Pre-Storage Leukocyte Reduction of Whole Blood and Blood Components Intended for Transfusion: Final Guidance for Industry

Administrative guidance, not enacted legislation. This captured publisher edition preserves the listed document and attachments; later developments are not independently consolidated.

Guidance for Industry
Pre-Storage Leukocyte Reduction of Whole
Blood and Blood Components Intended for
Transfusion
Additional copies of this guidance are available from the Office of Communication, Outreach and Development (OCOD),
(HFM-40), 1401 Rockville Pike, Suite 200N, Rockville, MD 20852-1448, or by calling 1-800-835-4709 or 301-827-1800,
or e-mail ocod@fda.hhs.gov, or from the Internet at http://www.fda.gov/BiologicsBloodVaccines/
GuidanceComplianceRegulatoryInformation/Guidances/default.htm.
For questions on the content of this guidance, contact OCOD at the phone numbers or e-mail address listed above.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research
September 2012

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TABLE OF CONTENTS
I. 	INTRODUCTION............................................................................................................. 1
II. 	BACKGROUND ............................................................................................................... 2
A. 	Changes from FDA Memorandum, “Recommendations and Licensure
Requirements for Leukocyte-Reduced Blood Products,” May 29, 1996 ......... 2
B. 	Established Benefits of Pre-Storage Leukocyte Reduction............................... 3
C. 	Potential Benefits of Pre-Storage Leukocyte Reduction ................................... 3
D. 	Safety Concerns Related to Bedside Leukocyte Reduction Filtration ............. 4
E. 	Definitions.............................................................................................................. 4
III. 	VALIDATION OF THE LEUKOCYTE REDUCTION PROCESS ........................... 5
A. 	Methods of Leukocyte Reduction ........................................................................ 6
B. 	Equipment Installation Qualification ................................................................. 6
C. 	Validation Protocol Development........................................................................ 6
D. 	Process Performance Qualification (Operator) ................................................. 7
E. 	Product Performance Qualification for the Leukocyte Reduction Process .... 7
F. 	Leukocyte Reduction Performance Qualification Criteria............................... 8
G. 	Investigation of Product Performance Qualification Failure ......................... 10
H. 	Re-Qualification/Re-Validation ......................................................................... 10
IV. 	QUALITY ASSURANCE AND MONITORING ........................................................ 10
A. 	Component Testing............................................................................................. 11
B. 	Equipment/Ancillary Supplies........................................................................... 12
C. 	Operator Training .............................................................................................. 12
D. 	Standard Operating Procedures........................................................................ 13
1. 	Requirements for Standard Operating Procedures (SOPs) ................................... 13
2. 	Additional Requirements and Recommendations to be included in SOPs ........... 13
V. 	LABELING ..................................................................................................................... 14
VI. 	REPORTING CHANGES TO AN APPROVED BIOLOGICS LICENSE
APPLICATION (BLA)................................................................................................... 15
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)) ........................................... 15
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)) ............................... 17
C. 	Changes to be Described in an Annual Report (Minor Changes) (21 CFR
601.12(d)) ............................................................................................................. 17
D. 	Submission of Documents................................................................................... 17
VII. 	CONTACT INFORMATION........................................................................................ 20
VIII. 	REFERENCES................................................................................................................ 21
APPENDIX.................................................................................................................................. 24
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Guidance for Industry
Pre-Storage Leukocyte Reduction of Whole Blood and Blood
Components Intended for Transfusion
This guidance represents the Food and Drug Administration’s (FDA’s) 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
We, FDA, are issuing this guidance document to provide you, blood establishments, with
recommendations for pre-storage leukocyte reduction of Whole Blood and blood components
intended for transfusion, including recommendations for validation and quality control
monitoring of the leukocyte reduction process. We also provide information to licensed blood
establishments for submitting biologics license application supplements to include leukocytes
reduced components. This guidance applies to Whole Blood, Red Blood Cells, Plasma, and
Platelets1 manufactured from Whole Blood or collected by automated methods2. This guidance
document finalizes the draft guidance of the same title dated January 2011 and supersedes the
FDA memorandum issued on May 29, 1996, entitled “Recommendations and Licensure
Requirements for Leukocyte-Reduced Blood Products.”
We support the use of leukocytes reduced blood and blood components for specific indications
(see section II.B) and seek to streamline the licensing procedure for leukocytes reduced blood
components to assist blood establishments in making pre-storage leukocytes reduced blood
components more widely available.
Although there have been reports of adverse events associated with leukocyte reduction by
filtration (Refs. 1 and 2), advances in blood cell separation technology generally enable the safe
reduction of leukocytes. We believe that increased availability of pre-storage leukocytes reduced
blood components for non-targeted recipients will support the treatment of recipients who may
1 The guidance document entitled “Guidance for Industry and FDA Review Staff: Collection of Platelets by
Automated Methods” dated December 2007 contains our recommendations for validating; quality assurance and
monitoring; labeling and licensure for leukocyte reduction of Platelet, Pheresis products.
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm07
3382.htm.
2 The guidance document entitled “Guidance for Industry: Recommendations for Collecting Red Blood Cells by
Automated Apheresis Methods” Technical Correction dated February 2001.
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm07
6756.htm.

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benefit from receiving leukocytes reduced components but have not been identified as falling
within the indications identified in section II.B. We suggest that consideration should be given
to making leukocytes reduced blood components more widely available.
FDA’s guidance documents, including this guidance, do not establish legally enforceable
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory requirements are cited.
The use of the word should in FDA’s guidances means that something is suggested or
recommended, but not required.
II. 	BACKGROUND
A. 	Changes from FDA Memorandum, “Recommendations and Licensure
Requirements for Leukocyte-Reduced Blood Products,” May 29, 1996
In a May 29, 1996 memorandum, we issued recommendations on leukocyte reduction, a
manufacturing step performed under controlled and monitored laboratory conditions.
Under those recommendations, leukocytes reduced components were to contain < 5.0 x
10 6 residual white blood cells (WBCs) per each Whole Blood, Red Blood Cells or
Platelets, Pheresis collection, and < 8.3 x 105 residual WBCs per each Platelets derived
from Whole Blood, with at least an 85 percent recovery of the original component. The
memorandum was consistent with the outcome of a public workshop held in March 1995
on leukocytes reduced products. This guidance document maintains those standards for
residual WBCs and modifies the 1996 recommendations as follows:
1. 	Statistical methods for validation and quality control monitoring of the
leukocyte reduction process are provided. Consideration is now given to the
distinction between process and non-process failures.
2. 	This document discusses certain donor specific traits which may affect
leukocyte reduction processes. Observations have identified a number of
donor-specific factors (such as abnormal polymerization of hemoglobin S
(HbS)) during the filtration process (Refs. 3 through 7) that may result in filter
blockage or inadequate leukocyte reduction. The identification of sickle cell
trait or other factors associated with incomplete filtration for a given donor is
an important adjunct to overall process control. We encourage blood
establishments to reduce component loss by identifying donors whose blood
fails to filter successfully and to divert subsequent donations from such donors
for uses other than leukocytes reduced transfusable Whole Blood and blood
components. Testing of donors for HbS may be appropriate.
3. 	We are also providing an option for supplemental labeling of blood
components (not applicable to Whole Blood derived Platelets) when the
residual WBC count of an individual component has been determined by
direct count to be < 1.0 x 10 6 . A supplemental label in the form of a tie-tag
may be affixed to the container stating: “The residual white blood cell count

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of this component has been determined to be < 1.0 x 106.” We make this
recommendation in response to comments requesting more specific labeling
for leukocytes reduced products with a lower WBC count.
4. 	We recommend that Red Blood Cell recovery should be calculated by
comparison of the post-filtration to pre-filtration volume x hematocrit, weight
x hematocrit, or weight unless otherwise instructed in the manufacturer’s
direction for use.
B. 	Established Benefits of Pre-Storage Leukocyte Reduction
Leukocytes reduced Whole Blood and blood components have been shown to reduce the
following:
 	recurrent febrile, non-hemolytic transfusion reaction (i.e., patients with a history
of two or more febrile reactions to transfusion) (Refs. 8 through 12);
 	alloimmunization to leukocyte antigens that may complicate care of patients who
undergo transplantation or chronic transfusion therapy (e.g., patients with aplastic
anemia or hematologic malignancies); and
 	transmission of cytomegalovirus (CMV) to patients at increased risk of CMV
disease (e.g., chemotherapy recipients for whom severe neutropenia is expected,
recipients of hematopoietic progenitor cell replacement therapy, CMV
seronegative recipients of CMV seronegative solid organ grafts, and low birth
weight premature infants) (Ref. 13).
We believe it is advantageous to provide leukocytes reduced components to reduce such
adverse events. In addition, we believe it is advantageous to provide pre-storage
leukocytes reduced components in preference to bedside filtered blood components based
on quality and safety considerations (Ref. 14). Routine use of leukocytes reduced blood
components further protects patients who have increased risk, but whose conditions have
not yet been identified.
C. 	Potential Benefits of Pre-Storage Leukocyte Reduction
Potential, but not established, benefits of leukocyte reduction include reduction of:
 	transfusion-associated immunomodulation (Ref. 15);
 	bacterial overgrowth (Refs. 8 and 16);
 	viral reactivation (Refs. 8 and 16);
 	reperfusion injury following cardiopulmonary bypass (Ref. 16);
 	red blood cell and platelet storage lesions (Ref. 17);
 	transfusion-transmitted Leishmania infection (Ref. 18); and
 	transfusion-transmitted variant Creutzfeldt-Jakob disease (vCJD) (Ref. 19).
Limited scientific data have suggested the possibility that leukocyte reduction may be a
useful measure against the risk of transfusion-transmitted vCJD (Refs. 19 through 23).

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Some international blood authorities have implemented or are considering the
implementation of a regulatory requirement to leukocyte reduce all Red Blood Cells and
Platelets intended for transfusion (universal leukocyte reduction), as well as plasma for
further manufacturing to reduce the risk of vCJD transmission.
Similarly, the potential to reduce infection by pathogens that are primarily WBC
associated may extend beyond CMV (Refs. 11 and 12) to include other known and
unknown agents potentially transmitted by WBCs (Ref. 19).
Leukocyte reduction is not considered appropriate for the prevention of transfusion-
associated graft-versus-host disease. At this time, irradiation of blood products is the
only definitive method available to prevent this serious and often fatal transfusion
outcome in patients at risk (Ref. 24).
D. 	Safety Concerns Related to Bedside Leukocyte Reduction Filtration
Bedside filtration remains available as a leukocyte reduction method to physicians
prescribing transfusion therapy. As a post-storage procedure, however, bedside filtration
has been associated with precipitous hypotension in the transfusion recipient, an
infrequent yet serious adverse effect not associated with pre-storage leukocyte reduction
(Ref. 25). Patients on medications that inhibit the angiotensin converting enzyme (ACE
inhibitors) appear to be particularly susceptible. Pre-storage leukocyte reduction allows
the leukocyte reduction process to be monitored under controlled conditions that assure
component purity, consistency, and safety and is therefore generally preferable to bedside
filtration (Refs. 25 through 27).
E. 	Definitions
For the purposes of the terms used in this guidance, the following definitions apply:
Automated Blood Cell Separator (ABCS): 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, collect one or more of the blood components and
return to the donor the remainder of the Whole Blood and blood components. The ABCS
device is intended for routine collection of blood and blood components for transfusion
or further manufacturing use.
Non-process failure: Failure of a leukocyte reduction process due to a non-controllable
parameter (i.e., donor specific characteristic such as HbS). Note: In your sampling plan
for validation or quality control (QC) testing, you may exclude (and replace) non-process
failures.
Percent recovery (of the original component): Ratio of the post-filtration to the pre-
filtration content of the component expressed as a percent.

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 	Red Blood Cells/Whole Blood: Red Blood Cell percent recovery of the original
component can be determined by comparing the pre-filtration content to the post-
filtration content by using any of the following methods:
o 	volume x hematocrit;
o 	weight x hematocrit;
o 	weight: The weight method should be used in conjunction with a
documented visual check to ensure that abnormal red blood cell
retention has not occurred; or
o 	as described by the manufacturer in the package insert.
 	Platelets: Because of selective removal of platelets by leukocyte reduction
filters, the percent recovery is to be determined by comparing the platelet yield
pre-filtration to the platelet yield post-filtration (i.e., not by weight).
Process failure: Failure of a leukocyte reduction process due to an error that was
avoidable if proper procedures, precautions and/or instructions were followed (i.e., not
following manufacturer’s directions) or a product/device defect.
Process validation: In brief, is the collection and evaluation of data from the process
design stage through production. This validation establishes scientific evidence that a
process is capable of consistently delivering quality product (Ref. 28).
Residual White Blood Cell (WBC) content: 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.
Yield: The quantity that is actually produced during manufacturing.
III. 	VALIDATION OF THE LEUKOCYTE REDUCTION PROCESS
The Current Good Manufacturing Practices (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 safety requirements of the Federal Food, Drug, and Cosmetic Act, 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 apply to Whole Blood and
blood components (21 CFR 210.2(a) and 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 “scientific evidence that a process is capable of consistently delivering
quality product”3 (Ref. 28). We recommend that establishing documentation of process
validation include, but not be limited to, equipment installation qualification, validation protocol
development, process operator performance qualification and product performance qualification
(Ref. 28).
3 The requirement for process control is set forth in general terms in 21 CFR 211.100.

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A. 	Methods of Leukocyte Reduction
Whole Blood and blood components (including components collected by automated
methods) intended for transfusion may be leukocyte reduced using any of the closed
system or functionally closed methods as follows:
 	filtration through an in-line filter integral to the blood collection set or apheresis
set with or without automated filtration (e.g., press through filtration)
 	filtration through a filter system attached to a blood component container using an
FDA cleared sterile tubing connecting device (STCD) (Ref. 29)
 	direct, in-process leukocyte reduction for certain plateletpheresis and
plasmapheresis collections (i.e., by ABCS devices).
B. 	Equipment Installation Qualification
Section 606.60(a) (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
initiation of an automated leukocyte reduction method, we recommend that the
equipment used for leukocyte reduction (e.g., leukocyte reduction filter, ABCS device)
be qualified as described in the operator’s manual or manufacturer’s directions for use.
C. 	Validation Protocol Development
An integral element of the performance and documentation of process validation is the
development of a validation protocol. You should refer to FDA’s “Guidance for
Industry: Process Validation: General Principles and Practices” (Ref. 28) as an outline
for developing your validation protocol. We recommend that the validation protocol
include, but may not be limited to:
 	a description of the leukocyte reduction method, including the device, to be used
 	acceptable values for the residual WBC count, including:
o 	residual WBC count post leukocyte reduction for the component (Whole
Blood, Red Blood Cells, Platelets, Plasma)
o 	percent recovery of the original component for Whole Blood, Red Blood
Cells, or Platelets when leukocytes are reduced by filtration or per the
manufacturer’s specifications, if different
 	manufacturer’s specifications for processing parameters (if given)
 	failure investigation criteria
 	personnel training criteria
 	standard operating procedures (SOPs) for performing each element of the
collection and manufacturing process
 	documentation of the validation protocol criteria for all of the above.

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D. 	Process Performance Qualification (Operator)
Each person engaged in the manufacture of leukocytes reduced components must have
adequate education, training, or experience to assure their competent use of the devices
involved (21 CFR 606.20(b)).
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 leukocytes reduced components meeting the
specifications for the specific leukocyte reduction methodology being qualified.
E. 	Product Performance Qualification for the Leukocyte Reduction Process
Various factors may adversely influence the leukocyte reduction process, e.g., donor
specific factors or improper use of an ABCS device. The objective of product
performance qualification is to verify that the leukocyte reduction method conforms to
the claims of the device manufacturer and the blood establishment. In addition,
appropriate testing will establish confidence that the final component meets all release
requirements for safety, purity, and potency (Refs. 28 through 31). All components
collected during the qualification process can be released for transfusion provided that
they meet minimum specifications as defined by the device manufacturer, are labeled
appropriately, and are otherwise suitable.
We believe that, generally, product performance qualification only needs to be performed
when the leukocyte reduction method (either by ABCS devices or filtration) is first put
into use at an establishment. We note the following:
 	For establishments using a single model ABCS device from only one
manufacturer, all instruments available for use with that ABCS device should be
included in the initial product performance qualification.
 	For establishments using multiple models of ABCS devices from one or more
manufacturers you should conduct full product performance qualification for each
device type on all instruments available for use with that ABCS device type.
 	For establishments using leukocyte reduction filters from different manufacturers,
or when there is a change to a different filter manufacturer, you should conduct
full product performance qualification for each filter type from each
manufacturer.
Product performance qualification should include testing for the residual WBC count and
percent recovery of the original component as recommended in section III.C, and testing
of components processed by all trained operators. In addition, we recommend you
perform residual WBC count testing within 48 hours of collection (Ref. 33) or per the
manufacturer’s directions for the cell counting methodology.
You must conduct an investigation of each product performance qualification failure, and
when appropriate, initiate corrective action and follow-up measures (21 CFR 211.192 and
606.100(c)). There should be ongoing assurance that the process continues to perform at

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the level established during the product performance qualification. Evaluating the
performance of the process identifies problems and determines whether action must be
taken to correct, anticipate, and prevent problems (21 CFR 211.180(e), 211.192, and
606.100(c)). We understand that some failures may occur due to conditions not resulting
from a failure of the process (e.g., failure due to donor specific characteristic such as
HbS).
F. 	Leukocyte Reduction Performance Qualification Criteria
Conformance to product standards must be assessed by a statistically valid method (see
21 CFR 211.160(b)). In the absence of a validation method (plan) provided by the
manufacturer, you should develop a statistically valid plan based on 95% confidence that
more than 95% of the components will meet the recommended results. One possible
approach to process validation is a two-stage sampling plan based upon the binomial
distribution. In this approach, an initial representative sample of components with a pre-
determined sample size should be tested consecutively (validation) or randomly (QC
monitoring). Identified non-process failures may be excluded from the sample size and
replaced. Conformance can be demonstrated if an acceptable number of process failures
are observed in this sample. In the event that there is one more process failure than
permitted in the initial sample, a second sample of components may be tested
consecutively. Conformance can be demonstrated if no further process failures are
observed in the second sample. The size of the second sample will depend on the size of
the first sample. We provide two examples to illustrate the use of this approach:
Example 1: The first stage sample is 60 consecutive collections. If no process
failures are observed among these 60 components, conformance has been
demonstrated and no further testing is required. If one process failure is observed
among the 60 components, a second sample of 71 consecutive collections may be
tested. If no further process failures are observed among these 71 components,
conformance has been demonstrated and no further testing is required. If more than
one process failure is observed among the first sample of 60 components, or if one or
more additional process failures are observed among the second sample of 71
components, the validation has failed and no additional testing is recommended to
qualify the process. A failure investigation should be undertaken. (See section
III.G.)
Example 2: The first stage sample is 94 consecutive collections. If zero or one
process failures are observed among these 94 components, conformance has been
demonstrated and no further testing is required. If two process failures are observed
among the 94 components, a second sample of 75 consecutive collections may be
tested. If no further process failures are observed among these 75 components,
conformance has been demonstrated and no further testing is required. If more than
two process failures are observed among the first sample of 94 components, or if one
or more additional process failures are observed among the second sample of 75
components, the validation has failed and no additional testing is recommended to
qualify the process. A failure investigation should be undertaken. (See section
III.G.)

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Note that the sample sizes are pre-determined and fixed based on the required statistical
criteria. For example, if you plan to test 94 samples and encounter no failure in the first
60 samples, changing your plan to 60 samples is not permitted.
In some cases, you may decide on a one-stage sampling strategy rather than the two-stage
strategy described above. Based on the binomial distribution, conformance can be
demonstrated by observing zero process failures in a fixed sample of 60 components, one
or fewer failures in a fixed sample of 94 components, or two or fewer failures in a fixed
sample of 124 components.
We recommend that the following parameters as listed in Table 1 should be assessed to
assure an overall statistically-based level of product conformance:
 	residual WBC content
 	percent recovery of the original component
OR per the manufacturer’s
specifications.
Table 1: Leukocyte Reduction (LR) Performance Qualification Criteria for Blood
and Blood Components (other than Platelets, Pheresis 4 )
Blood Component 	Recommended
Residual WBC
Content
Recommended Minimum Post-Filtration
Whole Blood, LR 	< 5.0 x 106* 85% recovery *** of original RBC content
Red Blood Cells, LR 	< 5.0 x 106* 85% recovery *** of original RBC content
Plasma Products that
are LR
< 5.0 x 106* N/A
Platelets, LR** 	< 8.3 x 105 per
individual (i.e.,
unpooled) unit
85% recovery *** of original platelet yield;
and a minimum of
> 5.5 x 1010 platelets for 75% of units
*Per component.
**Multiple units of Platelets are often pooled after storage and prior to filtration, rather than filtered
individually prior to storage and pooling. In this instance, the pooled and then filtered product for
transfusion should contain 5.0 x 10 6 residual WBCs. For example, multiple units of Platelets (4-6 units)
are pooled into a single platelet dose. The total (4-6 units) should contain 5.0 x 10 6 residual leukocytes.
The same recommendation for 5.0 x 10 6 residual WBCs applies if platelet units are pooled before storage,
whether filtered before or after storage.
*** Or per the device manufacturer’s specifications, if different.
Plasma components, when manufactured under cGMP, may inherently have a residual
WBC content of < 5.0 x 106 per unit. Currently accepted and validated cell counting
procedures may need to be modified for plasma components. Plasma components
(including Fresh Frozen Plasma and Cryoprecipitated Antihemophilic Factor) may be
4 See footnote 1.

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labeled “Leukocytes-Reduced” provided that manufacturing process validation as
described in this section (section III) includes these components and the ABCS device is
cleared to manufacture the product.
G. 	Investigation of Product Performance Qualification Failure
Section 211.192 (21 CFR 211.192) requires that the failure of a batch or any of its
components to meet any of its specifications be thoroughly investigated. If a post-
filtration residual WBC count is > 5 x 106 (> 8.3 x 10 5 for unpooled Platelets) and/or fails
to meet the percent recovery of the original component during validation, you must
conduct an investigation of the product performance qualification failure
(21 CFR 211.192 and 606.100(c)).
You must investigate collections that fail to meet the percent Red Blood Cell recovery or
Platelet recovery criteria (21 CFR 211.192 and 606.100(c)). However, the component
may be released if the actual platelet yield or Red Blood Cell volume is determined to be
suitable by the quality control unit and the component is labeled appropriately.
Product performance qualification failures may occur due to conditions not resulting
from a failure of the process. For example, if the observed failure is investigated and
found to be due to a donor-specific factor, it does not constitute a process failure and
should be excluded from the performance qualification evaluation.
When a failure during product performance qualification is investigated and found to be
due to an identified donor-specific factor, we encourage you to flag the donor record.
Upon a subsequent occurrence of incomplete filtration or inadequate WBC removal, we
encourage you to consider not using this donor for future donations of leukocytes reduced
components.
H. 	Re-Qualification/Re-Validation
 	Exceeding the allowable process failures of the product performance
qualification may indicate that the process is not in control. You must
investigate and take appropriate follow-up action on the source of this failure
(21 CFR 211.192 and 606.100(c)) and should repeat validation.
 	The manufacturer may provide re-qualification requirements for the device used
in the leukocyte reduction process.
IV. 	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. 30). When this is demonstrated, the process is considered to be in a state of
control. The determination of whether a process is operating in a state of control is made by
analyzing the day-to-day process, performance variability and the data for conformance with the

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manufacturer’s specifications. Please refer to FDA’s “Guideline for Quality Assurance in Blood
Establishments” (Ref. 30) for assistance in developing a QA and monitoring program. This
program is distinct from the initial validation described in section III.
You must have a QC unit that has the responsibility and authority to approve or reject all
components, containers, closures, in-process materials, packing materials, 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
unit’s 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, and 606.100(c)). In addition, your laboratory control
procedures must include adequate provisions for monitoring the reliability, accuracy, precision
and performance of laboratory test procedures and instruments (21 CFR 606.140(b)).
A. 	Component Testing
A QA program should include in-process monitoring of the manufacturing procedures
and QC testing (Ref. 16).
Under 21 CFR 211.160(b), laboratory controls must include the establishment of
scientifically sound and appropriate specifications, standards, sampling plans and test
procedures. We will consider statistical plans that confirm a < 5% non-conformance rate
with 95% confidence.
One example of a scientifically sound statistical sampling and analytic plan is based on a
two-stage binomial approach. The sampling sizes described in section III.F will confirm
with 95% confidence a < 5% non-conformance rate for residual WBC counts. Another
example of a scientifically sound plan is based on the hypergeometric distribution (see
Appendix). The hypergeometric plan is only for quality control sampling plans and
cannot be used for validation. Other statistical plans may also be appropriate, such as
the use of scan statistics (Ref. 32) or a lower confidence limit (e.g., for platelet yields we
will consider statistical plans that confirm a < 5% non-conformance rate with 75%
confidence).
As part of your QC procedures, we recommend that you:
 	define a plan which representatively identifies collections to be tested for each
component type (Whole Blood, Red Blood Cells, Platelets and Plasma) and
ensures testing for each leukocyte reduced method (i.e., each filter type in use or
each type of apheresis collection device) as detailed in Table 2;
 	test the component (Whole Blood, Red Blood Cells, Plasma, Platelets);
 	test for the residual WBC count within 48 hours after collection (Ref. 33), or per
the manufacturer’s directions for the cell counting methodology;
 	test for percent recovery of the original component for Whole Blood, Red Blood
Cells or Platelets or per manufacturer’s directions for use (e.g., minimum Red
Blood Cell volume);

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 	determine the volume of the collection/component on the day of QC testing, after
removal of all samples;
 	define procedures for investigating failures during QC, including the criteria that
will categorize a failure as either a process or non-process failure. Incomplete
filtration and post-filtration residual WBC counts in excess of the defined
standards are to be considered as two distinct types of process failure.
Table 2: For blood and blood components (other than Platelets, Pheresis 5 ), we
recommend the following QC results to be acceptable:
Blood Component 	Residual WBC
Content
Minimum Post-Filtration
Whole Blood, LR 	< 5.0 x 106* 85% recovery*** of original WB
content
Red Blood Cells, LR 	< 5.0 x 106* 85% recovery*** of original RBC
content
Plasma Products, LR 	< 5.0 x 10 6* N/A
Platelets, LR** 	< 8.3 x 10 5 per
individual (i.e.,
unpooled) unit
85% recovery*** of original platelet
yield; and a minimum of
> 5.5 x 10 10 platelets for 75% of units
*Per component.
** Multiple units of Platelets are often pooled after storage and prior to filtration, rather than filtered
individually prior to storage and pooling. In this instance, the pooled and then filtered product for
transfusion should contain < 5.0 x 10 6 residual WBCs. For example, for an adult transfusion recipient,
multiple units of Platelets (4-6 units) are pooled into a single platelet dose. The total (4-6 units) should
contain < 5.0 x 106 residual WBCs. The same recommendation for < 5.0 x 10 6 residual WBCs applies if
platelet units are pooled before storage, whether filtered before or after storage.
*** Or per the device manufacturer’s specifications, if different.
B. 	Equipment/Ancillary 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 ABCS, cell counting instrument(s),
scales, blood shaker and STCD.
Supplies and reagents must be used in a manner consistent with instructions provided by
the manufacturer (21 CFR 606.65(e)). In addition, all supplies (including filters) and
reagents must meet all of the requirements described in 21 CFR 606.65.
C. 	Operator Training
Operators must have adequate training, education, experience, or combination thereof, to
assure competent performance of their assigned functions (21 CFR 606.20(b)). Control
5 See footnote 1.

Contains Nonbinding Recommendations
13
over operational variables should be maintained through initial and continued staff
training, routine staff participation in leukocyte reduction and periodic assessment of
operator performance. We recommend that assessment of operators include scheduled
competency assessment and proficiency testing. In addition, we recommend that you
develop appropriate training on leukocyte reduction processes and procedures and/or
equipment maintenance as updated information becomes available.
D. 	Standard Operating Procedures
1. 	Requirements for Standard Operating Procedures (SOPs)
Equipment used for leukocyte reduction must “perform in the manner for which it
was designed” (21 CFR 606.60(a)). Supplies and reagents must be used in a
manner consistent with the instructions provided by the manufacturer
(21 CFR 606.65(e)). 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 and processing of
leukocytes reduced Whole Blood and blood components.
2. 	Additional Requirements and Recommendations to be included in SOPs
 	Sample handling: Blood samples should be collected, processed, and
tested within 48 hours (Ref. 33) (or per the manufacturer’s
recommendations for the methodology) of leukocyte reduction. The SOP
should adequately describe sample storage temperature, time, mixing, etc.
 	Leukocyte reduction filters: Leukocyte reduction filters are typically
component-specific; a filter intended for one component type should not
be used with other component types (Ref. 34). Leukocyte reduction filters
intended for bedside filtration should not be used for pre-storage leukocyte
reduction.
 	Abnormal Red Blood Cell Retention: Filtration steps should include
instructions on how to identify excessive red blood cell retention in the red
cell container and tubing above the filter.
 	Re-filtration: Components that fail to leukocyte reduce appropriately
should not be re-filtered, unless re-filtration is specified as appropriate by
the device manufacturer in the instructions for use.
 	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. For example:

Contains Nonbinding Recommendations
14
o 	A blood component that requires a filtration time longer than the
time interval specified in the manufacturer’s instructions for use
may be released by the QA unit for transfusion as leukocytes
reduced only if testing of that unit confirms acceptable component
specifications and there is an investigation of the delayed filtration
time.
o 	Leukocyte reduction by filtration can fail for Whole Blood and
Red Blood Cells collected from donors with sickle cell trait (Refs.
3 through 7 and Refs. 35 through 38) or other donor specific
factors. Tests for donor-specific factors may reduce the number of
components lost to filter failures. To address the investigation of
filtration failures, the SOP may include testing the blood
component for donor specific factors. The blood unit associated
with a filtration failure should not be released for transfusion as
leukocytes reduced unless testing of that unit confirms acceptable
component specifications.
 	Manufacturer’s performance specifications: You should state the
acceptable tolerance specifications for each leukocytes reduced blood
component as described by the manufacturer. You should have a
procedure addressing the handling of components that do not meet the
manufacturer’s performance specifications (e.g., use in research or further
manufacture).
 	Labeling: The general requirements for the labeling process are described
in 21 CFR 606.120 and must be followed.
V. 	LABELING
A circular of information 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. The container label must
include the proper name of the product, in a prominent position, with any appropriate modifier(s)
and attributes (21 CFR 606.121(c)(1)). One way to comply with the applicable labeling
requirements is through of use of standard terminology. For example, Table 3 lists the proper
names of the major leukocytes reduced blood components, followed by the corresponding
International Society of Blood Transfusion (ISBT) Code 128 name (Ref. 39). The component
labeling should include the phrase “Leukocytes Reduced.” The phrases “Leukocytes Removed,”
“Leukocyte Poor,” “Leukocytes Depleted,” and other similar terms should not be used in
component labeling.
Only those components meeting the recommended residual WBC content for leukocytes reduced
blood components or prepared by a validated method known to meet the recommended residual

Contains Nonbinding Recommendations
15
leukocyte content for leukocytes reduced blood components may be labeled as “Leukocytes
Reduced.”
Those components (except Whole Blood derived Platelets) that have been tested and found to
have a residual WBC count of < 1.0 x 10 6 may be labeled either with the actual residual
leukocyte content via a supplemental label or a tie-tag stating: “The residual white blood cell
count of this component has been determined to be < 1.0 x 106
.”
Table 3: Component Names for Container Labels
Proper Name 	ISBT 128 Name
Whole Blood Leukocytes Reduced 	WHOLE BLOOD LEUKOCYTES REDUCED
RED BLOOD CELLS LEUKOCYTES
REDUCED
Red Blood Cells Leukocytes Reduced APHERESIS RED BLOOD CELLS
LEUKOCYTES REDUCED
Platelets Leukocytes Reduced 	PLATELETS LEUKOCYTES REDUCED
VI. 	REPORTING CHANGES TO AN APPROVED BIOLOGICS LICENSE
APPLICATION (BLA)
An establishment that distributes leukocytes reduced blood components in interstate commerce
must have an approved BLA, including an approval for leukocytes reduced blood components, in
accordance with section 351 of the Public Health Service Act.
Licensed establishments must report changes to their approved application(s) in accordance with
21 CFR 601.12. For assistance in reporting your changes see FDA’s “Guidance for Industry:
Changes to an Approved Application: Biological Products: Human Blood and Blood
Components Intended for Transfusion or for Further Manufacture” dated July 2001.6 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 leukocytes
reduced blood components. You should prominently label each submission with the reporting
category under which you are reporting your change, e.g., “Prior Approval Supplement” or
“Supplement - Changes Being Effected in 30 Days,” 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).
6http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/Blood/ucm07
6729.htm.

Contains Nonbinding Recommendations
16
Under this regulation, 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 are a licensed blood establishment and you intend to change your Whole
Blood manufacturing procedures to include leukocyte reduction.
 	If you are currently approved to manufacture leukocytes reduced blood
components at a specific facility, and you intend to manufacture leukocytes
reduced blood components at a different facility, not under an approved
Comparability Protocol.
 	If you are approved to manufacture leukocytes reduced blood components, but
intend to change your manufacturing process in a manner that presents 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 and you are not making this change under an approved
Comparability Protocol.
 	If you intend to manufacture leukocytes reduced blood components using an
ABCS device new to your establishment and you are not making this change
under an approved Comparability Protocol.
 	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 implement this
change at multiple collection facilities under your direction and control, using the same
process to manufacture automated leukocytes reduced components prepared by apheresis.
We consider the recommendations in this guidance document to provide appropriate
criteria for a biologics license supplement for leukocytes reduced blood or blood
components. You may use an alternate 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 leukocytes reduced blood or
blood components are equivalent to components manufactured according to the
procedures described in this guidance.
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
supplement (21 CFR 601.12(b)(3)).

Contains Nonbinding Recommendations
17
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.
t
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.
 	Implementation of a new collection facility for leukocytes reduced Platelets,
Pheresis under an approved Comparability Protocol.
 	Certain software and hardware upgrades to the leukocyte reduction process for
apheresis collection.
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. 	Changes to be Described in an Annual Report (Minor Changes) (21 CFR
601.12(d))
Under 21 CFR 601.12(d), changes in the product, production process, quality controls,
equipment, facilities, or responsible personnel that have a minimal potential to have an
adverse effect on the identity, strength, quality, purity, or potency of the product as they
may relate to the safety or effectiveness of the product must be documented in an annual
report submitted each year within 60 days of the anniversary date of approval of the
application.
Changes from one type of FDA approved or cleared leukocyte reduction filter to another
ype of FDA approved or cleared leukocyte reduction filter is an example of a
manufacturing change that we believe falls within this category, if implemented
according to the instructions in the package insert without modification.
D. 	Submission of Documents
1. 	PAS: To comply with the requirements in 21 CFR 601.12(b)(3), the following
must be contained in the supplement.
 	Identification of the components involved (i.e., those to be leukocytes
reduced) and manufacturing facility(s) or area(s) affected, and a detailed
description of the manufacturing change (including device collection
technology for leukocyte reduction) (21 CFR 601.12(b)(3)(i) through

Contains Nonbinding Recommendations
18
(iii)). We recommend that this information be documented in a cover
letter and Form FDA 356h.
 	Product labeling for each component, if changed (21 CFR 601.12(f)). We
recommend submitting a Circular of Information (unless already on file at
FDA). To permit assessment of the manufacturing change we
recommend including copies of the following SOPs:
o 	labeling including acceptable and unacceptable units;
o 	a description of training (or an example of training document)
o 	component manufacturing;
o 	failure investigation;
o 	quality control including sampling scheme, sample handlings,
tracking and trending; and
o 	quarantine and disposition of unsuitable products.
 	A reference list of relevant SOPs (21 CFR 601.12(b)(3)(vii)). We
recommend submitting procedures unless they have been previously
approved by the FDA.
 	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;
o 	date of collection;
o 	date of testing;
o 	result interpretation(s);
o 	the identity of the person performing the testing;
o 	the identity of the collection facility;
o 	the identity of the testing facility;
o 	evidence of QA oversight; and
o 	expected component specifications for the residual WBC count.
Additionally, we recommend two months of QC data for component volume and
residual WBC count per component.
2. 	Comparability Protocol (21 CFR 601.12(e)). 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 VI.D.4 below), you must submit that protocol as a PAS
(21 CFR 601.12(e)). In addition to the information listed in section VI.D.1
above, we recommend that you include the following:

Contains Nonbinding Recommendations
19
 	Implementation plan; and
 	Proposed reporting category for changes made under the proposed
Comparability Protocol.
3. 	CBE-30 submissions (excluding new facilities under an approved
Comparability Protocol). Under 21 CFR 601.12(c)(3) and
21 CFR 601.12(b)(3)(i) through (vii), the following information must be
contained in your CBE-30 submission:
 	Identification of the components involved (i.e., those to be leukocytes
reduced) and manufacturing site(s) or area(s) affected, and a detailed
description of the proposed manufacturing change (including device
collection technology for leukocyte reduction). We recommend that you
document this information in a cover letter and Form FDA 356h. To
permit assessment of the documented manufacturing change, we
recommend that you include copies of any new or revised SOPs.
 	Product labeling for each component (21 CFR 601.12(f)).
 	Relevant validation protocols and data. We recommend that you submit a
copy of the validation summary, including the investigation of any
failures.
 	The data derived from studies. We recommend two months of QC data
for component volume, residual WBC count per component and percent
recovery or minimum Red Blood Cell volume if applicable.
 	A description of the methods used and studies performed to evaluate the
effect of the change and the data derived from such studies. We
recommend that you submit the following information:
o 	evidence of quality control oversight, including review and approval
of manufacturing records by a quality assurance unit; and
o 	expected component specifications including residual WBC count and
percent component recovery, if applicable.
4. 	CBE-30 submissions for new facilities under an approved Comparability
Protocol. To comply with 21 CFR 601.12(c)(3) and 21 CFR 601.12(b)(3)(i)
through (vii), the following information must be included:
 	Identification of the components involved (i.e., those blood component(s)
to be leukocytes reduced) and new manufacturing site(s) or area(s)
affected, and a description of the implementation plan (manufacturing
change including device collection technology for leukocyte reduction).
Additionally, we recommend that this information be documented in a
cover letter and FDA Form 356h.

Contains Nonbinding Recommendations
20
 	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.
In addition, you should include the submission tracking number (STN) of the
approved Comparability Protocol, and the STN(s) of changes to the SOPs
associated with an approved Comparability Protocol.
5. 	Annual Report. To comply with 21 CFR 601.12(d)(3), the following
information must be included:
 	a list of all products involved; and
 	a full description of the manufacturing and controls changes including the
manufacturing site(s) or area(a) involved.
VII. 	CONTACT INFORMATION
Questions about licensing and specific review questions about leukocyte reduction should be
directed to the Office of Blood Research and Review, Division of Blood Applications (DBA).
Submit all registration forms (Form FDA 2830) and licensure applications/supplements to the
Director, Center for Biologics Evaluation and Research (CBER). Table 4 presents FDA contact
information regarding leukocyte reduction.
Table 4: FDA Contact Information
Submissions:
Registrations
License Applications
Director, Center for Biologics Evaluation and Research, HFM-370,
Food and Drug Administration,
c/o Document Control Center, HFM-99,
1401 Rockville Pike, Suite 200N,
Rockville, MD 20852-1448.
Review Questions:
Licensing
Red Blood Cells
Whole Blood
Platelets
Platelets, Pheresis
Plasma
Director, Division of Blood Applications, HFM-370,
Food and Drug Administration,
c/o Document Control Center, HFM-99,
1401 Rockville Pike, Suite 200N,
Rockville, MD 20852-1448,
Voice 301-827-3543; Fax 301-827-3534.

Contains Nonbinding Recommendations
21
VIII. 	REFERENCES
1. 	Alvarado-Ramy, F., Kuehnert, M., Alonso-Echanove, J., Sledge, L., Haley, R., Epstein, J.,
Vostal, J., and Pearson, M. A multistate cluster of red blood cell transfusion reactions
associated with use of a leukocyte reduction filter. Transfusion Medicine 2006; 16:41-48.
2. 	Alonso-Echanove, J., Sippy, B.D., Chin, A.E., Cairns, L., Haley, R., Epstein, J.S., Richards,
M.J., Edelhauser, H., Hedberg, K., Kuehnert, M.J., Jarvis, W.R., Pearson, M.L., and the
Transfusion-Associated Red Eye Syndrome Study Group. Nationwide Outbreak of Red Eye
Syndrome Associated with Transfusion of Leukocyte-Reduced Red Blood Cell Units.
Infection Control and Hospital Epidemiology 2006; 27(11):1146-1152.
3. 	Lankford, K.V., Fields, A.C., Langley, P.C. et al. Ineffective prestorage leukoreduction
(PSLR) of whole blood (WB) from African American donors with sickle cell trait (HB AS)
versus controls. Transfusion 1999; 39 (Suppl) 108S.
4. 	Williamson, L.M., Beard, M., Seghatchian, J., et al. Leukocyte depletion of whole blood and
red cells from donors with hemoglobin sickle trait. Transfusion 1999; 39 (Suppl) 108S.
5. 	Gorlin, J,B,, Adams, C.L., Stefan, M.M., et al. Variable leukoreduction on units from donors
with sickle cell trait: A time-temperature donor reproducibility study. Transfusion 2000; 40
(Suppl) 55S.
6. 	Prihoda, L., Harbin, K., Thomas, A. Leukocyte-Reduction filter “failures”: Is hemoglobin S
the answer? Transfusion 2000; 40 (Suppl) 55S.
7. 	Harbin, K., Prihoda, L., Thomas, A. Residual WBCs in leukocyte-reduction filtered
hemoglobin S positive RBCs. Transfusion 2000; 40 (Suppl) 55S.
8. 	Dzik, W.H. Leukoreduced blood components: Laboratory and clinical aspects. In Rossi’s
Principles of Transfusion Medicine. Simon. T.L., Dzik, W.H., Snyder, E.L., Stowell, C.P.,
Strauss, R. (eds). 3rd ed. Philadelphia: Lippincott Williams & Wilkins 2002; 270-287.
9. 	Williamson, L.M., Wimperis, J.Z., Williamson, P., et al. Bedside Filtration of Blood
Products in the Prevention of HLA Alloimmunization: A Prospective Randomized Study.
Blood 1994; 83:3028-3035.
10. The Trial to Reduce Alloimmunization to Platelets Study Group. Leukocyte reduction and
ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet
transfusions. New England Journal of Medicine 1997; 337:1861-1869.
11. Bowden, R.A., Slichter, S.J., Sayers, M., et al. A Comparison of Filtered Leukocyte-
Reduced and Cytomegalovirus (CMV) Seronegative Blood Products for the Prevention of
Transfusion-Associated CMV Infection After Marrow Transplant. Blood 1995; 86:3598-
3603.
12. Strauss, R.G. Leukocyte-reduction to prevent transfusion-transmitted cytomegalovirus
infections. Pediatric Transplantation 1999; 3 (Suppl 1); 19-22.
13. Wu, Y. , Zou, S., Cable, R., Dorsey, K., Tang, Y., Hapip, C. A., Melmed, R., Trouern-Trend,
J., Wang, J., Champion, M., Fang, C., and Dodd, R. Direct assessment of cytomegalovirus
transfusion-transmitted risks after universal leukoreduction. Transfusion 2009; 50: 776-786.
14. Cyr, M., Eastlund, T., Blais, C., et al. Bradykinin metabolism and hypotensive transfusion
reactions. Transfusion 2001; 41:136-150.
15. Blajchman, M.A. Transfusion-associated immunomodulation and universal white cell
reduction: are we putting the cart before the horse? Transfusion 1999; 39:665-670.
16. Miller, J.P., Mintz, P.D. The use of leukocyte-reduced blood components.
Hematology/Oncology Clinics of North America 1995; 9:69-90.

Contains Nonbinding Recommendations
22
17. Reidner, C., Heim, M., Mempel, W., et al. Possibility to Improve Preservation of Whole
Blood by Leukocyte-Depletion before Storage. Vox Sanguinis 1990; 59:78-82.
18. Cardo, L.J., Salata, J., Harman, R., Mendez, J., Weina, P.J. Leukodepletion filters reduce
Leishmania in blood products when used at collection or at the bedside. Transfusion 2006;
46:896-902.
19. Murphy, M.F. New Variant Creutzfeldt-Jakob Disease (nvCJD): The Risk of Transmission
by Blood Transfusion and the Potential Benefit of Leukocyte-Reduction of Blood
Components. Transfusion Medicine Reviews 1999; 13:75-83.
20. Llewelyn, C.A., Hewitt, PE, et al. Possible transmission of variant Creutzfeldt-Jakob disease
by blood transfusion. Lancet 2004; 363: 417-21.
21. Peden, A.H., Head, M.W., et al. Preclinical vCJD after blood transfusion in a PRNP codon
129 heterozygous patient. Lancet 2004; 364(9433): 527-9.
22. Health Protection Agency. New case of transfusion-associated variant-CJD. CDR Weekly
2006; 16(6).
23. Health Protection Agency. 4th case of variant CJD infection associated with blood
transfusion. Health Protection Report 2007; 1(3).
24. FDA Memorandum: Recommendations Regarding License Amendments and Procedures for
Gamma Irradiation of Blood Components, July 22, 1993.
25. Zoon, K.C., Jacobson, E.D., Woodcock, J. Hypotension and Bedside Leukocyte Reduction
Filters. International Journal of Trauma Nursing 1999; 5:121-122.
26. Canadian Coordinating Office for Health Technology Assessment (CCOHTA).
Leukoreduction: The Techniques Used, Their Effectiveness, and Costs. International
Journal of Technology Assessment in Health Care 1998; 4:586-588.
27. Dzik, S., AuBuchon, J., Jeffries, L., et al. Leukocyte Reduction of Blood Components:
Public Policy and New Technology. Transfusion Medicine Reviews 2000; 14:34-52.
28. FDA Guidance for Industry: Process Validation: General Principles and Practices, January
2011.
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidance
s/UCM070336.pdf
29. FDA Guidance for Industry: Use of Sterile Connecting Devices in Blood Bank Practices,
November 2000.
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G
uidances/Blood/ucm076779.htm.
30. FDA Guideline for Quality Assurance in Blood Establishments, July 11, 1995.
http://www.fda.gov/downloads/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInf
ormation/Guidances/Blood/UCM164981.pdf.
31. FDA Guidance for Industry and FDA Review Staff: Collection of Platelets by Automated
Methods, December, 2007.
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G
uidances/Blood/ucm073382.htm.
32. Lachenbruch, P., Foulkes, M., Williams, A., Epstein, J. Potential Use of the Scan Statistic
For Quality Control in Blood Product Manufacturing. Journal of Biopharmaceutical
Statistics, 15: 353-366, 2005.
33. Dzik, S., Moroff, G., Dumont, L. A multicenter study evaluating three methods for counting
residual WBCs in WBC-reduced blood components: Nageotte hemocytometry, flow
cytometry, and microfluorometry. Transfusion 2000; 40:513-520.

Contains Nonbinding Recommendations
23
34. Circular of Information for the Use of Human Blood and Blood Components. AABB,
America’s Blood Centers, American Red Cross, Armed Services Blood Program, December
2009.
35. Bodensteiner, D. White cell reduction in blood from donors with sickle cell trait.
Transfusion 1994; 34:84. 139S.
36. Tinmouth, A.T., Naiman, R., Garel, B., et al. Sickle cell trait associated with filter
obstruction during pre-storage leukodepletion of red blood cell products. Transfusion 2000;
40 (Suppl) 59S.
37. Salamon, N., Allen, S., Anderson, J.K. Impact of sickle cell trait blood donations for a
community blood center after universal leukoreduction. Transfusion 2000; 40 (Suppl) 139S.
38. Ledent, E., Berlin, G. Factors influencing white cell removal from red cell concentrates by
filtration. Transfusion 1996; 36:714-718.
39. FDA Guidance for Industry: Recognition and Use of a Standard for Uniform Blood and
Blood Component Container Labels, September 2006.
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G
uidances/Blood/ucm073362.htm.
40. FDA Guidance for Industry: Recommendations for Collecting Red Blood Cells by
Automated Apheresis Methods - Technical Correction February 2001.
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/G
uidances/Blood/ucm076756.htm.
41. Romeu, J.L. Understanding Binomial Sequential Testing. RAC START, Volume 12,
Number 2. http://src.alionscience.com/pdf/BINSEQ.pdf.

Contains Nonbinding Recommendations
24
APPENDIX
QC testing and sample size calculations based on the hypergeometric distribution
Section III.F of this document describes a two-stage sampling approach to process validation
based on the binomial distribution. As discussed in Section IV.A, we consider this approach to
be a scientifically sound statistical sampling and analytic plan for QC testing as well as for
process validation. One limitation of the binomial distribution-based approach, however, is that
it assumes that the population of components being sampled from is infinite. This assumption
may not be ideal for sampling performed for monthly QC testing.
A two-stage sampling approach based on the hypergeometric distribution may be used for
monthly QC. Unlike the binomial approach, the hypergeometric approach assumes that a finite
number of components will be manufactured during a monthly QC period. In general, the
sample size for QC testing under the hypergeometric approach will be smaller than that for
binomial distribution-based sampling. However, you may prefer to use binomial distribution-
based sampling for other reasons, including familiarity and simplicity. The decrease in sample
size for the hypergeometric approach relative to the binomial approach is most noticeable when
the total number of collections to be performed during a given QC period is small.
The two-stage hypergeometric approach is similar in concept to the two-stage binomial
approach described in Section III.F. In the first stage, an initial representative sample of
components with a predetermined sample size should be tested consecutively. Identified non-
process failures may be excluded from the sample size and replaced. Conformance can be
demonstrated if an acceptable number of process failures are observed in this sample. In the
event that there is one more process failure than permitted in the initial sample, a second sample
of components may be tested consecutively. Conformance can be demonstrated if no further
process failures are observed in the second sample. The size of the second sample will depend
on the size of the first sample, and may encompass the entire remaining population of
components to be tested during a given QC period.
Table A details possible sampling plans and sample sizes for two-stage QC testing based on the
hypergeometric distribution for components other than platelets. Table B provides sampling
plans and sample sizes for platelet yield QC testing. Each of the sampling plans contained in
the tables satisfies the statistical criteria for successful QC testing provided in Section IV.A.
The tables may be used as follows:
1. 	Determine the number of components that will be manufactured during a given QC
period (i.e., one month of a given process at a given site). This corresponds to the
population size contained in the first column of the table. Choose the appropriate row of
the table corresponding to the population size for the given QC period. In general, this
will not be known precisely in advance and will need to be estimated. It is important
that the estimated population size be at least as large as the true population size. That is,
you should choose the maximum possible number of components for a given QC period
rather than, e.g., an average number of components.

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2. 	Once you have identified the appropriate row corresponding to the population size for a
given QC period, you can choose from up to three possible two-stage sampling plans,
distinguished by the number of failures allowed in the first stage: zero failures, one
failure or two failures.
3. 	The two columns headed by the sampling plan chosen in Step 2 above contain the
required sample sizes for the first and second stages of the sampling, respectively. In
some cases the sample size for the second stage is denoted “All.” This indicates that
every component in the given QC period must be tested in the event of one excess
process failure in the first sampling stage. In other cases, the sample size for the second
stage is denoted with a dash. This indicates that a two-stage approach is not possible for
the given population size and first stage sample, and that one excess process failure in
the first stage means overall failure of the QC testing for that QC period.
As an example of this approach, suppose that you intend to collect 100 leukocyte-reduced
plasma components on a given instrument at a given site during the next month. Note first that
you may test every one of these 100 units and, if 4 or fewer process failures are observed, the
process failure rate is less than 5% for that QC period. Adopting instead a statistical sampling
strategy, you may consult Table A and choose one of the three sampling plans provided in the
row corresponding to population size of 100. Suppose you choose the “zero failures allowed”
sampling plan in this row, which specifies a first stage sample size of 45 components and a
second stage sample size of 34 components. You would therefore test the first 45 consecutive
components for that month. If no process failures were observed among these 45 components,
the process would be considered to be in control and no further QC testing would be required
during that month. If one process failure is observed among the first 45 components, you would
test an additional 34 consecutive components. If no further process failures were observed
among the second stage sample of 34 components, the process would be considered to be in
control and no further testing would be required. If two or more process failures were observed
during the first stage sample of 45 components or if one or more process failures were observed
during the second stage sample of 34, the process would not be in control and QC testing would
have failed.
Statistical derivation of the sample sizes in Tables A and B
In Table A, for each fixed population size, N, and number of allowed failures, m, the first stage
sample size was calculated as the minimum number n1 such the probability of observing m or
fewer process failures in a sample of size n1 from a population of size N is at most 5% when the
true process failure rate is 5% or more. For example, assume that 100 components will be
collected during a QC period. Using the “zero failures allowed” first stage sampling plan, it can
be calculated based on the hypergeometric probability distribution that the probability of
observing zero failures in a sample of 45 components is 0.0462 if the true failure rate is at least
5% (that is, if there are at least 5 process failures among the 100 components to be collected).
On the other hand, the probability of observing zero failures in a sample of 44 components is
0.0507. Therefore, 45 is the minimum sample size such that the probability of observing zero
failures is less than 5% when the true failure rate of at least 5%.

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Once the first stage sample size has been determined, to obtain the second stage sample size, we
first calculated 0.05 minus the probability of observing m or fewer process failures in the first
stage when the true failure rate is at least 5%. Continuing our example above, this quantity
would be 0.05 – 0.0462 = 0.0038. The second stage sample size was then calculated as the
minimum number n2 such that the probability of observing (i) one failure among the first n1
samples at stage one and (ii) no failures among the n2 samples at stage two is less than 0.05
minus the probability of observing m or fewer process failures in the first stage when the true
failure rate is at least 5%. 	In the example here, with n2 = 33, this probability is 0.0044, which is
not less than 0.0038, whereas with n2 = 34, this probability is 0.0036 which is less than 0.0038.
Therefore, the required sample size at stage two for this example is 34. Romeu (Ref. 41) adopts
the same algorithm for an infinite population size based on the binomial distribution.
The derivation of the sample sizes in Table B followed the same process, but was based on
ruling out a true failure rate of at least 25% rather than 5% as in Table A. Note that
hypergeometric sampling schemes other than those presented in Tables A and B are possible.
For instance, in some cases it is possible to use a larger first stage sample size and smaller
second stage than that provided in the tables. We will consider any sampling plan that meets the
criteria described in Section IV.A.

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Table A. Sampling scheme for quality control testing based on hypergeometric distribution
(95%/95%).
Use for all QA and monitoring assessments under Section IV, except in accessing platelet yield.
See Table B for assessment of platelet yield.
95%/95%1
95% confidence that more than 95% of the components meet the standard
Sample size
Population
size2
# of failures
allowed in
population
0
failures
allowed 	Add 3
1
failure
allowed 	Add 3
2
failures
allowed 	Add 3
30 	1 	23 	All4 	30 	- 	- 	-
31 	1 	24 	All 	31 	- 	- 	-
32 	1 	25 	All 	32 	- 	- 	-
33 	1 	26 	All 	33 	- 	- 	-
34 	1 	26 	All 	34 	- 	- 	-
35 	1 	27 	All 	35 	- 	- 	-
36 	1 	28 	All 	36 	- 	- 	-
37 	1 	29 	All 	37 	- 	- 	-
38 	1 	30 	All 	38 	- 	- 	-
39 	1 	30 	All 	39 	- 	- 	-
40 	1 	31 	All 	39 	- 	- 	-
45 	2 	28 	15 5 	39 	All6 	45 	-
50 	2 	31 	18 	43 	All 	50 	-
55 	2 	35 	17 	48 	All 	55 	-
60 	2 	38 	19 	52 	All 	60 	-
65 	3 	34 	23 	49 	13 	59 	All7
70 	3 	37 	23 	52 	17 	63 	All
75 	3 	39 	29 	56 	17 	68 	All
80 	3 	42 	28 	60 	17 	72 	All
85 	4 	38 	30 	56 	19 	69 	13
90 	4 	40 	34 	59 	22 	73 	14
95 	4 	42 	41 	62 	25 	77 	15
100 	4 	45 	34 	65 	30 	81 	16
120 	5 	47 	40 	69 	37 	87 	25
140 	6 	48 	51 	72 	44 	92 	28
160 	7 	49 	62 	75 	39 	95 	42
180 	8 	50 	64 	77 	41 	98 	44
200 	9 	51 	61 	78 	51 	101 	39
220 	10 	52 	57 	79 	62 	103 	42
240 	11 	52 	73 	80 	71 	104 	55
260 	12 	53 	61 	81 	69 	106 	47
280 	13 	53 	72 	82 	63 	107 	52
300 	14 	54 	60 	83 	58 	108 	56
320 	15 	54 	67 	83 	94 	109 	57
340 	16 	54 	75 	84 	65 	110 	55
360 	17 	54 	91 	85 	57 	111 	53

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28
95%/95%1
95% confidence that more than 95% of the components meet the standard
Sample size
Population
size2
# of failures
allowed in
population
0
failures
allowed 	Add 3
1
failure
allowed 	Add
3
2
failures
allowed 	Add 3
380 	18 	55 	65 	85 	66 	111 	70
400 	19 	55 	70 	85 	85 	112 	60
450 	22 	54 	78 	84 	111 	111 	62
500 	24 	56 	69 	87 	70 	114 	76
550 	27 	55 	76 	86 	72 	113 	75
600 	29 	56 	85 	88 	74 	116 	67
650 	32 	56 	69 	87 	78 	115 	66
700 	34 	57 	71 	89 	70 	117 	73
750 	37 	56 	80 	88 	74 	116 	73
800 	39 	57 	78 	89 	95 	118 	71
850 	42 	56 	96 	89 	67 	117 	72
900 	44 	57 	86 	90 	73 	119 	66
950 	47 	57 	73 	89 	81 	118 	67
1000 	49 	57 	95 	90 	86 	119 	82
1500 	74 	58 	81 	91 	95 	121 	75
2000 	99 	58 	92 	92 	78 	122 	72
2500 	124 	58 	101 	92 	91 	122 	91
3000 	149 	58 	111 	92 	109 	123 	71
3500 	174 	58 	124 	93 	74 	123 	77
4000 	199 	58 	149 	93 	77 	123 	83
4500 	224 	59 	79 	93 	79 	123 	89
5000 	249 	59 	80 	93 	81 	123 	95
6000 	299 	59 	81 	93 	85 	123 	113
7000 	349 	59 	82 	93 	88 	124 	72
8000 	399 	59 	83 	93 	91 	124 	74
9000 	449 	59 	84 	93 	93 	124 	76
10000 	499 	59 	85 	93 	95 	124 	77
11000 	549 	59 	85 	93 	97 	124 	79
12000 	599 	59 	85 	93 	99 	124 	80
13000 	649 	59 	86 	93 	100 	124 	81
14000 	699 	59 	86 	93 	102 	124 	82
15000 	749 	59 	86 	93 	103 	124 	83
20000 	999 	59 	87 	93 	108 	124 	86
25000 	1249 	59 	88 	93 	112 	124 	88
30000 	1499 	59 	88 	93 	116 	124 	90
35000 	1749 	59 	89 	93 	119 	124 	91
40000 	1999 	59 	89 	93 	121 	124 	92
45000 	2249 	59 	89 	93 	123 	124 	93
50000 	2499 	59 	89 	93 	125 	124 	93
55000 	2749 	59 	89 	93 	126 	124 	94

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95%/95%1
Population
2
	size
95% confidence that more than 95% of the components meet the standard
# of failures
allowed in
population
Sample size
0
failures
allowed 	Add 3
1
failure
allowed 	Add
3
2
failures
allowed 	Add 3
60000 	2999 	59 	89 	93 	128 	124 	94
2.00E+07 8 	999999 	59 	90 	93 	163 	124 	100
1The inference that with 95% confidence more than 95% of the components meet the standard is only
applicable to the finite population from which the samples are drawn.
2The population size is the total number of products manufactured in a given quality control (QC) period (e.g.,
one month for a monthly QC) at a given site using a given instrument, etc.
3Additional testing if allowable process failures are exceeded (see footnotes 4 through 7)
4For a population size of 30, if you select a sample size of 23 and find one failure, test all the remaining
components and no additional failures are allowed.
5For a population size of 45, if you select a sample size of 28 and find one failure, test 15 additional samples
and no additional failures are allowed.
6For a population size of 45, if you select a sample size of 39 and find two failures, test the remaining
components and no additional failures are allowed.
7For a population size of 65, if you select a sample size of 59 and find three failures, test the remaining
components and no additional failures are allowed.
8With a very large population size, the sample size based on hypergeometric distribution converges to the
sample size based on the binomial distribution although the convergence is very slow in some cases.

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Table B. Sampling scheme for quality control testing based on hypergeometric distribution
(95%/75%).
Under 21 CFR 640.24(c), the platelet product must yield an acceptable count in at least 75
percent of the units tested. Table B applies only to platelet yield and does not pertain to the other
aspects of QC testing of platelet products (e.g., assessing white count, pH) where the appropriate
measure is 95%/95%.
95%/75%1
95% confidence that more than 75% of the components meet the standard
Sample size
Population
size2
# of
failures
allowed in
population
0
failures
allowed 	Add 3
1
failure
allowed 	Add 3
2
failures
allowed 	Add 3
30 	7 	9 	6 	13 	8 	17 	6
31 	7 	9 	7 	14 	5 	18 	5
32 	7 	9 	9 	14 	8 	18 	9
33 	8 	9 	6 	13 	8 	17 	7
34 	8 	9 	7 	14 	5 	18 	5
35 	8 	9 	8 	14 	7 	18 	8
36 	8 	9 	14 	15 	5 	19 	6
37 	9 	9 	7 	14 	5 	18 	5
38 	9 	9 	8 	14 	7 	18 	8
39 	9 	9 	10 	15 	5 	19 	5
40 	9 	10 	7 	15 	6 	19 	9
45 	11 	9 	9 	14 	8 	19 	5
50 	12 	9 	15 	15 	6 	19 	10
55 	13 	10 	8 	15 	10 	20 	7
60 	14 	10 	9 	16 	7 	21 	6
65 	16 	10 	7 	15 	9 	20 	7
70 	17 	10 	8 	16 	6 	20 	14
75 	18 	10 	10 	16 	8 	21 	7
80 	19 	10 	11 	16 	9 	21 	10
85 	21 	10 	9 	16 	7 	21 	7
90 	22 	10 	10 	16 	8 	21 	8
95 	23 	10 	11 	16 	10 	21 	13
100 	24 	10 	14 	16 	14 	22 	7
120 	29 	10 	17 	17 	7 	22 	9
140 	34 	11 	8 	17 	8 	22 	10
160 	39 	11 	8 	17 	9 	22 	13
180 	44 	11 	9 	17 	9 	22 	17
200 	49 	11 	9 	17 	9 	23 	7
220 	54 	11 	9 	17 	10 	23 	8
240 	59 	11 	9 	17 	10 	23 	8
260 	64 	11 	9 	17 	10 	23 	8
280 	69 	11 	9 	17 	11 	23 	8
300 	74 	11 	9 	17 	11 	23 	9
320 	79 	11 	10 	17 	11 	23 	9

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Population
2
	size
95%/75%1
95% confidence that more than 75% of the components meet the standard
# of
failures
allowed in
population
Sample size
0
failures
allowed 	Add 3
1
failure
allowed 	Add 3
2
failures
allowed 	Add 3
340 	84 	11 	10 	17 	12 	23 	9
360 	89 	11 	10 	17 	12 	23 	9
380 	94 	11 	10 	17 	12 	23 	9
400 	99 	11 	10 	17 	12 	23 	10
450 	112 	11 	10 	17 	12 	23 	9
500 	124 	11 	10 	17 	13 	23 	10
550 	137 	11 	10 	17 	12 	23 	10
600 	149 	11 	10 	17 	14 	23 	11
650 	162 	11 	10 	17 	13 	23 	10
700 	174 	11 	10 	17 	14 	23 	11
750 	187 	11 	10 	17 	14 	23 	11
800 	199 	11 	10 	17 	15 	23 	12
850 	212 	11 	10 	17 	14 	23 	11
900 	224 	11 	10 	17 	15 	23 	12
950 	237 	11 	10 	17 	15 	23 	12
1000 	249 	11 	10 	17 	16 	23 	12
1500 	374 	11 	11 	17 	17 	23 	13
2000 	499 	11 	11 	17 	19 	23 	14
2500 	624 	11 	11 	17 	20 	23 	14
3000 	749 	11 	11 	17 	21 	23 	15
3500 	874 	11 	11 	17 	21 	23 	15
4000 	999 	11 	11 	17 	22 	23 	15
4500 	1124 	11 	11 	17 	23 	23 	15
5000 	1249 	11 	11 	17 	23 	23 	15
6000 	1499 	11 	11 	17 	24 	23 	16
7000 	1749 	11 	11 	17 	26 	23 	16
8000 	1999 	11 	11 	17 	27 	23 	16
9000 	2249 	11 	11 	17 	28 	23 	16
10000 	2499 	11 	11 	17 	30 	23 	16
11000 	2749 	11 	11 	17 	33 	23 	16
12000 	2999 	11 	11 	17 	43 	23 	16
13000 	3249 	11 	11 	18 	8 	23 	16
14000 	3499 	11 	11 	18 	8 	23 	16
15000 	3749 	11 	11 	18 	8 	23 	16
20000 	4999 	11 	11 	18 	8 	23 	16
25000 	6249 	11 	11 	18 	8 	23 	17
30000 	7499 	11 	11 	18 	8 	23 	17
35000 	8749 	11 	11 	18 	8 	23 	17
40000 	9999 	11 	11 	18 	8 	23 	17
45000 	11249 	11 	11 	18 	8 	23 	17

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95%/75%1
95% confidence that more than 75% of the components meet the standard
Sample size
Population
size2
# of
failures
allowed in
population
0
failures
allowed 	Add 3
1
failure
allowed 	Add 3
2
failures
allowed 	Add 3
50000 	12499 	11 	11 	18 	8 	23 	17
55000 	13749 	11 	11 	18 	8 	23 	17
60000 	14999 	11 	11 	18 	8 	23 	17
2.00E+07 8 	4999999 	11 	11 	18 	8 	23 	17
1The inference that with 95% confidence more than 75% of the components meet the standard is only applicable
to the finite population from which the samples are drawn.
2The population size is the total number of products manufactured in a given quality control (QC) period (e.g.,
one month for a monthly QC) at a given site using a given instrument, etc.
3Additional testing if allowable process failures are exceeded (see footnotes 4 through 7)
4For a population size of 30, if you select a sample size of 23 and find one failure, test all the remaining
components and no additional failures are allowed.
5For a population size of 45, if you select a sample size of 28 and find one failure, test 15 additional samples
and no additional failures are allowed.
6For a population size of 45, if you select a sample size of 39 and find two failures, test the remaining
components and no additional failures are allowed.
7For a population size of 65, if you select a sample size of 59 and find three failures, test the remaining
components and no additional failures are allowed.
8With a very large population size, the sample size based on hypergeometric distribution converges to the
sample size based on the binomial distribution although the convergence is very slow in some cases.