# **Blood Products Advisory Committee**

**December 13-14, 2001**

**Gaithersburg, MD**

# 

# **Summary for Topic II, Discussion on Leukocyte Reduction Guidance**

# 

# **Issue:** FDA seeks the advice of the Committee on options for quality control of leukocyte reduction to be recommended in reissued draft guidance 

**Background:**

In September 1998, the FDA's Blood Product Advisory Committee advised
FDA that the benefit-to-risk ratio associated with leukocyte reduction
is sufficient to justify universal leukocyte reduction of blood
components for transfusion. In April 2001, the Public Health Service
Advisory Committee on Blood Safety and Availability recommended that FDA
move forward with rulemaking to require leukocyte reduction for
non-leukocyte blood components. Leukocyte reduction by pre-storage
filtration has been steadily increasing in the industry. Currently,
approximately 90% of components provided by the American Red Cross and
60% of components provided by independent blood establishments are
leukocyte reduced. Pending any rulemaking, and in recognition of the
increasing use of leukocyte reduced products, FDA seeks to update the
product standards applicable to such products.

In January 2001, FDA published draft guidance entitled "Pre-storage
Leukocyte Reduction of Whole Blood and Blood Components Intended for
Transfusion." This document proposed updated standards for leukocyte
reduction and included a statistically based quality control strategy.
FDA is bringing the issue of quality control of leukocyte reduction to
BPAC for discussion. The QC alternatives offered to the Committee for
consideration include counting each donation for residual leukocytes
(i.e. 100% validation), and a modification of the QC strategy outlined
in the current leukoreduction draft guidance document.

The FDA has received numerous comments on the draft leukoreduction
guidance. These comments included the following:

-   the medical relevance of the proposed 1 x 10 ^6^ residual white
    cells for a leukocyte reduced unit

-   the recommendation to screen all donors for sickle trait

-   the recommendation to count residual white cells in all units not
    tested for CMV antibodies that are released for CMV high risk
    patients

-   the recommended validation and statistical quality control testing
    procedure

In June 2001 the FDA brought the issue of filtration failures, including
problems related to sickle trait, to the BPAC for discussion. Based on
the BPAC recommendation and comments received, it is FDA's intention to
eliminate from the final guidance the proposed recommendation to screen
all donors for sickle trait. In consideration of the loss of 1% or more
collected units due to filter clogging, FDA also intends to recommend
that blood collectors should use validated shaker platforms or other
validated systems to minimize clot formation during whole blood
collection.

The FDA received numerous comments on the proposed standard for
leukocyte reduced units of 1 X 10 ^6^ residual white cells. Data
presented to the BPAC in June indicate that there is a wide variation in
filtration failures at this standard. In a survey conducted by Americas
Blood Centers, 7 centers had failure rates of 1-3%, 8 of 18 centers
reported failures of greater than 5%, and 3 had failure rates of less
than 1% at 1 x 10 ^6^. Only one center of eighteen reported a failure
rate greater than 1% when the 5 x 10 ^6^ standard was used. Yomtovian et
al. (Transfusion: 2001; 41:1030-1036) recently reported that 8.3% of
units failed to meet the 1 x 10 ^6^ proposed standard, but only 0.8%
failed to meet the 5 x 10 ^6^ standard. Based on comments received and
published reports, the FDA is prepared to revise its proposed standard
for leukocyte reduced units to 5 x 10 ^6^ residual leukocytes.

Unexpectedly high levels of residual leukocytes may compromise the
medical benefit of leukocyte reduced components. Such components are
increasingly being substituted for CMV antibody negative products for
use in low birth weight neonates and other immunocompromised patients.
Because of these concerns, the FDA is also reconsidering its proposed
quality control measures. In the draft guidance, the FDA proposed a
validation/quality control strategy that 95% of the units labeled as
leukocyte reduced meet product specifications with 95% confidence. To
accomplish this, FDA proposed that a facility should test 60 consecutive
products for each major process variation (e.g. filtration of Whole
Blood; filtration of Red Blood Cells; filtration of Platelets;
filtration of Platelets: apheresis) for each variation in filter and SOP
to validate the process. As QC, the blood center would then test a
minimum of 20 random products per month for each type of product or
process. This would then establish a three month cycle within which the
95%/95% standard (i.e. 60 counts with no failures) would be evaluated.
Because of the higher than expected filtration failure rate and reports
of individuals who fail filtration for reasons not associated with the
procedure, the FDA is considering alternatives.

**Discussion:**

Proposed modifications to the current draft guidance will be presented
(see attachments). In consideration of the questions that will be
proposed, the Committee will hear a discussion of the relationship
between WBC reduction levels and the medically desirable outcomes of
reduced febrile non-hemolytic (FNH) reactions, HLA alloimmunization, and
CMV transmission. Also included will be a presentation about currently
available methods to evaluate residual WBCs in leukoreduced products,
and an update of current knowledge about leukoreduction failures.
Finally, the proposed changes in the recommended validation/quality
control strategy will be presented and explained.

FDA will then propose the following options for consideration by the
committee:

[Option 1]{.underline}: FDA should recommend that all products labeled
as \"leukocytes reduced\" meet the defined standard as demonstrated by
counting [all]{.underline} such products being evaluated for residual
WBC.

[Advantages:]{.underline} Products labeled as \"leukocytes reduced\"
will be 100% validated for residual WBC content. When used in lieu of
CMV-seronegative products for patients who are susceptible to severe CMV
infection, 100% validation will help ensure that a product labeled as
\"leukocytes reduced\" does not have a WBC level that exceeds the
product standard. A recommendation for 100% WBC counting will also
stimulate the appearance of new technologies that will facilitate
cost-effective WBC enumeration.

[Disadvantages:]{.underline} A recommendation for 100% validation has
practical difficulties because of the current high cost and/or
unavailability of reagents to automate the WBC counting process. The
workload to manually count every product may be an overwhelming burden
for blood centers. Blood centers may choose to provide fewer
leukoreduced products.

## [Option 2]{.underline}: FDA should recommend that blood centers validate the leukoreduction process utilizing statistical quality control strategy (as proposed below) to ensure with a defined level of confidence that products labeled as \"leukocytes reduced\" meet a defined standard. 

## 

## Elements of the proposed Validation/QC strategy include the following: (See attached table for more detail)

> **1. Incomplete filtration and a post-filtration residual white blood
> cell (WBC) count in excess of the defined standard are to be
> considered as two distinct types of process failure.**
>
> **2. Incomplete filtration rates should not exceed 0.5% of filtered
> products (excluding incomplete filtration due to identified
> donor-specific factors).**
>
> **3. The recommended standard for residual WBC in filtered RBC and
> platelet products is ≤ 5 x 10^6.^**
>
> **4. For purposes of validation, 95% of products should contain ≤ 5 x
> 10^6^ residual WBC with 95% confidence (zero failures per SOP @ n= 60
> consecutive counts). This calculation is based upon an exact binomial
> distribution, therefore validation and QC may be accomplished either
> by enumeration of residual WBC, or by a validated method that will
> provide a simple pass/fail designation for evaluated products.**
>
> **5. Variations in time after collection, temperature of filtration,
> duration of filtration, type of filter, or other process variables may
> require separate SOPs with individual validation and QC procedures.**
>
> **6. As a QC minimum, a random 1% of all leukoreduced products should
> be evaluated for residual WBC content. SOPs used for filtration in a
> given week should be considered individually so that as part of the QC
> process a minimum of 5 random products/week (60 products/3 months) are
> counted per SOP. *(Note: Revised draft guidance will provide examples
> to help clarify this recommendation) ***
>
> **7. If a post-filtration WBC count exceeds 5 x 10^6^, the cause
> should be investigated. Simultaneously, the next consecutive 60
> products prepared under that SOP should be counted.**
>
> **a. If the observed failure is due to a donor-specific factor, it
> does not constitute a process failure. The consecutive counting may be
> discontinued and donor management procedures as described below should
> be implemented.**
>
> **b. If the observed failure is not due to a donor-specific factor, it
> should be assumed to be a process failure. Failure investigation
> should be initiated and corrective action taken.**
>
> **c. If the 60 consecutive counts following the observed failure [do
> not]{.underline} identify product failures and corrective action has
> been taken, normal QC should resume.**
>
> **d. If the 60 consecutive counts following the observed failure
> identify one or more additional process failures, the process should
> be considered out of control. Failure investigation should be
> initiated and corrective action taken. The SOP should then be
> re-validated as described above. All leukoreduced products produced
> under that SOP since the last acceptable QC cycle (n=60 counted units)
> should be counted prior to release if less than 48 hrs has elapsed
> since filtration. If unavailable, the center SOP should define
> procedures for product withdrawal, consignee notification, and product
> recall.**
>
> **8. When a failure is due to an identified donor-specific factor, the
> donor record should be flagged. Upon a second occurrence of incomplete
> filtration or inadequate WBC removal, the donor should become
> ineligible for donation of filtered products, unless a validated
> alternative procedure is used that prevents such failure.**
>
> **9. Alternate approaches to the recommended validation/QC procedure
> will be considered. Appropriate SOPs should be submitted to FDA as
> prior approval supplements.**

Advantages: The proposed strategy assures that ninety five percent of
products labeled as \"leukocytes reduced\" will meet the product
standard with 95% confidence. The quality control workload at blood
collection centers will be considerably less than would be needed to
count all products. (Note: Protection for CMV-susceptible patients will
be considered by discussing (but not recommending) that transfusing
physicians may also wish to provide such patients with products that are
CMV seronegative.)

Disadvantages: While not recommended by FDA as \"CMV-safe\",
leukoreduced products are currently commonly substituted for
CMV-seronegative products. Occasional products that have levels of
residual WBCs that exceed the product standard may unknowingly be
transfused to CMV-susceptible patients. The QC strategy proposed is
somewhat complex for blood centers, as well as QA and regulatory
inspectors.

## [Questions for the Committee]{.underline}

1\. Does the Committee recommend Option 1; i.e. that FDA should
recommend to industry that all products labeled as \"leukocytes
reduced\" meet the defined standard as demonstrated by evaluating
[all]{.underline} such products for residual WBC content.

2\. If no to question 1, does the Committee concur with the modified
statistical quality control strategy as outlined?

3\. If no to questions 1 and 2, what elements of the modified
statistical quality control strategy outlined in Table 1 are in need of
further consideration?