Changes in Equipment for Processing Blood Donor Samples
(7/21/92)

DATE:     July 21, 1992

FROM:     Director, Center for Biologics Evaluation and
          Research

SUBJECT:  Changes in Equipment for Processing Blood Donor
          Samples

TO:       All Licensed Blood Establishments

The Code of Federal Regulations, 21 CFR 640.5(b) and (c) requires
that each container of Whole Blood be classified as to ABO and Rh
group.  Routine blood bank practice also includes performing
blood group related antibody screening tests on a sample from
each donor.  In the past, this testing was most often performed
using manual slide or tube procedures.  In recent years, however,
various automated methods and equipment have been developed to
perform this testing.

It has been the policy of the Center for Biologics Evaluation and
Research (CBER) both to review automated blood grouping and
antibody test systems as medical devices used in blood and blood
component manufacturing prior to marketing, and to also consider
a licensed blood establishment's original or modified use of the
medical device to be an important change in manufacturing methods
[21 CFR 601.12(b)] that required review and acceptance by this
Center prior to implementation. 

We have evaluated the Center's past experience in the review and
approval process for use of these devices.  The results of our
evaluation indicated that blood safety will not be adversely
affected if licensed blood establishments implement use of
medical devices approved for automated blood grouping after
appropriate installation and on-site instrument qualification in
the licensed blood establishment.  The establishment should
report the changes in procedures or equipment to the Director,
CBER, consistent with 21 CFR 601.12(a) not less than 30 days in
advance of implementation.  However, the establishment does not
need a specific approval from CBER prior to implementing.  The
FDA will review documentation supporting the change at the time
of the next scheduled inspection. 

A copy of the change notification sent to CBER, and
acknowledgment of receipt by CBER, should also be available at
the facility for review during FDA inspections.

Henceforth, any establishment electing to use automated blood
grouping or antibody test systems approved for testing blood
donor samples may do so consistent with the manufacturer's
directions, following on-site instrument qualification, parallel
testing as appropriate, and documentation of staff proficiency in
each facility.   Any departure from the manufacturer's
instructions, however, represents an unapproved method and will
continue to require review and approval in the form of a product
license application amendment prior to implementation.

Establishments that are currently awaiting approval of license
amendments for the use of such equipment should submit a letter
requesting withdrawal of the amendment application, if
appropriate.

FDA will review the documentation in support of the procedural
change at the firm's next inspection to determine that the
manufacturer's directions are being followed, that adequate
standard operating procedures are in place and being followed,
that staff are appropriately trained and that appropriate
qualification testing was performed, evaluated and documented
prior to implementation of the change.  The addendum further
explains the kind of information that should be available for
evaluation upon request by FDA.

Questions regarding this policy may be directed to the Division
of Product Certification, (301) 295-8428, FAX (301) 295-8528;
technical questions should be referred to the Division of
Transfusion Science, Laboratory of Blood Bank Practices, FAX
(301) 227-6431.

     ______________________
     Kathryn C. Zoon, Ph.D.

_____________________________________________________
         Addendum to FDA Memorandum Regarding:
   Documentation of Changes in Equipment for ABO/Rh 
 and Antibody Screening Processing Blood Donor Samples

As automation becomes an integral part of all laboratories, many
blood establishments are purchasing equipment for use in the
collection, processing, and testing of blood and blood products. 
Equipment used in blood establishments is subject to approval by
the Center for Biologics Evaluation and Research and/or the
Center for Devices and Radiological Health (CDRH) through the
process of a 510(k) Pre-Market Notification or a Pre-Market
Approval Application (PMA).  Test kits and reagents to perform
required tests for licensed blood products are also subject to
approval by FDA.

In the past, the implementation of automated equipment for ABO/Rh
blood grouping tests and related antibody screening tests has
been considered a major change in manufacturing, requiring
approval of a product license amendment (PLA from the Food and
Drug Administration (FDA/CBER).  The attached memorandum informs
establishments that review of implementation procedures for new
equipment already cleared by the FDA and used according to the
manufacturer's directions will now be performed during routine
inspections.  This step will eliminate duplication of review and
streamline procedures for blood establishments implementing
changes that include new equipment.

Documentation for changes that include use of new equipment
should include the following procedures prior to acceptance for
testing blood and blood components.  Deviation from the
manufacturer's instructions requires justification; licensed
establishments also need written approval from CBER for the
variation.

General Procedures

1.   Calibration

     Automated equipment should be calibrated after installation
     and periodically according to the manufacturer's
     recommended schedule for maintenance.  This may be
     performed by the device manufacturer at the time of
     installation.  The blood establishment should keep a record
     of the calibration procedures performed, identifying the
     name of the person(s) performing the calibration, and
     listing the date(s) of calibration and any subsequent re-
     calibration.

2.   Validation (Qualification)

     Validation establishes that a specific process will
     consistently produce a product meeting predetermined
     specifications.  Blood establishments should have written
     specifications for automated equipment performance and the
     equipment should be evaluated to determine that it meets
     these specifications.  Performance qualification is a part
     of validation involving rigorous testing to demonstrate
     effectiveness and reproducibility of the specific process
     being tested.  Qualification includes testing a process
     with challenge conditions that simulate conditions that
     will be encountered during equipment use.  The number of
     specimens tested or the number of test runs performed
     should be sufficient to ensure that the equipment meets the
     specifications determined by the blood establishment. 
     There should be written records of qualification testing,
     including the names of personnel performing the testing and
     the date(s) of testing.

3.   Parallel Testing

     Because it is very difficult to evaluate the precision and
     accuracy of some serological tests (e.g., blood grouping
     tests) in any other way, testing in parallel with an FDA
     licensed reagent used by another approved method has been a
     primary part of some types of new equipment validation. 
     Parallel testing is functional testing performed using both
     the new test method and the reference method on the same
     samples to determine that the new method provides accuracy
     comparable to or better than the reference method.  The
     number of specimens tested should be sufficient to show
     that the new method is equivalent to or better than the
     reference method.

     a.   Test adequate numbers of samples to document
          consistent determination of accurate ABO and Rh
          groups. Compare to results with licensed reagents
          used by a method accepted by the FDA for testing
          donor samples.  The number of tests necessary to
          demonstrate adequacy of the new method is dependent
          upon many factors including the number of
          discrepancies and the range of phenotypes
          encountered.  It may be necessary in most situations
          to supplement the routine donor samples with known
          examples of less common blood groups such as group
          A2B or weak D(Du).

          If during the evaluation process the protocol changes
          or equipment adjustments are made, it will be
          necessary to test additional samples.  The number of
          tests should be adequate to show both proficiency of
          technologists and reproducibility of results.  In all
          cases the number of parallel tests to be performed
          should include:

          A minimum of 500 samples. A minimum of 3 days
          testing under representative conditions.

     b.   Maintain a summary of all of the experience with the
          instrument.  (i.e., a complete history of testing
          performed, including test data, problems, equipment
          adjustments or repairs, protocol changes, and
          conclusions.)

     c.   Maintain documentation regarding discrepant results,
          identification of the problems, and the resolution of
          problems.  All additional testing done on problem
          samples should be fully documented.

     d.   The NTD (no type determined) rate should not be
          greater than 6% of the total number of tests
          performed.  An SOP should be prepared describing in
          detail how NTD samples will be handled.

     e.   Record the names, lot numbers and manufacturers of
          all reagents used.  If tests were performed to
          determine dilutions of reagents to be used, there
          must be documentation of these tests and consistent
          application of a protocol to choose correct dilution
          of each lot.

4.   Quality Control

     Quality control should be performed on all automated
     equipment prior to implementation and periodically
     thereafter as required by the manufacturer and the
     establishment SOP.  Quality control data should meet
     predetermined acceptability criteria.  If these criteria
     are not met, corrective actions should be taken and
     documented.  The corrective action should be evaluated to
     ensure that the problem was corrected.

5.   Maintenance

     A schedule for preventative (routine) maintenance and a
     maintenance log should be developed prior to implementation
     of new automated equipment.  The log should also include
     procedures for re-qualification after preventive
     maintenance and repairs, and documentation that these
     procedures were followed.  Simple calibration may be
     sufficient following scheduled preventive maintenance,
     whereas complete re-qualification may be necessary
     following major repairs.  The SOP should clearly define
     what will be required and/or the criteria for decisions
     concerning the extent of quality control or validation
     testing before donor testing is resumed.

6.   Emergency Plans

     The blood establishment should have a back-up system for
     providing test results in the event of equipment failure. 
     The SOP should describe the alternative system(s), and
     staff proficiency for employing the alternative system
     should be documented.