platelet pre-donation count recommendations in section III.B.1., and 
set an appropriate target platelet yield as recommended by the automated blood 
cell separator device manufacturer to maximize the likelihood that each 
transfusable component contains > 3.0 x 1011 platelets and the target collection 
type (single, double, triple) is achieved.  
  pH as a measurement of quality after storage: 
o  determine pH on the date the product is issued or on the date the product expires 
(outdates). 
o  each transfusable component should have a pH > 6.2 
  percent platelet retention 
o  perform when the automated blood cell separator device or filtration method is 
first put into use at an establishment and/or as recommended by the automated 
blood cell separator device manufacturer. 
o  if leukocytes are reduced by filtration and there is access to both a pre-filtration 
and post-filtration sample, calculate percent platelet retention using pre- and 
post-filtration volume and cell content. 
  residual WBC count: 
o  perform when the automated blood cell separator device or filtration method is 
first put into use at an establishment and/or as recommended by the automated 
blood cell separator device manufacturer. 
10  Contains Nonbinding Recommendations 
 
o  perform within 48 hours of collection or per the manufacturers directions for the 
cell counting methodology used (Ref. 15). 
o     conduct testing on the collection (parent container) and on the individual 
components from double and triple collections 
  volume: 
o  determine the volume after removal of samples for testing (i.e., cell count, 
bacterial contamination testing). 
o  fill each storage container consistent with the manufacturers 
minimum/maximum specifications.  
o  equilibrate storage containers for double or triple collections + 10 mL, or per the 
manufacturers directions if different. 
 
You also should qualify devices and perform failure investigations as follows: 
 
  Devices: 
o  complete product performance qualification for apheresis devices from different 
manufacturers, and for each model.  
o  obtain data from all automated blood cell separator devices at each site for initial 
product performance qualification.  If additional devices of the same model are 
added at the facility after qualification, include qualification data in monthly QC 
only.  
  Failure investigation:  Conduct an investigation for all component qualification 
failures, and when appropriate, initiate corrective action and follow-up measures (see 
21 CFR 211.192; 606.100(c)).  We understand that some failures may occur due to 
conditions not resulting from a failure of the process (e.g., automated blood cell 
separator device failures, donor reactions).  In addition, you should: 
o  investigate as qualification failures residual WBC counts that exceed the 
following: 
  single collection:  > 5.0 x 106 (collection)  
  double collection:  > 8.0 x 106 (collection), and > 5.0 x 106 (either or both 
components) 
  triple collection:  > 1.2 x 107 (collection), and > 5.0 x 106 (one, two or all 
three components).  
 
o  However, each transfusable component from a double or triple collection of 
Platelets, Pheresis may be labeled as Leukocytes Reduced provided the residual 
WBC count on the component is found to be < 5.0 x 106. investigate collections 
that fail to meet the percent platelet retention, if performed. However, the 
component may be transfused if the actual platelet yield is determined subsequent 
to filtration, and the component is labeled appropriately. 
 
Variation in the actual platelet count might be due to the platelet counter used and the 
type of platelet count used at the time of collection (pre-donation or historic average).  
However, you should select a statistically sound sample size, based on 95% confidence 
that 75% of components (platelet yield) will meet the recommended results (see Table 
1).  For pH and recommended residual WBC count, you should select a statistically 
11  Contains Nonbinding Recommendations 
 
sound sample size, based on 95% confidence that 95% of components (pH) or 
collections (residual WBC count) will meet the recommended results.  Using the 
binomial statistic for example, a minimum of 60 components/collections should be 
tested, with zero process failures (93 tested with one process failure, 124 tested with two 
process failures, etc.) to qualify the process.  Determine the sample size selection before 
starting the qualification process.  For example, if you test 60 samples and encounter a 
failure, you should not continue with the testing of an additional 33 components.  If you 
select a sample size of 93 and encounter a failure during testing, you may continue to 
test but there should be no additional failures.  Similarly, if you select a sample size of 
124 and encounter two failures, you may continue to test, but there should be no 
additional failures. 
12  Contains Nonbinding Recommendations 
 
Table 1.  Product Performance Qualification Criteria for the Platelet Component 
Collection Process 
 
Test  Recommended Results  Target1   Allowable Process Failures2 to achieve 
recommended results for a set of N tests3
 
                   
Actual platelet  > 3.0 x 1011 95%/75% *  N=11 ** N=18 ** N=23 **
yield of 
transfusable  0  1  2 
component 
pH   > 6.2  95% / 95% *** N=60  N=93  N=124 
0  1  2 
Percent  > 85% component  95%/95%  N=60  N=93  N=124 
component  retention if performed   
retention  **** 0  1  2 
Residual WBC  Single collection:   95% / 95%  N= 60  N=93  N=124 
count *****            < 5.0 x 106     collections  collections  collections 
 
0  1  2 
 
Double collection:   95%/95%  N=60  N=93  N=124 
Collection: < 8.0 x 106   collections   collections   collections  
or Components: < 5.0 x  0  1  2 
106  
Triple collection:  95%/95%  N=60  N=93  N=124 
Collection: < 1.2 x 107 collections   collections   collections 
or Components: < 5.0 x 
0  1  2  
106
1, 2   Process failures only; non-process failures should be excluded. 
3   Corrective actions for exceeding allowable process failures  
  if you select a sample size of 11 and find one failure, 17 additional samples would need to be 
tested with no additional failures. 
  if you select a sample size of 60 and find one failure, 91 additional samples would need to be 
tested with no additional failures.  If you select a sample size of 93 and find two failures, 157 
additional samples should be tested with no failures.  If you select a sample size of 124 and find 
three failures, 127 additional samples should be tested with no failures.  
*   95% confidence that greater than 75% of the components meet the standard. 
**   The sample size numbers can be used in a sampling plan that should be representative of products 
collected on each machine type in each facility.  
***   95% confidence that greater than 95% of the components meet the standard. 
****   Or per the container/automated blood cell separator device manufacturers specifications  
*****  The stratified recommended results should ensure that the individual transfusable units will be < 5.0 x 
106 even with a 25% error in equilibration of the volume for double and triple collections. 
 
13  Contains Nonbinding Recommendations 
 
E.  Re-Qualification/Re-Validation 
 
  Exceeding the allowable process failures of the collection process qualification may 
indicate that the process is not in control.  You must investigate and correct the 
source of this failure (see 21 CFR 211.192, 606.100(c)) and should repeat validation. 
 
  The manufacturer may provide re-qualification requirements for the automated blood 
cell separator device to be followed. 
 
 
VII.  QUALITY ASSURANCE AND MONITORING 
 
Quality assurance (QA) is the sum of activities planned and performed to provide confidence 
that all systems and system elements that influence the quality of the component are functioning 
as expected (Ref. 13).  When this is demonstrated, the process is considered to be in a state of 
control.  Whether a process is operating in a state of control is determined by analyzing the day-
to-day process and the data for conformance with the manufacturers specifications and for 
variability.   
 
You must have a quality control (QC) unit that has the responsibility and authority to approve or 
reject all components, containers, closures, in-process materials, packaging material, labeling 
and drug products and the authority to review production records to assure that no errors have 
occurred or, if errors have occurred, that they have been fully investigated (21 CFR 211.22(a)).  
Thus, the QC units responsibilities include the review of production records, and the review of 
complaints involving the possible failure of a product to meet its specifications.  (See, for 
example, 21 CFR 211.22, 211.192, 211.198, 606.100(c)).  Please refer to FDAs Guideline for 
Quality Assurance in Blood Establishments (Ref. 13) for developing a QA and Monitoring 
program. 
 
A.  Standard Operating Procedures (SOPs) and Recordkeeping 
 
1.  Requirements for SOPs 
 
  An automated blood cell separator device must perform in the manner for 
which it was designed (21 CFR 606.60(a)) during the collection or 
processing of apheresis components.  Written SOPs must be maintained and 
must include all steps to be followed in the collection, processing, 
compatibility testing, storage, and distribution of blood and blood 
components (21 CFR 606.100(b)).  Therefore, you must have written SOPs 
for each step in the collection of Platelets, Pheresis. 
 
2.  Additional Provisions Applicable to SOPs 
 
  Adverse reactions:  You must have a written SOP for investigating adverse 
donor and recipient reactions (21 CFR 606.100(b)(9)).  In addition, you 
should have a written SOP for managing a cardiopulmonary emergency or 
14  Contains Nonbinding Recommendations 
 
any other adverse reactions associated with donation, containing steps for 
contacting physicians, obtaining an emergency rescue squad response, and 
transporting the donor to the hospital. 
 
  Hematocrit:  If the final platelet collection contains more than 2 mL of 
packed RBCs, you should attach a sample of donor blood to the platelet 
storage container for compatibility testing to prevent the possibility of an 
adverse reaction during transfusion.  In addition, you should hold the 
Platelets, Pheresis collection prior to distributing as Leukocytes Reduced 
until a residual WBC count of the transfusable component can be determined 
and found to be < 5.0 x 106.   
 
  Component volume:  You should describe how to process components in the 
event the volume exceeds the automated blood cell separator device 
manufacturers specifications.  In addition, the volume in the storage 
containers from double or triple collections should be within +10 mL of each 
other or per the manufacturers directions if different. 
 
  Samples for QC:  Containers for QC samples should be attached to the 
component/collection set using a sterile connecting device, to ensure the 
maintenance of the closed system. 
 
  Actual platelet yield:  The platelet yield from each collection of Platelets, 
Pheresis should be available to provide to the transfusion facility. 
 
  pH measurement:  Accurate pH measurement is time dependent, and 
samples should be tested within 1 hour of sampling, or as suggested by the 
manufacturer of the pH measurement system.  We recommend that a pH 
meter or gas analyzer be routinely used rather than pH (nitrazine) paper.  
However, if you choose to determine pH measurements with nitrazine paper, 
the selected paper should read in increments of one-tenth units, or it may 
provide inaccurate measurements. 
 
  RBC loss:  You must have a written SOP for your collection procedure, 
including in-process precautions to measure accurately the quantity of blood 
removed from the donor (21 CFR 606.100(b)(5)). You should calculate the 
donors RBC loss, which may include the residual RBCs remaining in the 
apheresis collection set after a collection of or discontinued collection of 
Platelets, Pheresis; the extracorporeal RBCs remaining in event of no RBC 
rinseback; the RBC loss from collection of tubes for testing; and/or collection 
of a concurrent RBC.  You should record such RBC loss in the donors 
record, in a manner that allows tracking of cumulative RBC loss over time. 
15  Contains Nonbinding Recommendations 
 
  Bacterial contamination testing:  You must maintain written SOPs and 
include all steps to be followed in the testing of blood and blood components 
(21 CFR 606.100(b)).  Bacterial contamination testing should be performed 
using a culture based methodology, and using your established procedures. 
 
  QC failures:  You must thoroughly investigate any unexplained discrepancy 
or the failure of a batch to meet any of its specifications (21 CFR 211.192).  
You should define appropriate criteria for retesting of components, testing of 
additional components, final labeling, and disposition of components that fail 
to meet specifications. 
 
  Failure investigations:  (see 21 CFR 211.192; 606.100(c)) The criteria to 
assess in the performance of a thorough failure investigation (including the 
conclusions and followup) should include, but not be limited to:  donor 
characteristics or specifications; operation and or performance of the 
collection device; adherence to SOPs; lot numbers of reagents or supplies; 
sample collection, handling, storage or shipping; operator performance, 
training or competency; and cell counting instrument performance including 
shifts or trends in controls. 
 
  Manufacturers performance specifications:   You should state the 
acceptable tolerance specifications for the volumes, platelet concentration, 
and/or actual platelet yield for each storage container as described by the 
manufacturer.  You should have a procedure addressing the handling of 
components that do not meet the manufacturers performance specifications 
(e.g., use in research or further manufacture). 
 
  Labeling: 
o  The final component volume stated on the label should be determined 
after removal of samples for platelet count determination, QC, and/or 
bacterial contamination testing. 
o  Platelets, Pheresis for transfusion should routinely contain > 3.0 x 1011 
platelets.  When special circumstances warrant their use, Platelets, 
Pheresis components containing less than 3.0 x 1011 platelets should be 
labeled with the actual platelet content. 
 
  Component Storage: 
o  If Platelets, Pheresis are stored at 20 to 24 oC, you must maintain a 
continuous gentle agitation throughout the storage period (21 CFR 
640.25(a)).  You should describe how temperature and agitation will be 
monitored, and the disposition of platelet components that are not stored 
properly. 
o  You must follow the automated blood cell separator device 
manufacturers directions for use (21 CFR 606.60(a)).  If sterile 
connecting an additional container(s) is necessary, use a container(s)  
16  Contains Nonbinding Recommendations 
 
designed to achieve and protect a sterile conduit.  Because of differences 
in container specifications, you should use containers from the same 
manufacturer. 
  
3.  Recordkeeping 
 
All recordkeeping requirements of 21 CFR Part 606, Current Good 
Manufacturing Practice for Blood and Blood Components, Subpart I (Records and 
Reports); Part 211, Current Good Manufacturing Practice for Finished 
Pharmaceuticals, Subpart J (Records and Reports); and applicable provisions of 
21 CFR 640.20 through 640.27, must be met. 
 
B.  Donor Monitoring 
 
1.  Platelet Counts 
 
If  the platelet count is known, you should notify your Medical Director when a 
donor has a post collection platelet count less than 100,000/uL, and you should 
defer the donor until his/her platelet count has returned to at least 150,000/uL. 
 
Transient decreases in platelet counts have been reported in donors undergoing 
multiple collections of Platelets, Pheresis (Ref. 16).  You should periodically 
review a donors records to monitor platelet counts. 
 
2.  Adverse Reactions in Donors 
 
Records must be maintained of any reports of complaints of adverse reactions 
regarding each unit of blood or blood product arising as a result of blood 
collection or transfusion and a thorough investigation of each reported adverse 
reaction must be made (21 CFR 606.170(a)).   
 
3.  Red Blood Cell Loss 
 
  Per collection:  
o  If the collection procedure needs to be discontinued for any reason before 
completion, and if the Operators Manual allows, you should attempt to 
return RBCs to the donor.   
o  Donor eligibility based on RBC loss (with or without RBC rinseback, and 
including all other types of donation) is described in Table 2.  
17  Contains Nonbinding Recommendations 
 
Table 2:  Recommendations for donor eligibility based on RBC loss per collection  
 
Donors Initial  Donors Second  Eligibility 
packed RBC loss  packed RBC loss 
within 8 weeks 
Less than 200 mL   No donation or  No deferral of donor for packed RBC loss; 
total from initial  frequency of donation of Platelets, Pheresis 
and second loss  as discussed in section III.B.2 
less than 200 mL  
Less than 200 mL  More than 200 mL  Donor is not eligible to donate for 8 weeks 
but less than 300  from 2nd loss 
mL total   
More than 200 mL  NA  Donor is not eligible to donate for 8 weeks 
but less than 300 mL  from initial loss 
Less than 200 mL  Total loss from  Donor is not eligible to donate for 16 weeks 
initial and second  from the 2nd loss 
loss of more than 
300 mL 
300 mL or more  NA  Donor is not eligible to donate for 16 weeks 
from initial loss. 
 
  Per 12 months: 
Under 21 CFR 640.3(b), a person may not serve as a source of Whole Blood 
more than once in 8 weeks.  In any such assessment, and in assessing a 
donors RBC loss during the past rolling 12-month period, the RBC loss 
associated with the collection of Platelets, Pheresis, and including any other 
donation type (i.e., Whole Blood, RBC by apheresis), should also be 
considered. 
  Total plasma volume loss per 12 months: 
The maximum volume (excluding anticoagulant) collected from a donor 
during a rolling 12-month period, and including any other donation type (i.e. 
Whole Blood, plasmapheresis) should not exceed: 
o  12 liters (12,000 mL) for donors weighing 110  175 lbs 
o  14.4 liters (14,400 mL) for donors weighing more than 175 lbs 
(Ref. 2). 
 
C.  Component Testing 
 
1.  Component Specification Check 
 
  Actual platelet yield (volume x platelet count) must be determined after each 
collection (21 CFR 211.103). 
  Weight/volume conversion is necessary to determine the volume of each 
collection.  To convert weight to volume, divide the weight of the collection 
(the total weight minus the weight of the bag) by the specific gravity (1.03). 
18  Contains Nonbinding Recommendations 
 
  Bacterial contamination testing:  You should perform bacterial testing as 
specified by the storage container manufacturer (i.e., 7-day storage of 
Platelets, Pheresis, Leukocytes Reduced). 
 
2.  QC Monitoring 
 
Under 21 CFR 211.160(b), laboratory controls must include the establishment of 
scientifically sound and appropriate specifications, standards, sampling plans and 
test procedures to assure that components and products conform to appropriate 
standards.  One example of a scientifically sound statistical sampling and 
analytic plan is based on a binomial approach (see Table 1:  Product Performance 
Qualification Criteria for the Platelet Component Collection Process).  The 
sampling sizes described in Table 1 will confirm with 95% confidence a < 5% 
non-conformance rate for pH and residual WBC count, and < 25% non-
conformance rate for actual platelet yield. 
 
    However, other statistical plans may also be appropriate, such as the use of scan 
    statistics. 
 
    As part of your QC protocol you should: 
 
  define a plan for non-selectively identifying collections to be tested.  This 
should ensure testing of components collected on each individual automated 
blood cell separator device, each collection type, and each location.  
  define sampling schemes for actual platelet yield (including volume 
determination) and pH, and residual WBC.  We recognize that these sampling 
schemes may be mutually exclusive.  However, the platelet yield of the 
collection (and designation of single, double or triple) should be made prior 
to performing the residual WBC count QC. 
  test actual platelet yield (platelet count times the volume) and pH at the 
maximum allowable storage time for the container system used (or 
representing the dating period).  Title 21 CFR 640.25(b) specifies that QC 
testing, including platelet count and measurement of actual plasma volume, 
be performed at the end of the storage period.  We believe that such testing 
may be conducted at issue or within 12 hours after expiration.  In addition, 
actual platelet yield and pH testing may be conducted on one storage 
container of a double or triple collection. 
  include the residual WBC count (Ref. 1) for Leukocytes Reduced collections, 
if manufacturing leukocytes reduced products. 
o  Perform the residual WBC count on the collection.  For the purpose of 
labeling as Leukocytes Reduced (see 21 CFR 606.121(c)(1)), you may 
also perform a residual WBC count on the transfusable units for double 
and triple collections that fail the collection acceptance criteria listed (see 
below in this section). 
19  Contains Nonbinding Recommendations 
 
o  Test for the residual WBC count within 48 hours after collection (Ref. 
15), or per the manufacturers directions for the cell counting 
methodology, to reduce aberrant results due to cellular deterioration and 
clumping. 
o  Test for percent platelet retention, if leukocytes reduced by filtration. 
  describe the criteria for investigation of failures during QC, including the 
factors to consider in categorizing a failure as process or non-process. 
  have a method to document all calculations and test results.  
 
We recommend that you consider the following QC results to be acceptable: 
 
  pH > 6.2.  If one component from a double or triple collection is found to 
have a pH < 6.2, the corresponding component(s) from the collection should 
be retrieved and/or quarantined until they are tested and found to be 
acceptable. 
  transfusable Platelets, Pheresis components > 3.0 x 1011 platelets. 
  residual WBC count: 
o  Single collection:  < 5.0 x 106 WBC 
o  Double collection:  < 8.0 x 106 WBC 
    Note:  If > 8.0 x 106, but each transfusable component is < 5.0 x106, this 
    is not considered a collection failure. 
o  Triple collection:  <1.2 x 107 
Note:  If > 1.2 x 107, but each transfusable component is < 5.0 x106, this 
is not considered a collection failure. 
  percent platelet retention should be > 85% or per the manufacturers 
specifications.  Components with < 85% platelet retention may be distributed, 
but a failure investigation should be performed. 
  negative for bacterial contamination testing, when performed. 
 
D.  Equipment/Supplies 
 
Equipment must be observed, standardized, and calibrated on a regularly scheduled basis 
as prescribed in the Standard Operating Procedures Manual (21 CFR 606.60(a)).  Such 
equipment includes, but may not be limited to, the automated blood cell separator 
device, cell counting instrument(s), pH meter, scales and sterile connector. 
 
All supplies (including containers) and reagents must meet all of the requirements 
described in 21 CFR 606.65. 
 
E.  Operator Training 
 
Operators must have adequate training, education and experience, or combination 
thereof, to assure competent performance of their assigned functions 
(21 CFR 606.20(b)).  We recommend that assessment of operators include scheduled  
20  Contains Nonbinding Recommendations 
 
competency assessment and proficiency testing.  In addition, we recommend that you 
develop and document appropriate training on component preparation and/or machine 
maintenance as updated information becomes available (Ref. 12). 
 
F.  Quality Monitoring 
 
You should assess the following: 
 
  total component volume and equal distribution of volume in double and triple 
component collection containers.  This assessment should include checking the 
performance of the scale; the use of the tare weight of the empty containers/tubing; 
and the weight/volume conversion. 
  component bacterial contamination testing:  Rates of bacterial contamination of 
plateletpheresis should be monitored, and bacterial contamination rates that exceed 
1:3000 (Refs. 10 and 12) should be investigated. 
 
 
VIII.  PROCESSING AND TESTING 
 
A.  Processing 
 
Platelets, Pheresis must be processed as described in 21 CFR 640, Subpart C  Platelets 
(21 CFR 640.20-640.27). 
 
B.  Communicable Disease Testing 
 
Donations of Platelets, Pheresis must be tested for communicable diseases (21 CFR 
610.40, 640.5(a) through (c), 640.23).  Platelets, Pheresis may be released or shipped 
prior to completion of communicable disease testing in accordance with 
21 CFR 610.40(g). 
 
You must test donations of human blood and blood components from a donor whose 
donations are dedicated to and used solely by a single identified recipient except that, if 
the donor makes multiple donations for a single identified recipient, you may perform 
such testing only on the first donation in each 30-day period (21 CFR 610.40(c)(1)(i)). 
 
C.  Expiration Date 
 
The dating period for Platelets, Pheresis collected using an FDA cleared or approved 
collection container under a closed or functionally closed system will be specified by the 
collection container manufacturer.   
 
In accordance with such instructions and our recommendation, Platelets, Pheresis 
collected in an open system expire 24 hours from the termination of the procedure if the 
integrity of the hermetic seal is broken during processing.  
 
21  Contains Nonbinding Recommendations 
 
If the integrity of the hermetic seal is broken after collection, the Platelets, Pheresis 
expire 4 hours from the time of the integrity violation, or at the original expiration date, 
whichever is earlier (21 CFR 606.122(l)(2)).  
 
 
IX.  LABELING 
 
An instruction circular must be available for distribution if the product is intended for 
transfusion (21 CFR 606.122).     
 
Your container labels must comply with 21 CFR 606.121 and 610.60. 
 
In addition: 
 
  The label should include the estimated amount of anticoagulant in the component container. 
  Platelets, Pheresis components for transfusion, containing less than 3.0 x 1011 platelets per 
storage container, should be labeled with the actual platelet content. 
  A component from a double or triple Platelets, Pheresis may accurately be labeled as 
Leukocytes Reduced when the residual WBC count of the collection is > 8.0 x 106 (double) 
or > 1.2 x 107 (triple) IF the transfusable component is tested and found to have a residual 
WBC count < 5.0 x 106. 
  Platelets, Pheresis may be labeled (i.e., tie-tag) with the residual WBC count if counted and 
found to contain < 1.0 x 106. 
 
 
X.  REPORTING CHANGES TO AN APPROVED BIOLOGICS LICENSE 
APPLICATION (BLA) 
 
Licensed establishments must report changes to their approved application(s) in accordance with 
21 CFR 601.12.  For assistance in reporting your changes see FDAs Guidance for Industry:  
Changes to an Approved Application:  Biological Products:  Human Blood and Blood 
Components Intended for Transfusion or for Further Manufacture.  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 manufacture of Platelets, Pheresis.  You should 
prominently label each submission with the reporting category under which you are reporting 
your change, e.g., Prior Approval Supplement; Supplement - Changes Being Effected in 30 
Days; Supplement - Changes Being Effected; or Annual Report. 
 
A.  Prior Approval Supplement (PAS):  Changes Requiring Supplement 
Submission and Approval Prior to Distribution of the Product Made Using 
the Change (Major Changes) (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). 
22  Contains Nonbinding Recommendations 
 
Under this standard, the following kinds of manufacturing changes would fall within this 
category, warranting submission of your request to implement the following changes to 
your approved BLA as a PAS: 
 
  if you currently hold an unsuspended, unrevoked BLA to manufacture blood 
components other than Platelets, Pheresis, and you intend to manufacture and 
distribute Platelets, Pheresis under that license. 
  if you are currently approved to manufacture Platelets, Pheresis at a specific facility, 
and you intend to manufacture Platelets, Pheresis at a different facility, not under an 
approved Comparability Protocol.  To submit a request for a Comparability Protocol 
see below. 
  if you are approved to manufacture Platelets, Pheresis, but intend to change your 
manufacturing process in a manner that presents a substantial potential for an 
adverse effect on the product.  FDA believes that such manufacturing changes 
include:  change in storage conditions; change in anticoagulant; leukocyte reduction; 
and collection of an additional or different product. 
  if you intend to collect Platelets, Pheresis using an automated blood cell separator 
device new to the market or new to your establishment. 
  if you are requesting approval for a Comparability Protocol.  The Comparability 
Protocol described in 21 CFR 601.12(e) is a supplement that describes the specific 
tests and validation studies and acceptable limits to be achieved to demonstrate the 
lack of adverse effect for specified types of manufacturing changes on the identity, 
strength, quality, purity, or potency of the product as they may relate to the safety or 
effectiveness of the product.  A new Comparability Protocol, or a change to an 
existing one, requires approval from FDA prior to distribution of the product which, 
if approved, may justify a reduced reporting category for the particular change 
because the use of the protocol for that type of change reduces the potential risk of 
an adverse effect (21 CFR 601.12(e)). 
 
A Comparability Protocol is appropriate, but not required, if you wish to add 
multiple collection facilities under your direction and control, using the same process 
to manufacture Platelets, Pheresis.  If you request approval for a Comparability 
Protocol, you should describe the procedures and processes that each new collection 
facility will implement to ensure conformance with the Comparability Protocol.  You 
may identify one or more collection facilities for the purpose of validation and 
submission of the Comparability Protocol and supporting data to CBER for review.  
Approval of such a Comparability Protocol for future collection facilities justifies a 
reduced reporting category for the particular change because the use of the protocol 
for that type of change reduces the potential risk of an adverse effect. 
 
If you are using an approved Comparability Protocol, you should routinely review 
the procedures and specifications in the Comparability Protocol to assure that they 
remain current and consistent with the applicable application and current guidance.  
If modifications are required, you should contact FDA to discuss the change and to 
determine the appropriate reporting category. 
 
23  Contains Nonbinding Recommendations 
 
  We consider the recommendations in this guidance document to provide appropriate 
criteria for a biologics license application or supplement for Platelets, Pheresis.  You 
may use an alternative approach if such approach satisfies the requirements of the 
applicable statutes and regulations.  Your alternative procedure(s) may be acceptable 
if you demonstrate that the resulting Platelets, Pheresis components meet applicable 
standards.  We have determined that it may be adequate to determine the actual 
platelet yield at collection, and that re-determination of the actual platelet yield at 
issue or outdate is unlikely to provide additional relevant information.  If you choose 
to discontinue determining the platelet count for QC testing as described under 
21 CFR 640.25(b)(1), you must submit a request for an alternative procedure under 
21 CFR 640.120. 
 
You must not distribute in interstate commerce blood components made using a changed 
manufacturing process requiring a PAS until you have received our approval of your 
PAS (21 CFR 601.12(b)(3)). 
 
B.  Changes Being Effected in 30 Days (CBE-30) Supplement:  Changes 
Requiring Supplement Submission at Least 30 Days Prior to Distribution of 
the Product Made Using the Change (21 CFR 601.12(c)) 
 
Under 21 CFR 601.12(c), changes that have a moderate 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 Changes 
Being Effected in 30 days (CBE-30) supplement. 
 
You must submit your request to implement manufacturing changes with a moderate 
potential for an adverse effect to your approved BLA as a CBE-30 supplement under 21 
CFR 601.12(c).  The manufacturing changes described below are examples of changes 
that we believe fall within this category: 
 
  certain software and hardware upgrades provided by the manufacturer to your 
cleared or approved automated blood cell separator device 
  addition of concurrent plasma collection 
  implementation of a new collection facility under an approved Comparability 
Protocol 
 
You may distribute your blood components made using the change requested in your 
CBE-30 supplement in interstate commerce 30 days after we receive your supplement, 
unless we notify you otherwise (21 CFR 601.12(c)(4)). 
 
C.  Submission Inclusion Documents 
 
1.  PAS:  To comply with the requirements in 21 CFR 601.12(b)(3), the following must 
be included in the supplement: 
 
24  Contains Nonbinding Recommendations 
 
  identification of the components involved (e.g., single plateletpheresis component, 
double plateletpheresis components, and/or triple plateletpheresis components) and 
manufacturing site(s) or area(s) affected, and a detailed description of the 
manufacturing change (including device collection technology and the collection 
protocol(s)) (21 CFR 601.12(b)(3)(i) through (iii)).  We recommend that this 
information be documented in a cover letter and FDA Form 356h.  To permit 
assessment of the manufacturing change we recommend including copies of the 
following SOPs: 
o  collection 
o  informed consent 
o  labeling including labels 
o  donor qualification, deferral and adverse event follow-up 
o  a description of training (or an example of training documents)   
o  component manufacturing 
o  monitoring donor RBC and plasma loss 
o  failure investigation 
o  quality control including sampling scheme, sample handling, tracking and 
trending 
o  equipment standardization/calibration 
o  quarantine and disposition of unsuitable products 
 
Additionally, we recommend that the following SOPs, if already approved for other 
blood collection activities and unrevised, would not need to be submitted: 
o  sample preparation 
o  component storage and shipping  
o  donor arm preparation 
 
  product labeling for each component, if changed (21 CFR 601.12(f)).  We 
recommend submitting a Form FDA 2567 including Circular (unless already on file 
at FDA) 
  a reference list of relevant SOPs (21 CFR 601.12(b)(3)(vii))  
  relevant validation protocols and data (21 CFR 601.12(b)(3)(vi)).  We recommend a 
summary of the validation protocol, including failure investigations. 
  a description of the methods used and studies performed to evaluate the effect of the 
change and the data derived from such studies (21 CFR 601.12(b)(3)(iv) through 
(v)).  We recommend submitting the following information and data: 
o  the device manufacturer 
o  the device type 
o  blood unit number 
o  component description (i.e., leukocytes reduced) 
o  date of collection 
o  date of testing 
o  result interpretation(s) 
o  the identity of the person performing the testing 
25  Contains Nonbinding Recommendations 
 
o  the identity of the collection facility 
o  evidence of QA oversight, and  
o  expected component specifications. 
 
  Additionally, we recommend two months of QC data for actual platelet yield and 
volume, pH, and residual WBC count (if requesting approval for Leukocytes 
Reduced platelets).  
 
We further recommend that you provide an agreement to summarize bacterial 
contamination testing results for the first two hundred and fifty (250) Platelets, Pheresis 
collections in your Annual Report. 
 
2.  Comparability Protocol:  If you are an establishment with multiple manufacturing 
sites and wish to submit a comparability protocol to justify a reduced reporting 
category for a manufacturing change at multiple sites (see Section X.C.4 below), you 
must submit that protocol as a PAS (21 CFR 601.12(e)).  In addition to the 
information listed in Section X.C.1 above , we recommend that you include the 
following: 
 
  implementation plan 
  proposed reporting category for changes made under proposed Comparability 
Protocol 
 
3.  CBE-30 submissions (excluding new facilities under an approved Comparability 
Protocol):  Under 21 CFR 601.12(c)(3) and 601.12(b)(3)(i) through (vii), the 
following information must be included in your CBE-30 submission: 
 
  identification of the Platelets, Pheresis components involved (e.g., single 
plateletpheresis component, double plateletpheresis components, and/or triple 
plateletpheresis components) and manufacturing site(s) or area(s) affected, and a 
detailed description of the proposed manufacturing change (including device 
collection technology and the collection protocol(s)).  We recommend that you 
document this information in a cover letter and FDA Form 356h.  To permit 
assessment of the documented manufacturing change, we recommend that you 
include copies of any new or revised SOPs. 
 
  relevant validation protocols and data.  We recommend that you submit a summary 
of the validation protocol, including failure investigation. 
 
  the data derived from such studies.  We recommend two months of QC data for 
actual platelet yield and volume, pH, and residual WBC count (if requesting 
approval for Leukocytes Reduced platelets).  
  
4.  CBE-30 submissions for new facilities under an approved Comparability Protocol:  
To comply with 21 CFR 601.12(c)(3) and 601.12(b)(3)(i) through (vii), the 
following information must be included: 
26  Contains Nonbinding Recommendations 
 
  identification of the components involved (e.g., single plateletpheresis component, 
double plateletpheresis components, and/or triple plateletpheresis components) and 
new manufacturing site(s) or areas(s) affected, and a detailed description of the 
proposed implementation plan (manufacturing change including device collection 
technology and the collection protocol(s)).  Additionally, we recommend that this 
information be documented in a cover letter and FDA Form 356h.  
 
  relevant validation protocols and data.  We recommend a summary of the validation 
protocol, including failure investigations to meet the requirement. 
 
  the data derived from studies.  We recommend two months of QC data for actual 
platelet yield and volume, pH, and residual WBC count (if requesting approval for 
Leukocytes Reduced platelets).  
 
In addition, you should include the submission tracking number (STN) of the approved 
Comparability Protocol, or the STN(s) of changes to the SOPs associated with an 
approved Comparability Protocol. 
 
D.  Submission of Platelets, Pheresis Sample(s) to CBER 
 
To obtain a biologics license under Section 351 of the Public Health Service Act for any 
biological product, the manufacturer must submit an application to CBER, and sample(s) 
representative of the product must be listed in the application (21 CFR 601.2(a)).  
  
 
We recommend that: 
 
  applicants with no prior experience in the collection of Platelets, Pheresis schedule 
submission of Platelets, Pheresis products to CBER.  
  applicants who submit a CBE-30 for an additional facility under an approved 
Comparability Protocol generally would not need to submit Platelets, Pheresis 
  products to CBER.   
 
CBER may request the submission of product samples by other applicants, as necessary, 
during the review process or at any other time (21 CFR 610.2(a)). 
 
  E.  Shipping Platelets, Pheresis Sample(s) to CBER 
 
If CBER has requested you to submit a Platelets, Pheresis sample(s) to CBER, you 
should contact CBER Division of Hematology, Laboratory of Cellular Hematology at 
(301) 496-2577 to schedule delivery of the products to arrive prepaid.  Platelets, Pheresis 
sample(s) should be shipped to the following address between 8:30 a.m. and 4:00 p.m. 
Monday through Friday, excluding Federal holidays: 
27  Contains Nonbinding Recommendations 
 
Center for Biologics Evaluation and Research (CBER) 
Food and Drug Administration 
8800 Rockville Pike 
Building 29, Room 323 
Bethesda, Maryland 20892 
 
We recommend that you enclose a pre-paid, self-addressed shipping label to allow return 
of shipping boxes and coolants, if desired. 
 
We recommend that you ensure that the Platelets, Pheresis sample(s) arrives at CBER 
prior to the expiration time.  The Platelets, Pheresis sample(s) should not expire on 
Friday or Saturday at midnight, or at midnight on the day before a Federal holiday.  
 
Labeling and processing, including required testing for evidence of infection due to 
communicable disease agents (21 CFR 610.40), should be complete prior to shipment. 
 
 
When shipping to us, you should follow your SOPs for collection, processing, storage 
and distribution of blood components intended for transfusion.  
 
 
XI.  CONTACT INFORMATION 
 
You may direct questions specific to Platelets, Pheresis application submissions to the Division 
of Blood Applications.  You may also direct questions to the Office of Communications, 
Training, and Manufacturers Assistance (OCTMA) as an initial general point of contact.  
Submit all registration forms (Form FDA 2830) and licensure applications/supplements to the 
Director, CBER. 
28  Contains Nonbinding Recommendations 
 
Table 3:  FDA Contact Information 
Director, Division of Blood Applications 
Center for Biologics Evaluation and Research, HFM-370, 
Submissions:  
Food and Drug Administration, 
(cid:31) Registrations  
c/o Document Control Center, HFM-99, 
(cid:31) License Applications 
1401 Rockville Pike, Suite 200N, 
Rockville, MD 20852-1448. 
Director, OCTMA, HFM-40, 
Food and Drug Administration, 
c/o Document Control Center, HFM-99, 
General Questions 
1401 Rockville Pike, Suite 200N, 
Rockville, MD 20852-1448, 
Voice (301) 827-2000; Fax (301) 827-3843. 
Director, Division of Blood Applications,  
Center for Biologics Evaluation and Research, HFM-370, 
Food and Drug Administration, 
Application Submission  c/o Document Control Center, HFM-99, 
1401 Rockville Pike, Suite 200N, 
Rockville, MD 20852-1448, 
Voice (301) 827-3543; Fax (301) 827-3534. 
Center for Biologics Evaluation and Research (CBER) 
Food and Drug Administration 
Platelets, Pheresis Samples to   8800 Rockville Pike 
CBER  Building 29, Room 323 
Bethesda, Maryland 20892 
 
 
 
29  Contains Nonbinding Recommendations 
 
XII.  REFERENCES  
   
1.  FDA Recommendations and Licensure Requirements for Leukocyte-Reduced Blood 
Products, May 29, 1996. 
 
2.  FDA Memorandum to Registered Blood and Source Plasma Establishments, Revision of 
FDA Memorandum of August 27, 1982:  Requirements for Infrequent Plasmapheresis 
Donors - 3/10/1995. 
 
3.  FDA Guidance for Industry:  Recommendations for Collecting Red Blood Cells by 
Automated Apheresis Methods - Technical Correction February 2001 - 2/13/2001. 
 
4.  Murphy S. Platelet storage for transfusion. Seminars in Hematology 1985 July; 22(3):165-77. 
 
5.  Dumont LJ, VandenBroeke T. Seven-day storage of apheresis platelets:  report of an in vitro 
study. Transfusion. 2003 Feb; 43(2):143-50. 
 
6.  Sonksen JR, Kong KL, Holder R. Magnitude and time course of impaired primary 
haemostatis after stopping chronic low and medium does aspirin in healthy volunteers. 
British Journal of Anaesthesia. 1999 Mar; 82(3):360-5. 
 
7.  Cronberg S, Wallmark E, Soderberg I. Effect on platelet aggregation of oral administration of 
10 non-steroidal analgesics to humans. Scandinavian Journal of Haematology. 1984 Aug; 
33(2):155-9. 
 
8.  Quinn MJ, Fitzgerald DJ. Ticlopidine and Clopidogrel. Circulation. 1999(100):1667-72. 
 
9.  Blajchman MA. Incidence and significance of the bacterial contamination of blood 
components. Developmental Biology 2002; 108: 59-67. 
 
10. Hillyer CD, Josephson CD, Blajchman, MA, Vostal JG, Epstein JS, Goodman JL. Bacterial 
contamination of blood components: risks, strategies, and regulation:  Joint ASH and AABB 
Educational Session in Transfusion Medicine. Hematology 2003; 575-89. 
 
11. FDA Guideline on General Principles of Process Validation, May 1987, reprinted February 
1993. 
 
12. FDA Guidance for Industry:  Use of Sterile Connecting Devices in Blood Bank Practices - 
11/22/2000. 
 
13. FDA Guideline for Quality Assurance in Blood Establishments, July 11, 1995. 
 
14. Dumont LJ, Dzik WH, Rebulla P, et al.  Practical guidelines for process validation and 
process control of white-cell reduced blood components:  report of the Biomedical 
Excellence for Safer Transfusion (BEST) working party of the International Society of Blood 
Transfusion (ISBT).  Transfusion 1996; 36: 11-20. 
30  Contains Nonbinding Recommendations 
 
15. Dzik WH, Ragosta A, Cusack WF. Flow-cytometric method for counting very low numbers 
of leukcoytes in platelet products. Vox Sang. 1990; 59:153-9. 
 
16. Lazarus EF, Browning J, Norman J, Oblitas J, Leitman SF. Sustained decreases in platelet 
count associated with multiple, regular plateletpheresis donations. Transfusion. 2001 June; 
41:756-761. 
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