FDA Blood Bank & Blood Tranfusion
FDA Blood Bank & Blood Tranfusion
FDA Blood Bank & Blood Tranfusion
BLOODBOOK.COM
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PRESENTED ON THIS PAGE IS AN ACTUAL FDA BLOOD BANK INSPECTION
GUIDE WHICH WILL GIVE AN IDEA OF BLOOD BANK INSPECTION ISSUES.
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TABLE OF CONTENTS
Subject ................................................................................Page
Introduction............................................................................Pg 1
General Information.................................................................Pg 1
Operations...............................................................................Pg 2
Records...................................................................................Pg 2
Quality Assurance.....................................................................Pg 4
Part B - Laboratory...................................................................Pg 7
Part E - Platelets........................................................................Pg 12
Part K - Computerization............................................................Pg 15
INTRODUCTION
2609. This guide, which provides the most updated interpretation of certain
regulations and guidelines, was prepared by the FDA, Office of Regulatory
Affairs and the Center for Biologics Evaluation and Research.
The Blood Bank Inspection Checklist and Report, and the Instruction Booklet
for Blood Bank Inspection Checklist and Report, FDA-2609, are no longer in
effect. Consequently, field investigators are no longer required to fill out the
checklist during establishment inspections nor submit it with inspectional
reports.
The checklist and instruction booklet were last published in May 1991. Since
May 1991, CBER issued a number of memoranda to industry, depicting new
recommendations, and modifications to previous guidance, in addition to
guidelines on quality assurance and validation of computer systems.
Although the agency, at the time of this publication, is in the process of
revising the regulations on blood and blood products, it will take some time
before such revisions are in effect. The current guide provides interim
inspectional direction.
GENERAL INFORMATION
Investigators should note the U.S. License number, if applicable (and location
number) of facilities. This will serve to identify establishments in
correspondence, applications and other forms of communications.
Registration numbers, essentially central file numbers, are not the same as
license numbers.
OPERATIONS
determine how many units of whole blood and red blood cells (RBCs) are
received from outside sources each year, how many are autologous and how
many are directed.
If the facility being inspected is licensed and pheresis products, i.e, Platelets,
Pheresis and Fresh Frozen Plasma, are prepared by automated methods at
other locations, the firm's license should be amended to permit these
products collected at the other locations to be shipped in interstate
commerce.
RECORDS
limited to, those who test repeatedly reactive for anti-HIV or HBsAg and have
not been properly reentered or have a medical history which would preclude
donation. The regulations do not prohibit firms from collecting blood from
deferred donors. A firm may collect blood from deferred donors if it is not
precluded by its SOP; however, the firm must have a system to prevent the
distribution of these blood components.
LOOKBACK POLICY
See the April 23, 1992 memorandum, "Revised Recommendations for the
Prevention of Human Immunodeficiency Virus (HIV) Transmission by Blood
and Blood Products" for additional guidance.
FACILITIES
OSHA published the final rule for the "Occupational Exposure to Bloodborne
Pathogens" in the December 6, 1991 Federal Register. Included in the rule are
requirements for facilities to develop procedures to ensure the safety of
employees with a potential for exposure to biohazardous materials and
procedures for medical waste disposal. FDA requires hand-washing facilities
for staff drawing and handling blood and the safe and sanitary disposal of
trash. At some mobile sites where hand washing facilities may not be
available, an alternate method to clean hands, i.e., bactericidal hand wipes, is
acceptable.
The Centers for Disease Control (CDC) and the National Institutes of Health
(NIH) published a booklet entitled Biosafety in Microbiological and Biomedical
Laboratories which recommends precautions laboratory employees should
follow. The booklet is available through the Department of Health and Human
Services (DHHS). It is publication No. (CDC) 88-8395, 94-95, 2nd Edition,
Washington, DC: US Government Printing Office, 1988.
Unauthorized persons may not wander through an area where blood is being
drawn, therefore, the traffic flow of the facility, especially mobile sites, must
be properly monitored and controlled.
The interview area has to offer the donor a degree of privacy so that the
donor will be comfortable answering the questions without fear of being
overheard.
EQUIPMENT
Procedures should provide for the calibration of the autoclave before initial
use and after repairs. Calibration procedures should provide assurance that
the autoclave functions as intended, i.e., sterilization of arm preparation
supplies and/or decontamination of biohazardous material. Biologic indicators
must be used periodically and a temperature control, such as heat sensitive
tape, should be used with each run to verify that the materials are being
sterilized. A minimum of 121.5oC (251oF) for 60 minutes by saturated steam
at a pressure of 15 atmospheres is recommended for materials contaminated
with blood; 20 minutes at the same temperature is required for arm
preparation supplies.
PERSONNEL
Staff of mobile sites must have the same degree of training and supervision
as for fixed donor sites located in the blood bank or in a donor center.
Volunteers are permitted to assist in various areas and must be adequately
trained. Training should be documented.
QUALITY ASSURANCE
FDA advises that state and local laws should be followed. All blood
contaminated waste should be autoclaved (121.5oC/251oF for 60 minutes) or
incinerated. The firm's SOP should contain specific language for disposal of
contaminated waste. Needles should be disposed of in a container designed
to prevent accidental puncturing of personnel. If contaminated waste is
disposed of by a contract waste disposal firm, a contracted agreement should
be on file at the facility, and specify that Biohazardous material is disposed of
appropriately according to EPA, state and/or local regulations. Inappropriate
disposal practices should be referred to state authorities for follow-up.
Donor Suitability
DONOR HISTORY
Infectious Skin Diseases: Mild skin disorders such as acne, psoriasis, or the
rash of poison ivy are not cause for deferral unless they affect the skin in the
phlebotomy area. Donors with boils or other severe skin infections should be
deferred until the phlebotomy area is free of infection. Malaria: See the July
26, 1994 memorandum, "Recommendations for Deferral of Donors for Malaria
Risk", for additional guidance. CDC provides a booklet, "Health Information
for International Travelers," which should be used rather than the maps that
were once used. This booklet is updated yearly and the firm should be using a
recent edition.
Plasmapheresis donations that are also used for the preparation of Platelets
are not exempted from the malaria restrictions.
Hepatitis: Donors who have had close contact with a patient with viral
hepatitis should be deferred for at least twelve months. Hospital personnel
working in areas where hepatitis is endemic, such as renal dialysis units,
should be excluded for at least twelve months after employment in such
areas. Prospective donors who have received HBIG following a hepatitis
exposure should be deferred for at least 12 months.
The containers for the copper sulfate (CuSO4) solution must be covered when
not in use so that the solution will not evaporate. In order to prevent dilution
of the copper sulfate, which might result in selection of donors with
inadequate hemoglobin levels, containers must be thoroughly dry before use.
Generally, 25 ml vials of copper sulfate solution are used. Because the
blood:copper sulfate ratio is one drop of blood:one ml of copper sulfate, the
copper sulfate should be discarded after 25 donors have been tested.
ARM PREPARATION
Arm preparation supplies, such as gauze, cotton balls, and applicators may
be prepared by the establishment. If the arm preparation supplies are
sterilized by a central supply which is a part of a hospital's operation, it is not
necessary to observe these preparation procedures or to review the records
for these supplies.
Arm preparations should be done with care and for the full amount of time as
stated in the SOP, and ideally with vigorous scrubbing.
BLOOD COLLECTION
After the venipuncture area is prepared, the vein may be palpated above or
below the prepared area; however the site of needle insertion should not be
touched prior to venipuncture. It is not permissible to put iodine or sterile
gauze on the finger to palpate the intended venipuncture site. Needles may
be used for only one venipuncture. If a venipuncture is unsuccessful, a new
needle must be used and the arm preparation repeated.
The completion of the donation may be signaled by a trip scale or vacuumassist method based on mass or volume. Otherwise, the bag must be
weighed (spring scales) and the flow stopped manually. The blood should be
mixed gently (either manually or mechanically) during collection. The final
unit should weigh approximately 425-525 grams plus the weight of the
container and anticoagulant (approximately 90 grams). Low volume
collections, e.g., pediatric autologous collections, are acceptable providing
the establishment has an SOP. For low volume collections to be shipped in
interstate commerce, the facility must have CBER approval.
Specific gravity of whole blood = 1.053 gm/mL for blood containing 12.5
gm/dL of hemoglobin. The following calculation is used to convert volume to
weight: 1.053 gm/mL X 500 mL =526.5 gm
There are firms with approval from CBER to collect FFP or other plasma
byproducts using hemapheresis devices. Some firms are approved to aliquot
the FFP (or other products) into smaller containers using a sterile tubing
connecting device (STCD). An STCD is a device which seals two pieces of
"like" (same size and composition) tubing together to make a sterile
connection. Licensed establishments must have FDA approval for
manufacturing components with an SCD. For additional guidance, see the July
29, 1994 memorandum, "Use of an FDA Cleared or Approved Sterile
Connecting Device (STCD) in Blood Bank Practice."
LABORATORY SAMPLES
Pilot (laboratory) samples containing blood for ABO, Rh, antibody screening
and viral testing are collected at the time of donation. The tubes must be
identified to accurately relate them to the unit. The method used for
collection of the pilot sample should be one that precludes contamination of
the donor unit, minimizes personnel exposure to blood, and maintains donor
safety. See the AABB Technical Manual, for methods of pilot sample collection.
DATING PERIOD
Expiration dates vary from 21 days for ACD, CPD, and CP2D, 35 days for
CPDA-1 in whole blood and red blood cells, to 42 days for red blood cells to
which additive solutions have been added, i.e., ADSOLR (Fenwal), NutricellR
(Cutter) and OptisolR (Terumo).
Autologous units are blood or blood products collected from a person for
his/her own use at a later time. These predeposited blood products are
handled and processed as similarly as possible to homologous units. CBER
sent the following memoranda concerning autologous donations to all
registered blood establishments: "Guidance for Autologous Blood and Blood
Components" on March 15, l989 and "Autologous Blood Collection and
Processing Procedures" on February 12, l990 and "Disposition of Blood
Products Intended for Autologous Use that Test Repeatedly Reactive for AntiHCV", dated September 11, 1991.
THERAPEUTIC PHLEBOTOMY
DONOR REACTIONS
A blood bank should be aware of the nature and frequency of donor reactions.
Adequate records for each reaction should be kept and should include followup in order to insure adequate donor protection. The blood bank's SOP
manual should list and describe donor reactions it considers to be adverse, as
well as the procedures to be followed for handling and investigating these
reactions. Severe donor reactions may include fainting, convulsions, severe
hematomas (infiltration), or injury caused by falling. Mild donor reactions
include feeling faint, nauseated, or dizzy.
PART B - LABORATORY
Blood Grouping Reagents are used to determine the blood group. Anti-A will
agglutinate or clump group A red cells. Anti-B will agglutinate group B red
cells. Anti-D is used to determine Rho (D) factor.
Test methods used for ABO, Rh and antibody screening, which are different
from the manufacturer's instructions, should not be cited as deviations if they
are not prohibited by the manufacturer, have been demonstrated to be
satisfactory, or have been approved for use by CBER. For example, the
MicrotiterTM plates and GroupamaticTM machines may be used for ABO, Rh,
and antibody testing. The reagents must be tested and shown to perform
adequately or satisfactorily when using these techniques.
Not all anti-D reagents may be used for Du testing; the package insert must
include directions for Du testing.
The manufacturer's instructions specify that the storage requirement for AntiA, Anti-B, and Anti-D reagents is between 2-8oC; however, it is accepted
practice for these reagents to stay at room temperature for the duration of
the working day. This will usually not diminish the potency of the products
throughout the normal period of use.
Laboratory records for automated testing should include the name of the
person who prepared the reagents. If the system does not provide positive
sample identification, a record must be made for the loading pattern and the
record must include the name of the person(s) who loaded and unloaded the
sampler; if results are visually interpreted, the record must include the name
of the person(s) interpreting and transferring the results.
If the firm used automated methods for ABO and Rh typing at the time of
licensure, a separate letter of approval from CBER for automated ABO and Rh
testing will not be issued to the establishment. Reagents used in microplate
test systems should be recommended for this use by the manufacturer's
package insert. If not originally licensed for the use of the microplate test
system, a licensed establishment should have on file a letter from CBER
approving its use. Gamma-Micro-U microtiter plates are approved for use only
with the Gamma microtiter reagent unless the reagent has been evaluated
and found acceptable for such use according to an established protocol.
All units of blood must be tested by an acceptable serological test for syphilis
(STS). For further guidance, refer to CBER's December 12, 1991
memorandum to registered blood establishments on "Clarification of FDA
Recommendations for Donor Deferral & Product Distribution Based on the
Results of Syphilis Testing".
Each collection of whole blood and blood components must be tested for antiHIV, syphilis, and HBsAg. In addition, they should be tested for anti-HCV, antiHBc, and anti-HTLV-I per recommendations from FDA. Testing for alanine
aminotransferase (ALT) was implemented as a surrogate marker for viral
hepatitis. FDA has not made any recommendations as to whether or not
blood banks should perform ALT testing; however, ALT testing has become an
industry standard. If an establishment has implemented ALT testing, they
should be following the manufacturer's instructions and their SOP for
performing the test and interpreting the test results.
Each unit of blood must be tested for HBsAg by a licensed third generation
test. Third generation tests include radioimmunoassay (RIA), reverse passive
hemagglutination (RPHA), or enzyme-linked immunosorbent assay (ELISA or
EIA).
Each unit must be tested for antibody to HIV with a licensed test kit. There
are three types of licensed kits based upon different manufacturing
technologies:
Synthetic peptides.
Products from Donors with Positive Tests for Infectious Disease Markers ('High
Risk' Donors)", dated April 17, 1991
In the past, the area used for HBsAg and anti-HIV testing would, by design, be
in rooms separated from other blood bank activities. This is no longer
considered to be important as all blood samples should be treated as capable
of transmitting an infectious disease, and Biosafety Level 2 precautions
should be applied in all areas where open samples are handled. However, if
RIA procedures are used in the facility these areas still must be physically
separated from other areas. Work areas, such as counter tops, should be
constructed of non-porous materials and designed to permit thorough
cleaning and disinfection. There should be policies to prevent excessive traffic
of unauthorized personnel through viral testing areas.
PROFICIENCY TESTING
A proposed rule was published in the June 6, 1989, Federal Register to require
that each establishment or laboratory responsible for performing FDA
required tests for HBsAg and anti- HIV participate in an approved program to
demonstrate proficiency in performing these tests. The final regulation
proposed by FDA has not been published, however, the final rule proposed by
HCFA, which regulates laboratories receiving Medicare and Medicaid
reimbursement, was published in the March 14, 1990, Federal Register. This
final rule requires laboratories to have policies and procedures for an ongoing
program to assure that employees are competent and maintain their
competency to perform their duties.
The results and interpretations of all (initial and repeat) tests performed and
an explanation of any symbols or phrases used in reporting results should be
provided by the testing facility to the blood bank. The blood bank should have
an SOP for the interpretation of the reports obtained from outside testing
laboratories and written assurance that the outside testing laboratory
interprets test results according to FDA requirements. The raw test data, i.e.,
absorbance readings from the spectrophotometer, need not be sent to the
blood bank. In addition, if the blood establishment is re-entering donors with
previously repeatedly reactive anti-HIV test results, the establishment must
determine if the outside testing laboratory is performing Western blot assays
with licensed test kits.
Except for emergencies, no units should be issued until written hepatitis and
HIV antibody test results are in the possession of the blood bank.
OPEN SYSTEM
ADDITIVE SOLUTIONS
Quality control testing should be performed and the firm should take
corrective action when test results are out of the firm's established
parameters as stated in the SOP's. Quality control testing may include
periodic sterility testing, monitoring the removal of the glycerol and the
amount of the free hemoglobin in the final product, and the RBC recovery.
Certain blood centers have approval for an SOP that does not require sterility
checks on Red Blood Cells, Deglycerolized, on a periodic basis if the facilities
where the product is prepared are monitored for cleanliness and good
housekeeping procedures, including proper maintenance of air filters in the
heating, ventilation and air conditioning (HVAC) system.
An area of concern is that the firm has adequate procedures to assure that
the final container is accurately identified to relate it to the donor. For
example, if several units of blood are frozen and deglycerolized
simultaneously, what controls does the firm utilize to assure against mix-ups?
ABO and Rh checks should be performed after a unit is deglycerolized to
verify the blood type.
REJUVENATING SOLUTIONS
There are several methods for removing leukocytes from RBC's. These
methods include centrifugation with or without saline washing,
microaggregate blood filtration, freezing and deglycerolizing, washing (using
either a manual or automated method) and filtration with filters designed and
approved specifically for leukocyte removal.
IRRADIATED BLOOD
Each final container of plasma for transfusion prepared from a whole blood
collection shall be in an integrally attached satellite bag at the time of
collection; it must be transparent and hermetically sealed by a dielectric
sealer, metal clamp, or tightly drawn "white knot;" and its label must be
marked by number or other symbol so that it can be traced back to the donor.
The final product should be stored in a manner which will show evidence of
thawing. This may be accomplished in a variety of ways, e.g., by storing it
upside down after freezing, or by placing a rubber band around the middle of
the container and removing it when the unit has frozen.
RECOVERED PLASMA
Recovered Plasma does not have an expiration date, therefore, records are to
be kept indefinitely.
PART E - PLATELETS
Platelets may be pooled by the blood bank personnel, upon the request of a
physician; however, this is done following designation of the platelets to a
specific recipient, and the resultant pool is not considered a licensed product.
The label of the pooled components should indicate the individual donor
numbers comprising the pool or a pool number that relates it to individual
donor numbers comprising the pool. Final containers must be transparent and
hermetically sealed by a dielectric sealer, metal clamp, or tightly drawn
"white knot." The expiration time for pooled platelets is limited to 4 hours.
Until data are available indicating the effectiveness of the platelets is
maintained for a longer period of time and CBER approval is obtained, the
expiration time of Platelets which are pooled with the aid of a sterile
connecting device is also limited to four hours.
QUALITY CONTROL
Quality control testing must be performed each month platelets are prepared,
using one unit obtained from each of four different donors. Platelet counts
(5.5 x 1010 in 75% of the units tested), Ph determination (>= 6.0) and
measurement of plasma volume should be made at the end of the
storage/dating period.
If quality control testing is not under the supervision and control of the
establishment, determine where the testing is performed and how test results
are reviewed and handled by the establishment.
Firms may have approval for variances under 21 CFR 640.120 from the
regulations for manufacturing Cryoprecipitated AHF, i.e., preparing
Cryoprecipitated AHF within 15 hours after phlebotomy. The firm should have
written approval from CBER for any variance.
QUALITY CONTROL
Quality control testing need be performed only in the months in which the
product is prepared. Four units must be tested, but they may be pooled
before the quality control assay is performed.
CIRCULARS
The circulars are of great importance now that uniform or commonality labels
are in use. The new labels have less information on them so that attention
will be focused on the blood group (ABO and Rh). Information that has been
deleted must be in the circular. The circular of information is an extension of
the container labels and viewed as labeling containing statements of
purported product quality. It should describe each component available for
patient transfusion and give indications and contraindications for use. The
blood supplier should have a plan for distributing the instruction circulars,
COMPATIBILITY TESTING
Hospitals may elect not to crossmatch blood for certain surgical procedures
that usually do not require the transfusion of blood. This procedure is referred
to as "type and screen" and requires: 1) determination of the patient's blood
group; 2) tests of patient's serum for unexpected antibodies; and 3)
availability of units of blood in case the patient does need blood during the
operation.
ANTIBODY TESTING
EMERGENCY TRANSFUSIONS
Records should be kept of receipt of recipient's sample and the ABO and Rh
test results; lot numbers of reagents used for testing; and routine and
emergency crossmatches and direct antiglobulin testing (if done). The vital
signs of a recipient are not required to be on file at the blood bank.
The blood bank's SOP manual should list and describe recipient reactions it
considers to be adverse, as well as the procedures to be followed for handling
and investigating these reactions. Recipient reactions usually not considered
serious include low fever and chills of short duration, hives, or urticaria.
Serious adverse recipient reactions usually include hemolysis, bacteremia, or
septicemia.
If the blood bank acts as a transfusion service and receives blood from other
sources, errors in the ABO and Rh grouping should be reported to the
suppliers. Procedures should be established between the suppliers and users
of blood and blood products for monitoring recipient adverse reactions which
occur outside the supplying facility. If the supplier of mistyped blood is a
licensed establishment, it is the responsibility of that establishment to report
any errors to CBER, Office of Compliance. Refer to CBER's memorandum to
industry dated March 20, 1991, titled "Responsibilities of Blood
Establishments Related to Errors & Accidents in the Manufacture of Blood
Components".
PHYSICAL STORAGE
INSPECTION
Blood should be visually inspected at the time of issue for any abnormality,
such as hemoglobin in the plasma from red cell lysis, purple tinged red cells
due to bacterial contamination, or blood clots.
SHIPPING
REISSUE
Blood banks should have written criteria for reissuing blood that is returned
to the blood bank. Studies have shown that the unit of blood sitting at room
temperature usually maintains a temperature of 10oC for 30 minutes. Blood
that has been issued for transfusion may be reissued if it is returned to the
blood bank within 30 minutes, and was kept at room temperature or colder
while out of the blood bank's control.
Refer to the October, l988, memorandum from CBER to all registered blood
establishments "Revised Guideline for the Collection of Platelets, Pheresis."
PART K - COMPUTERIZATION
Refer to the FDA "Draft Guideline for the Validation of Blood Establishment
Computer Systems." This document focuses on computer system definitions,
testing, manuals, maintenance, security, training, audits, FDA references and
reportable activities to the FDA. The final document will supersede the April
6, 1988, memorandum from CBER to all registered blood establishments
"Recommendations for Implementation of Computerization in Blood
Establishments", and the September 8, l989, memorandum "Requirements
for Computerization of Blood Establishments".
A "shared" computer system is a system used by both the blood bank and
other sections of a clinical laboratory or the entire hospital. Security
procedures should have been established regarding limiting access to
confidential blood bank information, e.g., donor deferral records. In addition,
access to blood bank data should be limited so that inadvertent or
unauthorized changes in data do not occur.
Antibody Screen - Donor or patient serum is tested with reagent red cells of
known antigenic makeup; the purpose is to determine if the donor or patient
has antibodies in his or her serum.
Directed Donor - A donor who donates a unit of blood for a specific patient.
These donors should meet all suitability requirements and be tested as
allogeneic donors. Occasionally, a directed donation may not meet all
suitability and testing requirements, in which case, the patient's physician
may make a medical decision to use the directed donation.
A typical ELISA test such as that used for the detection of antibody to HIV
utilizes beads or microtiter wells coated with disrupted, inactivated HIV
agents and goat anti-human Ig conjugated or "linked" to an enzyme, which on
incubation with the appropriate substance, will produce a color.
Hematocrit - The percentage of red blood cells present in the whole blood
volume.
Hemoglobin - The main component of the red blood cell - an iron containing
protein which serves as the vehicle for the transportation of oxygen and
carbon dioxide.
Major Crossmatch - Patient's serum tested with donor's red cells; the purpose
is to determine if the patient has an antibody to an antigen found on the
donor's cells.
Minor Crossmatch - Donor's serum tested with patient's red cells; the purpose
is to determine if the donor has an antibody to an antigen found on the
patient's cells.
Plasma - Separated from red blood cells within 26 days after phlebotomy
(within 40 days after phlebotomy when CPDA-1 solution is used as the
anticoagulant). Stored at -18oC or colder within six hours after separation
(see instruction booklet). Dating period is five years. Platelets and/or
Cryoprecipitated AHF may be removed from product.
1. Liquid plasma: Separated from red blood cells within 26 days after
phlebotomy (within 40 days after phlebotomy when CPDA-1 solution is used
as the anticoagulant). Stored at 1-6oC for a total of 26 days (40 days when
CPDA-1 is used).
Plasmapheresis - A process in which red blood cells are separated from the
plasma of a blood donor and returned to the donor's circulatory system.
Specific gravity of whole blood - 1.053 gm/ml for blood containing 12.5 gm/dl
of hemoglobin. The following calculation is used to convert volume to weight:
1.053 gm/ml X 500 ml = 526.5 gm.
STS - Serological test for syphilis, e.g., VDRL, RPR, and the treponema-based
hemagglutination test on the Olympus automated blo
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