[Title 21 CFR 640]
[Code of Federal Regulations (annual edition) - April 1, 1996 Edition]
[Title 21 - FOOD AND DRUGS]
[Chapter I - FOOD AND DRUG ADMINISTRATION,]
[Subchapter F - BIOLOGICS]
[Part 640 - ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS]
[From the U.S. Government Publishing Office]
21
FOOD AND DRUGS
7
1996-04-01
1996-04-01
false
ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS
640
PART 640
FOOD AND DRUGS
FOOD AND DRUG ADMINISTRATION,
BIOLOGICS
PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS--Table of Contents
Subpart A--Whole Blood
Sec.
640.1 Whole Blood.
640.2 General requirements.
640.3 Suitability of donor.
640.4 Collection of the blood.
640.5 Testing the blood.
640.6 Modifications of Whole Blood.
Subpart B--Red Blood Cells
640.10 Red Blood Cells.
640.11 General requirements.
640.12 Suitability of donor.
640.13 Collection of the blood.
640.14 Testing the blood.
640.15 Pilot samples.
640.16 Processing.
640.17 Modifications for specific products.
Subpart C--Platelets
640.20 Platelets.
640.21 Suitability of donors.
640.22 Collection of source material.
640.23 Testing the blood.
640.24 Processing.
640.25 General requirements.
640.27 Emergency provisions.
Subpart D--Plasma
640.30 Plasma.
640.31 Suitability of donors.
640.32 Collection of source material.
640.33 Testing the blood.
640.34 Processing.
Subpart E--[Reserved]
Subpart F--Cryoprecipitate
640.50 Cryoprecipitate AHF.
640.51 Suitability of donors.
640.52 Collection of source material.
640.53 Testing the blood.
640.54 Processing.
640.55 U.S. Standard preparation.
640.56 Quality control test for potency.
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Subpart G--Source Plasma
640.60 Source Plasma.
640.61 Informed consent.
640.62 Medical supervision.
640.63 Suitability of donor.
640.64 Collection of blood for Source Plasma.
640.65 Plasmapheresis.
640.66 Immunization of donors.
640.67 Laboratory tests.
640.68 Processing.
640.69 General requirements.
640.70 Labeling.
640.71 Manufacturing responsibility.
640.72 Records.
640.73 Reporting of fatal donor reactions.
640.74 Modification of Source Plasma.
640.76 Products stored or shipped at unacceptable temperatures.
Subpart H--Albumin (Human)
640.80 Albumin (Human).
640.81 Processing.
640.82 Tests on final product.
640.83 General requirements.
640.84 Labeling.
Subpart I--Plasma Protein Fraction (Human)
640.90 Plasma Protein Fraction (Human).
640.91 Processing.
640.92 Tests on final product.
640.93 General requirements.
640.94 Labeling.
Subpart J--Immune Globulin (Human)
640.100 Immune Globulin (Human).
640.101 General requirements.
640.102 Manufacture of Immune Globulin (Human).
640.103 The final product.
640.104 Potency.
Subpart K--Measles Immune Globulin (Human)
640.110 Measles Immune Globulin (Human).
640.111 General requirements.
640.112 Manufacture of Measles Immune Globulin (Human).
640.113 The final product.
640.114 Potency.
Subpart L--Alternative Procedures
640.120 Alternative procedures.
Authority: Secs. 201, 501, 502, 503, 505, 510, 701 of the Federal
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 353, 355, 360,
371); secs. 215, 351, 352, 353, 361 of the Public Health Service Act (42
U.S.C. 216, 262, 263, 263a, 264).
Source: 38 FR 32089, Nov. 20, 1973, unless otherwise noted.
Cross References: For U.S. Customs Service regulations relating to
viruses, serums, and toxins, see 19 CFR 12.21--12.23. For U.S. Postal
Service regulations relating to the admissibility to the United States
mails see parts 124 and 125 of the Domestic Mail Manual, that is
incorporated by reference in 39 CFR part 111.
Subpart A--Whole Blood
Sec. 640.1 Whole Blood.
The proper name of this product shall be Whole Blood. Whole Blood is
defined as blood collected from human donors for transfusion to human
recipients.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]
Sec. 640.2 General requirements.
(a) Manufacturing responsibility. All manufacturing of Whole Blood,
including donor examination, blood collection, laboratory tests,
labeling, storage and issue, shall be done under the supervision and
control of the same licensed establishment except that the Director,
Center for Biologics Evaluation and Research, may approve arrangements,
upon joint request of two or more licensed establishments, which he
finds are of such a nature as to assure compliance otherwise with the
provisions of this subchapter.
(b) Periodic check on sterile technique. Where blood is collected in
an open system, that is, where the blood container is entered, at least
one container of such blood that upon visual examination appears normal
shall be tested each month between the 18th and 24th day after
collection (between the 32d and 38th day after collection when CPDA-1
solution is used as the anticoagulant), as a continuing check on
technique of blood collection, as follows: The test shall be performed
with a total sample of no less than 10 milliliters of blood and a total
volume of fluid thioglycollate medium 10 times the volume of the sample
of blood. The test sample shall be inoculated into one or more test
vessels in a ratio of blood to medium of 1 to 10 for each vessel, mixed
thoroughly, incubated for 7 to 9 days at a temperature of 30 deg. to
32 deg. C, and examined for evidence of growth of microorganisms every
workday throughout the test period. On the
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third, fourth, or fifth day, at least 1 milliliter of material from each
test vessel shall be subcultured in additional test vessels containing
the same culture medium and in such proportion as will permit
significant visual inspection, mixed thoroughly, incubated for 7 to 9
days at a temperature of 30 deg. to 32 deg. C, and examined for evidence
of growth of microorganisms every workday throughout the test period. If
growth is observed in any test vessel, the test shall be repeated to
rule out faulty test procedure, using another sample of blood from
either, (1) the container from which the initial test sample was taken;
(2) the residual cells or plasma from that blood; or (3) two different
containers of blood, each 18 to 24 days old (32 to 38 days old when
CPDA-1 solution is used as the anticoagulant) and each tested
separately. The formula for Fluid Thioglycollate Medium shall be as
prescribed in Sec. 610.12(e)(1) of this chapter. Media and design of
container shall meet the requirements prescribed in Sec. 610.12(e)(2)
(i) and (ii) of this chapter. In lieu of performing one test using an
incubation temperature of 30 deg. to 32 deg. C, two tests may be
performed: Each in all respects as prescribed in this paragraph, one at
an incubation temperature of 18 deg. to 22 deg. C and one at an
incubation temperature of 35 deg. to 37 deg. C.
(c) Final container. The original blood container shall be the final
container and shall not be entered prior to issue for any purpose except
for blood collection. Such container shall be uncolored and transparent
to permit visual inspection of the contents and any closure shall be
such as will maintain an hermetic seal and prevent contamination of the
contents. The container material shall not interact with the contents
under the customary conditions of storage and use, in such a manner as
to have an adverse effect upon the safety, purity, or potency of the
blood.
(d) [Reserved]
(e) Reissue of blood. Blood that has been removed from storage
controlled by a licensed establishment shall not be reissued by a
licensed establishment unless the following conditions are observed:
(1) The container has a tamper-proof seal when originally issued and
this seal remains unbroken;
(2) An original pilot sample is properly attached and has not been
removed, except that blood lacking a pilot sample may be reissued in an
emergency provided it is accompanied by instructions for sampling and
for use within six hours after entering the container for sampling;
(3) The blood has been stored continuously at 1 deg. to 6 deg. C.
and shipped between 1 deg. and 10 deg. C;
(4) The blood is held for observation until a significant inspection
consistent with the requirements of Sec. 640.5(e) can be made.
(f) Issue prior to determination of test results. Notwithstanding
the provisions of Sec. 610.1 of this chapter, blood may be issued by the
manufacturer on the request of a physician, hospital, or other medical
facility before results of all tests prescribed in Sec. 640.5, the test
for hepatitis B surface antigen prescribed in Sec. 610.40(a) of this
chapter, and a test for antibody to Human Immunodeficiency Virus (HIV)
prescribed in Sec. 610.45(a) of this chapter have been completed, where
such issue is essential to allow time for transportation to ensure
arrival of the blood by the time it is needed for transfusion: Provided,
That (1) the blood is shipped directly to such physician or medical
facility, (2) the records of the manufacturer contain a full explanation
of the need for such issue, and (3) the label on each container of such
blood bears the information required by Sec. 606.121(h) of this chapter.
(Information collection requirements approved by the Office of
Management and Budget under number 0910-0227)
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 4015, Jan. 28, 1976; 42
FR 59878, Nov. 22, 1977; 43 FR 34460, Aug. 4, 1978; 49 FR 15187, Apr.
18, 1984; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan. 29, 1985; 53 FR
116, Jan. 5, 1988; 55 FR 11013, Mar. 26, 1990]
Sec. 640.3 Suitability of donor.
(a) Method of determining. The suitability of a donor as a source of
Whole Blood shall be determined by a qualified physician or by persons
under his supervision and trained in determining suitability. Such
determination shall
[[Page 121]]
be made on the day of collection from the donor by means of medical
history, a test for hemoglobin level, and such physical examination as
appears necessary to a physician who shall be present on the premises
when examinations are made, except that the suitability of donors may be
determined when a physician is not present on the premises, provided the
establishment (1) maintains on the premises, and files with the Center
for Biologics Evaluation and Research, a manual of standard procedures
and methods, approved by the Director of the Center for Biologics
Evaluation and Research, that shall be followed by employees who
determine suitability of donors, and (2) maintains records indicating
the name and qualifications of the person immediately in charge of the
employees who determine the suitability of donors when a physician is
not present on the premises.
(b) Qualifications of donor; general. Except as provided in
paragraph (f), a person may not serve as a source of Whole Blood more
than once in 8 weeks. In addition, donors shall be in good health, as
indicated in part by:
(1) Normal temperature;
(2) Demonstration that systolic and diastolic blood pressures are
within normal limits, unless the examining physician is satisfied that
an individual with blood pressures outside these limits is an otherwise
qualified donor under the provisions of this section;
(3) A blood hemoglobin level which shall be demonstrated to be no
less than 12.5 gm. of hemoglobin per 100 ml. of blood;
(4) Freedom from acute respiratory diseases;
(5) Freedom from any infectious skin disease at the site of
phlebotomy and from any such disease generalized to such an extent as to
create a risk of contamination of the blood;
(6) Freedom from any disease transmissible by blood transfusion,
insofar as can be determined by history and examinations indicated
above; and
(7) Freedom of the arms and forearms from skin punctures or scars
indicative of addiction to self-injected narcotics.
(c) Additional qualifications of donor; viral hepatitis. No
individual shall be used as a source of Whole Blood if he has--
(1) A history of viral hepatitis;
(2) A history of close contact within six months of donation with an
individual having viral hepatitis;
(3) A history of having received within six months human blood, or
any derivative of human blood which the Food and Drug Administration has
advised the licensed establishment is a possible source of viral
hepatitis.
(d) Therapeutic bleedings. Blood withdrawn in order to promote the
health of a donor otherwise qualified under the provisions of this
section, shall not be used as a source of Whole Blood unless the
container label conspicuously indicates the donor's disease that
necessitated withdrawal of blood.
(e) Immunized donors. Blood withdrawn from donors known to have been
immunized to human blood cell antigens shall not be used for Whole Blood
unless the container label conspicuously indicates such information.
(f) Qualifications; donations within less than 8 weeks. A person may
serve as a source of Whole Blood more than once in 8 weeks only if at
the time of donation the person is examined and certified by a physician
to be in good health, as indicated in part in paragraph (b) of this
section.
[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50
FR 4138, Jan. 29, 1985; 51 FR 15611, Apr. 25, 1986; 55 FR 11013, Mar.
26, 1990]
Sec. 640.4 Collection of the blood.
(a) Supervision. Blood shall be drawn from the donor by a qualified
physician or under his supervision by assistants trained in the
procedure. A physician shall be present on the premises when blood is
being collected, except that blood may be collected when a physician is
not present on the premises, provided the establishment (1) maintains on
the premises, and files with the Center for Biologics Evaluation and
Research, a manual of standard procedures and methods, approved by the
Director of the Center for Biologics Evaluation and Research, that shall
be followed by employees who collect blood, and (2) maintains records
indicating the name and qualifications of the person immediately in
charge of
[[Page 122]]
the employees who collect blood when a physician is not present on the
premises.
(b) The donor clinic. The pertinent requirements of Secs. 600.10 and
600.11 of this chapter shall apply at both the licensed establishment
and at any other place where the bleeding is performed.
(c) Blood containers. Blood containers and donor sets shall be
pyrogen-free, sterile and identified by lot number. The amount of
anticoagulant required for the quantity of blood to be collected shall
be in the blood container when it is sterilized. In addition, all
container and donor set surfaces that come in contact with blood used in
the processing of Heparin Whole Blood shall be water repellent.
(d) The anticoagulant solution. The anticoagulant solution shall be
sterile and pyrogen-free. One of the following formulae shall be used in
the indicated volumes:
(1) Anticoagulant citrate dextrose solution (ACD).
------------------------------------------------------------------------
Solution A Solution B
------------------------------------------------------------------------
Tri-sodium citrate (Na3C6H5O72H2O).
Citric acid (C6H8O7H2O).. 8.0 gm........... 4.8 gm.
Dextrose (C6H12O6H2O).... 24.5 gm.......... 14.7 gm.
Water for injection (U.S.P.) to 1,000 ml......... 1,000 ml.
make.
Volume per 100 ml. blood........... 15 ml............ 25 ml.
------------------------------------------------------------------------
(2) Anticoagulant heparin solution.
Heparin sodium (U.S.P.)................... 75,000 units.
Sodium chloride injection (U.S.P.) to make 1,000 ml.
Volume per 100 ml. blood.................. 6 ml.
A buffer to maintain stability shall be added, if necessary.
(3) Anticoagulant citrate phosphate dextrose solution (CPD).
Tri-sodium citrate (Na3C6H5O72H2O).
Citric acid (C6H8O7H2O)......... 3.27 gm.
Dextrose (C6H12O6H2O)........... 25.5 gm.
Monobasic sodium phosphate (NaH2PO4H2O).
Water for injection (U.S.P.) to make...... 1,000 ml.
Volume per 100 ml. blood.................. 14 ml.
(4) Anticoagulant citrate phosphate dextrose adenine solution (CPDA-
1).
Tri-sodium citrate (Na3C6H5O72H2O).
Citric acid (C6H8O7H2O)......... 3.27 gm.
Dextrose (C6H12O6H2O)........... 31.9 gm.
Monobasic sodium phosphate (NaH2PO4H2O).
Adenine (C5H5N5).......................... 0.275 gm.
Water for injection (U.S.P.) to make...... 1,000 ml.
Volume per 100 ml blood................... 14 ml.
(e) Donor identification. Each unit of blood shall be so marked or
identified by number or other symbol as to relate it to the individual
donor whose identity shall be established to the extent necessary for
compliance with Sec. 640.3.
(f) Prevention of contamination of the blood. The skin of the donor
at the site of phlebotomy shall be prepared thoroughly and carefully by
a method that gives maximum assurance of a sterile container of blood.
The blood shall be collected by aseptic methods in a sterile system
which may be closed or may be vented if the vent protects the blood
against contamination.
(g) Pilot samples for laboratory tests. Pilot samples for laboratory
tests shall meet the following standards:
(1) One or more pilot samples shall be provided with each unit of
blood when issued or reissued except as provided in Sec. 640.2(e)(2) and
all pilot samples shall be from the donor who is the source of the unit
of blood.
(2) All samples for laboratory tests performed by the manufacturer
and all pilot samples accompanying a unit of blood shall be collected at
the time of filling the final container by the person who collects the
unit of blood.
(3) All containers for all samples shall bear the donor's
identification before collecting the samples.
(4) All containers for pilot samples accompanying a unit of blood
shall be attached to the whole blood container before blood collection,
in a tamperproof manner that will conspicuously indicate removal and
reattachment.
(5) When CPDA-1 is used, pilot samples for compatibility testing
shall contain blood mixed with CPDA-1.
(h) Phlebotomy for Heparin Whole Blood. Heparin Whole Blood shall be
collected with minimal damage to and minimal manipulation of the donor's
tissue, and with a single, uninterrupted, freeflowing venipuncture.
(i) Storage. Immediately after collection, unless the blood is to be
used as a source for Platelets, it shall be placed in storage at a
temperature between 1 deg. and 6 deg. C unless it must be transported
from the donor clinic to the processing laboratory. In the latter case,
the blood shall be placed in temporary storage having sufficient
refrigeration
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capacity to cool the blood continuously toward a range between 1 deg.
and 6 deg. C until it arrives at the processing laboratory, where it
shall be stored at a temperature between 1 deg. and 6 deg. C. Blood from
which Platelets is to be prepared shall be held in an environment
maintained at a temperature range 20 deg. to 24 deg. C until the
platelets are separated. The red blood cells shall be placed in storage
at a temperature between 1 deg. and 6 deg. C immediately after the
platelets are separated.
[38 FR 32089, Nov. 20, 1973, as amended at 42 FR 59878, Nov. 22, 1977;
43 FR 34460, Aug. 4, 1978; 49 FR 23834, June 8, 1984; 50 FR 4138, Jan.
29, 1985; 55 FR 11013, Mar. 26, 1990]
Sec. 640.5 Testing the blood.
All laboratory tests shall be made on a pilot sample specimen of
blood taken from the donor at the time of collecting the unit of blood,
and these tests shall include the following:
(a) Serological test for syphilis. Whole Blood shall be negative to
a serological test for syphilis.
(b) Determination of blood group. Each container of Whole Blood
shall be classified as to ABO blood group. At least two blood group
tests shall be made and the unit shall not be issued until grouping
tests by different methods or with different lots of antiserums are in
agreement. Only those Anti-A and Anti-B Blood Grouping Reagents licensed
under, or that otherwise meet the requirements of, the regulations of
this subchapter shall be used, and the technique used shall be that for
which the serum is specifically designed to be effective.
(c) Determination of the Rh factors. Each container of Whole Blood
shall be classified as to Rh type on the basis of tests done on the
pilot sample. The label shall indicate the extent of typing and the
results of all tests performed. If the test, using Anti-D Blood Grouping
Reagent, is positive, the container may be labeled ``Rh Positive''. If
this test is negative, the results shall be confirmed by further testing
which may include tests for the Rho variant (Du) and for other
Rh-Hr factors. Blood maybe labeled ``Rh Negative'' if negative to tests
for the Rho (D) and Rho variant (Du) factors. If the test
using Anti-D Blood Grouping Reagent is negative, but not tested for the
Rho variant (Du), the label must indicate that this test was
not done. Only Anti-Rh Blood Grouping Reagents licensed under, or that
otherwise meet the requirements of, the regulations of this subchapter
shall be used, and the technique used shall be that for which the serum
is specifically designed to be effective.
(d) Sterility test. Whole Blood intended for transfusion shall not
be tested for sterility by a method that entails entering the final
container before the blood is used for transfusion.
(e) Inspection. Whole Blood shall be inspected visually during
storage and immediately prior to issue. If the color or physical
appearance is abnormal or there is any indication or suspicion of
microbial contamination the unit of Whole Blood shall not be issued for
transfusion.
(f) Test for antibody to HIV. Whole Blood shall be tested for
antibody to HIV as prescribed in Sec. 610.45 of this chapter.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985; 53
FR 117, Jan. 5, 1988; 53 FR 12764, Apr. 19, 1988]
Sec. 640.6 Modifications of Whole Blood.
Upon approval by the Director, Center for Biologics Evaluation and
Research, of a supplement to the product license application for Whole
Blood a manufacturer may prepare Whole Blood from which the
antihemophilic factor has been removed, provided the Whole Blood meets
the applicable requirements of this subchapter and the following
conditions are met:
(a) The antihemophilic factor shall be removed in accordance with
paragraphs (a), (b), and (c) of Sec. 640.52.
(b) Although the closed system between the red blood cells and
plasma shall be maintained, the red blood cells shall be maintained
between 1 and 6 deg. C at all times, including that time when the plasma
is being frozen for removal of the antihemophilic factor.
(c) If containers for pilot samples are detached from the blood
container during removal of the antihemophilic factor the pilot samples
shall be reattached to the unit of Whole Blood Cryoprecipitate Removed
as soon as the plasma is returned to the red blood
[[Page 124]]
cells. The reattachment of the pilot samples shall be in a tamperproof
manner that will conspicuously indicate removal and reattachment.
[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 50
FR 4138, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept.
28, 1994]
Subpart B--Red Blood Cells
Sec. 640.10 Red Blood Cells.
The proper name of this product shall be Red Blood Cells. The
product is defined as red blood cells remaining after separating plasma
from human blood.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4138, Jan. 29, 1985]
Sec. 640.11 General requirements.
(a) Storage. Immediately after processing, the Red Blood Cells shall
be placed in storage and maintained at a temperature between 1 deg. and
6 deg. C.
(b) Inspection. The product shall be inspected immediately after
separation of the plasma, periodically during storage, and at the time
of issue. The product shall not be issued if there is any abnormality in
color or physical appearance or if there is any indication of microbial
contamination.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 42
FR 59878, Nov. 11, 1977; 50 FR 4139, Jan. 29, 1985]
Sec. 640.12 Suitability of donor.
The source blood for Red Blood Cells shall be obtained from a donor
who meets the criteria for donor suitability prescribed in Sec. 640.3.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985]
Sec. 640.13 Collection of the blood.
(a) The source blood shall be collected as prescribed in Sec. 640.4,
except that paragraphs (d)(2), and (g), and (h) shall not apply.
(b) Source blood may also be derived from Whole Blood manufactured
in accordance with applicable provisions of this subchapter.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985]
Sec. 640.14 Testing the blood.
Blood from which Red Blood Cells are prepared shall be tested as
prescribed in Secs. 610.40 and 610.45 of this chapter and Sec. 640.5
(a), (b), and (c).
[53 FR 117, Jan. 5, 1988]
Sec. 640.15 Pilot samples.
Pilot samples collected in integral tubing or in separate pilot
tubes shall meet the following standards:
(a) One or more pilot samples of either the original blood or of the
Red Blood Cells being processed shall be provided with each unit of Red
Blood Cells when issued or reissued.
(b) Before they are filled, all pilot sample tubes shall be marked
or identified so as to relate them to the donor of that unit of red
cells.
(c) Before the final container is filled or at the time the final
product is prepared, the pilot sample tubes to accompany a unit of cells
shall be attached securely to the final container in a tamper proof
manner that will conspicuously indicate removal and reattachment.
(d) All pilot sample tubes accompanying a unit of Red Blood Cells
shall be filled at the time the blood is collected or at the time the
final product is prepared, in each instance by the person who performs
the collection or preparation.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4139, Jan. 29, 1985]
Sec. 640.16 Processing.
(a) Separation. Within 21 days from date of blood collection (within
35 days from date of blood collection when CPDA-1 solution is used as
the anticoagulant), Red Blood Cells may be prepared either by
centrifugation done in a manner that will not tend to increase the
temperature of the blood or by normal undisturbed sedimentation. A
portion of the plasma sufficient to insure optimal cell preservation
shall be left with the red cells except when a cryoprotective substance
is added for prolonged storage.
(b) Sterile system. All surfaces that come in contact with the red
cells shall be sterile and pyrogen-free. If an open system is used, that
is, where the
[[Page 125]]
transfer container is not integrally attached to the blood container,
and the blood container is entered after blood collection, the plasma
shall be separated from the red blood cells with positive pressure
maintained on the original container until completely sealed. If the
method of separation involves a vented system, that is, when an airway
must be inserted in the container for withdrawal of the plasma, the
airway and vent shall be sterile and constructed so as to exclude
microorganisms and maintain a sterile system.
(c) Final containers. Final containers used for Red Blood Cells
shall be the original blood containers unless the method of processing
requires a different container. The final container shall meet the
requirements for blood containers prescribed in Sec. 640.2(c). At the
time of filing, if a different container is used, it shall be marked or
identified by number or other symbol so as to relate it to the donor of
that unit of red cells.
[38 FR 32089, Nov. 20, 1973, as amended at 43 FR 34460, Aug. 4, 1978; 50
FR 4139, Jan. 29, 1985]
Sec. 640.17 Modifications for specific products.
Red Blood Cells Frozen: A cryophylactic substance may be added to
the Red Blood Cells for extended manufacturers' storage at -65 deg. C.
or colder, provided the manufacturer submits data considered by the
Director, Center for Biologics Evaluation and Research, as adequately
demonstrating through in vivo cell survival and other appropriate tests
that the addition of the substance, the materials used and the
processing methods results in a final product that meets the required
standards of safety, purity, and potency for Red Blood Cells, and that
the frozen product will maintain those properties for the prescribed
dating period. Section 640.11 (a) and (b) do not apply while a
cryophylactic substance is present.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 18292, May 3, 1976; 49
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26,
1990]
Subpart C--Platelets
Sec. 640.20 Platelets.
(a) Proper name and definition. The proper name of this product
shall be Platelets. The product is defined as platelets collected from
one unit of blood and resuspended in an appropriate volume of original
plasma, as prescribed in Sec. 640.24(d).
(b) Source. The source material for Platelets shall be plasma which
may be obtained by whole blood collection, by plasmapheresis, or by
plateletpheresis.
[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 50
FR 4139, Jan. 29, 1985]
Sec. 640.21 Suitability of donors.
(a) Whole blood donors shall meet the criteria for suitability
prescribed in Sec. 640.3.
(b) Plasmapheresis donors shall meet the criteria for suitability
prescribed in Sec. 640.63, excluding the phrase ``other than malaria''
in paragraph (c)(9). Informed consent shall be required as prescribed in
Sec. 640.61.
(c) Plateletpheresis donors shall meet criteria for suitability as
described in a license application or a supplement to the product
license, and must have the written approval of the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration.
[40 FR 4304, Jan. 29, 1975, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]
Sec. 640.22 Collection of source material.
(a) Whole blood used as the source of Platelets shall be collected
as prescribed in Sec. 640.4, except that paragraphs (d)(2) and (h) shall
not apply.
(b) If plasmapheresis is used, the procedure for collection shall be
prescribed in Secs. 640.62, 640.64 (except paragraph (c)(3)), and
640.65.
(c) If plateletpheresis is used, the procedure for collection shall
be as described in a license application or a supplement to a product
license, and must have the written approval of the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration.
[[Page 126]]
(d) The phlebotomy shall be performed by a single uninterrupted
venipuncture with minimal damage to, and minimal manipulation of, the
donor's tissue.
[40 FR 4304, Jan. 29, 1975, as amended at 45 FR 27927, Apr. 25, 1980; 49
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26,
1990; 59 FR 49351, Sept. 28, 1994]
Sec. 640.23 Testing the blood.
(a) Blood from which plasma is separated for the preparation of
Platelets shall be tested as prescribed in Secs. 610.40 and 610.45 of
this chapter and Sec. 640.5 (a), (b), and (c).
(b) The tests shall be performed on a sample of blood collected at
the time of collecting the source blood, and such sample container shall
be labeled with the donor's number before the container is filled.
[40 FR 4304, Jan. 29, 1975, as amended at 50 FR 4139, Jan. 29, 1985; 53
FR 117, Jan. 5, 1988]
Sec. 640.24 Processing.
(a) Separation of plasma and platelets and resuspension of the
platelets shall be in a closed system. Platelets shall not be pooled
during processing.
(b) Immediately after collection, the whole blood or plasma shall be
held in storage between 20 deg. to 24 deg. C, unless it must be
transported from the donor clinic to the processing laboratory. During
such transport, all reasonable methods shall be used to maintain the
temperature as close as possible to a range between 20 deg. and 24 deg.
C until it arrives at the processing laboratory where it shall be held
between 20 deg. and 24 deg. C until the platelets are separated. The
platelet concentrate shall be separated within 4 hours after the
collection of the unit of whole blood or plasma.
(c) The time and speed of centrifugation must have been demonstrated
to produce an unclumped product, without visible hemolysis, that yields
a count of not less than 5.5 x 1010 platelets per unit in at least
75 percent of the units tested.
(d) The volume of original plasma used for resuspension of the
platelets shall be determined by the maintenance of a pH of not less
than 6.0 during the storage period. The pH shall be measured on a sample
of platelets which has been stored for the maximum dating period at the
selected storage temperature. One of the following storage temperatures
shall be used continuously:
(1) 20 deg. to 24 deg. C.
(2) 1 deg. to 6 deg. C.
(e) Final containers used for Platelets shall be colorless and
transparent to permit visual inspection of the contents; any closure
shall maintain a hermetic seal and prevent contamination of the
contents. The container material shall not interact with the contents,
under the customary conditions of storage and use, in such a manner as
to have an adverse effect upon the safety, purity, potency, or efficacy
of the product. At the time of filling, the final container shall be
marked or identified by number so as to relate it to the donor.
[40 FR 4304, Jan. 29, 1975, as amended at 42 FR 10983, Feb. 25, 1977; 47
FR 49021, Oct. 29, 1982; 50 FR 4139, Jan. 29, 1985]
Sec. 640.25 General requirements.
(a) Storage. Immediately after resuspension, Platelets shall be
placed in storage at the selected temperature range. If stored at
20 deg. to 24 deg. C, a continuous gentle agitation of the platelet
concentrate shall be maintained throughout the storage period. Agitation
is optional if stored at a temperature between 1 deg. and 6 deg. C.
(b) Quality control testing. Each month four units prepared from
different donors shall be tested at the end of the storage period as
follows:
(1) Platelet count.
(2) pH of not less than 6.0 measured at the storage temperature of
the unit.
(3) Measurement of actual plasma volume.
(4) If the results of the quality control testing indicate that the
product does not meet the prescribed requirements, immediate corrective
action shall be taken and a record maintained of such action.
(c) Manufacturing responsibility. All manufacturing of Platelets
shall be performed at the same licensed establishment, except that the
quality control testing under paragraph (b) of this section may be
performed by a clinical laboratory which meets the standards
[[Page 127]]
of the Clinical Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C.
263a) and is qualified to perform platelet counts. Such arrangements
must be approved by the Director, Center for Biologics Evaluation and
Research, Food and Drug Administration. Such testing shall not be
considered as divided manufacturing, as described in Sec. 610.63 of this
chapter, provided the following conditions are met:
(1) The results of each test are received within 10 days of the
preparation of the platelet concentrate, and are maintained by the
establishment licensed for Platelets so that they may be reviewed by an
authorized representative of the Food and Drug Administration.
(2) The licensed Platelets manufacturer has obtained a written
agreement that the testing laboratory will permit an authorized
representative of the Food and Drug Administration to inspect its
testing procedures and facilities during reasonable business hours.
(3) The testing laboratory will participate in any proficiency
testing programs undertaken by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
[40 FR 4304, Jan. 29, 1975, as amended at 47 FR 49021, Oct. 29, 1982; 49
FR 23834, June 8, 1984; 50 FR 4139, Jan. 29, 1985; 55 FR 11013, Mar. 26,
1990]
Sec. 640.27 Emergency provisions.
The use of the plateletpheresis procedure to obtain a product for a
specific recipient may be at variance with Secs. 640.21(c) and
640.22(c): Provided, That: (a) A licensed physician has determined that
the recipient must be transfused with the platelets from a specific
donor, and (b) the plateletpheresis procedure is performed under the
supervision of a qualified licensed physician who is aware of the health
status of the donor and the physician has certified in writing that the
donor's health permits plateletpheresis.
[40 FR 53544, Nov. 18, 1975]
Subpart D--Plasma
Sec. 640.30 Plasma.
(a) Proper name and definition. The proper name of this product
shall be Plasma. The product is defined as the fluid portion of one unit
of human blood intended for intravenous use which in a closed system,
has been collected, stabilized against clotting, and separated from the
red blood cells.
(b) Source. (1) Plasma shall be obtained by separating plasma from
blood collected from blood donors or by plasmapheresis.
(2) Plasma may be obtained from a unit of Whole Blood collected by
another licensed establishment.
[42 FR 59878, Nov. 22, 1977; 48 FR 13026, Mar. 29, 1983, as amended at
50 FR 4139, Jan. 29, 1985]
Sec. 640.31 Suitability of donors.
(a) Whole blood donors shall meet the criteria for donor suitability
prescribed in Sec. 640.3.
(b) Plasmapheresis donors shall meet the criteria for donor
suitability prescribed in Sec. 640.63, excluding the phrase ``other than
malaria'' in paragraph (c)(9) of that section. Informed consent shall be
required as prescribed in Sec. 640.61.
(c) Donors shall not be suitable if they are known to have been
immunized within the past 6 months by injection with human red blood
cells.
[42 FR 59878, Nov. 22, 1977]
Sec. 640.32 Collection of source material.
(a) Whole blood shall be collected, transported, and stored as
prescribed in Sec. 640.4, except that paragraphs (d)(2) and (h) of that
section shall not apply. When whole blood is intended for Plasma, Fresh
Frozen Plasma, and Liquid Plasma, it shall be maintained at a
temperature between 1 deg. and 6 deg. C until the plasma is removed.
Whole blood intended for Platelet Rich Plasma, shall be maintained as
prescribed in Sec. 640.24 until the plasma is removed. The red blood
cells shall be placed in storage at
[[Page 128]]
a temperature between 1 deg. and 6 deg. C immediately after the plasma
is separated.
(b) Plasma obtained by plasmapheresis shall be collected as
prescribed in Secs. 640.62, 640.64 (except that paragraph (c)(3) of
Sec. 640.64 shall not apply), and Sec. 640.65.
[42 FR 59878, Nov. 22, 1977, as amended at 45 FR 27927, Apr. 25, 1980;
50 FR 4139, Jan. 29, 1985]
Sec. 640.33 Testing the blood.
(a) Blood from which plasma is separated shall be tested as
prescribed in Secs. 610.40 and 610.45 of this chapter and Sec. 640.5
(a), (b), and (c).
(b) Manufacturers of Plasma collected by plasmapheresis shall have
testing and recordkeeping responsibilities equivalent to those
prescribed in Secs. 640.71 and 640.72.
[42 FR 59878, Nov. 22, 1977, as amended at 44 FR 17658, Mar. 23, 1979;
50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988]
Sec. 640.34 Processing.
(a) Plasma. Plasma shall be separated from the red blood cells
within 26 days after phlebotomy (within 40 days after phlebotomy when
CPDA-1 solution is used as the anticoagulant), and shall be stored at
-18 deg. C or colder within 6 hours after transfer to the final
container, unless the product is to be stored as Liquid Plasma .
(b) Fresh Frozen Plasma. Fresh Frozen Plasma shall be prepared from
blood collected by a single uninterrupted venipuncture with minimal
damage to and minimal manipulation of the donor's tissue. The plasma
shall be separated from the red blood cells, frozen solid within 6 hours
after phlebotomy, and stored at -18 deg. C or colder.
(c) Liquid Plasma. Liquid Plasma shall be separated from the red
blood cells within 26 days after phlebotomy (within 40 days after
phlebotomy when CPDA-1 solution is used as the anticoagulant) and shall
be stored at a temperature of 1 deg. to 6 deg. C within 4 hours after
filling the final container.
(d) Platelet Rich Plasma. Platelet Rich Plasma shall be prepared
from blood collected by a single uninterrupted venipuncture with minimal
damage to and manipulation of the donor's tissue. The plasma shall be
separated from the red blood cells by centrifugation within 4 hours
after phlebotomy. The time and speed of centrifugation shall have been
shown to produce a product with at least 250,000 platelets per
microliter. The plasma shall be stored at a temperature between 20 deg.
to 24 deg. C or between 1 deg. and 6 deg. C, immediately after filling
the final container. A gentle and continuous agitation of the product
shall be maintained throughout the storage period, if stored at a
temperature of 20 deg. to 24 deg. C.
(e) Modifications of Plasma. It is possible to separate Platelets
and/or Cryoprecipitated AHF from Plasma. When these components are to be
separated, the plasma shall be collected as described in Sec. 640.32 for
Plasma.
(1) Platelets shall be separated as prescribed in subpart C of part
640, prior to freezing the plasma. The remaining plasma may be labeled
as Fresh Frozen Plasma, if frozen solid within 6 hours after phlebotomy.
(2) Cryoprecipitated AHF shall be removed as prescribed in Subpart F
of part 640. The remaining plasma may be labeled Plasma.
(3) Plasma remaining after both Platelets and Cryoprecipitated AHF
have been removed may be labeled Plasma.
(f) The final container. (1) The final container shall have no color
added to the plastic and shall be transparent to permit visual
inspection of the contents; any closure shall maintain a hermetic seal
and prevent contamination of the contents.
(2) The final container material shall not interact with the
contents, under the customary conditions of storage and use, in such a
manner as to have an adverse effect upon the safety, purity, potency,
and effectiveness of the product.
(3) Prior to filling, the final container shall be identified by
number so as to relate it to the donor.
(g) The final product. (1) The final product shall be inspected
immediately after separation of the plasma and shall not be issued for
transfusion if there is (i) any abnormality in color or physical
appearance, or (ii) any indication of contamination.
(2) With the exception of Platelet Rich Plasma and Liquid Plasma,
the
[[Page 129]]
final product shall be stored in a manner that will show evidence of
thawing and shall not be issued if there is any evidence of thawing of
the product during storage or breakage of the container.
(3) No preservative shall be added to the final product.
[42 FR 59878, Nov. 22, 1977, as amended at 43 FR 34460, Aug. 4 1978; 48
FR 13026, Mar. 29, 1983; 50 FR 4139, Jan. 29, 1985]
Subpart E--[Reserved]
Subpart F--Cryoprecipitate
Sec. 640.50 Cryoprecipitated AHF.
(a) Proper name and definition. The proper name of this product
shall be Cryoprecipitated AHF. The product is defined as a preparation
of antihemophilic factor, which is obtained from a single unit of plasma
collected and processed in a closed system.
(b) Source. The source material for Cryoprecipitated AHF shall be
plasma which may be obtained by whole blood collection or by
plasmapheresis.
[42 FR 21774, Apr. 29, 1977; 48 FR 13026, Mar. 29, 1983; as amended at
50 FR 4139, Jan. 29, 1985]
Sec. 640.51 Suitability of donors.
(a) Whole blood donors shall meet the criteria for suitability
prescribed in Sec. 640.3.
(b) Plasmaphersis donors shall meet the criteria for suitability
prescribed in Sec. 640.63, excluding the phrase ``other than malaria''
in paragraph (c) (9) of that section. Informed consent shall be required
as prescribed in Sec. 640.61.
(c) Donors shall not be suitable if they are known to have been
immunized by injection with human red blood cells within the last 6
months.
[42 FR 21774, Apr. 29, 1977]
Sec. 640.52 Collection of source material.
(a) Whole blood used as a source of Cryoprecipitated AHF shall be
collected as prescribed in Sec. 640.4, except that paragraphs (d) (2),
(g), and (h) of that section shall not apply. Whole blood from which
both Platelets and Cryoprecipitated AHF is derived shall be maintained
as required under Sec. 640.24 until the platelets are removed.
(b) If plasmapheresis is used, the procedure for collection shall be
as prescribed in Secs. 640.62, 640.64 (except that paragraph (c)(3) of
that section shall not apply), and 640.65.
[42 FR 21774, Apr. 29, 1977, as amended by 50 FR 4139, Jan. 29, 1985]
Sec. 640.53 Testing the blood.
(a) Blood from which plasma is separated for the preparation of
Cryoprecipitated AHF shall be tested as prescribed in Secs. 610.40 and
610.45 of this chapter and Sec. 640.5 (a), (b), and (c).
(b) The tests shall be performed on a sample of blood collected at
the time of collecting the source blood, and such sample container shall
be labeled with the donor's number before the container is filled.
(c) Manufacturers of Cryoprecipitated AHF obtained from plasma
collected by plasmapheresis shall have testing and record-keeping
responsibilities equivalent to those prescribed in Secs. 640.71 and
640.72.
[42 FR 21774, Apr. 29, 1977, as amended at 42 FR 37546, July 22, 1977;
42 FR 43063, Aug. 26, 1977; 50 FR 4139, Jan. 29, 1985; 53 FR 117, Jan.
5, 1988]
Sec. 640.54 Processing.
(a) Processing the plasma. (1) The plasma shall be separated from
the red blood cells by centrifugation to obtain essentially cell-free
plasma.
(2) The plasma shall be frozen solid within 6 hours after blood
collection. A combination of dry ice and organic solvent may be used for
freezing: Provided, That the procedure has been shown not to cause the
solvent to penetrate the container or leach plasticizer from the
container into the plasma.
(3) Immediately after separation and freezing of the plasma, the
plasma shall be stored and maintained at --18 deg. C or colder until
thawing of the plasma for further processing to remove the
Cryoprecipitated AHF.
(b) Processing the final product. (1) The Cryoprecipitated AHF shall
be separated from the plasma by a procedure that has been shown to
produce an average of no less than 80 units of antihemophilic factor per
final container.
[[Page 130]]
(2) No diluent shall be added to the product by the manufacturer
prior to freezing.
(3) The final container used for Cryoprecipitated AHF shall be
colorless and transparent to permit visual inspection of the contents;
any closure shall maintain a hermetic seal and prevent contamination of
the contents. The container material shall not interact with the
contents under customary conditions of storage and use in such a manner
as to have an adverse effect upon the safety, purity, potency and
effectiveness of the product. At the time of filling, the final
container shall be identified by a number so as to relate it to the
donor.
[42 FR 21774, Apr. 29, 1977, as amended at 47 FR 15330, Apr. 9, 1982; 50
FR 4139, Jan. 29, 1985]
Sec. 640.55 U.S. Standard preparation.
A U.S. Standard Antihemophilic Factor (Factor VIII) preparation may
be obtained from the Center for Biologics Evaluation and Research, Food
and Drug Administration, for use in the preparation of a working
reference to be employed in a quality control potency test of
Cryoprecipitated AHF.
[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]
Sec. 640.56 Quality control test for potency.
(a) Quality control tests for potency of antihemophilic factor shall
be conducted each month on at least four representative containers of
Cryoprecipitated AHF.
(b) The results of each test are received by the establishment
licensed for Cryoprecipitated AHF within 30 days of the preparation of
the cryoprecipitated antihemophilic factor and are maintained at that
establishment so that they may be reviewed by an authorized
representative of the Food and Drug Administration.
(c) The quality control test for potency may be performed by a
clinical laboratory which meets the standards of the Clinical
Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C. 263a) and is
qualified to perform potency tests for antihemophilic factor. Such
arrangements must be approved by the Director, Center for Biologics
Evaluation and Research, Food and Drug Administration. Such testing
shall not be considered as divided manufacturing, as described in
Sec. 610.63 of this chapter, provided the following conditions are met:
(1) The establishment licensed for Cryoprecipitated AHF has obtained
a written agreement that the testing laboratory will permit an
authorized representative of the Food and Drug Administration to inspect
its testing procedures and facilities during reasonable business hours.
(2) The testing laboratory will participate in any proficiency
testing programs undertaken by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
(d) If the average potency level of antihemophilic factor in the
containers tested is less than 80 units of antihemophilic factor per
container, immediate corrective actions shall be taken and a record
maintained of such action.
[42 FR 21774, Apr. 29, 1977, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]
Subpart G--Source Plasma
Sec. 640.60 Source Plasma.
The proper name of the product shall be Source Plasma. The product
is defined as the fluid portion of human blood collected by
plasmapheresis and intended as source material for further manufacturing
use. The definition excludes single donor plasma products intended for
intravenous use.
[41 FR 10768, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985]
Sec. 640.61 Informed consent.
The written consent of a prospective donor shall be obtained after a
qualified licensed physician has explained the hazards of the procedure
to the prospective donor. The explanation shall include the risks of a
hemolytic transfusion reaction if he is given the cells of another
donor, and the hazards involved if he is hyperimmunized. The explanation
shall consist of such disclosure and be made in such a manner that
intelligent and informed consent
[[Page 131]]
be given and that a clear opportunity to refuse is presented.
Sec. 640.62 Medical supervision.
A qualified licensed physician shall be on the premises when donor
suitability is being determined, immunizations are being made, whole
blood is being collected, and red blood cells are being returned to the
donor.
Sec. 640.63 Suitability of donor.
(a) Method of determining. The suitability of a donor for Source
Plasma shall be determined by a qualified licensed physician or by
persons under his supervision and trained in determining donor
suitability. Such determination shall be made on the day of collection
from the donor by means of a medical history, tests, and such physical
examination as appears necessary to the qualified licensed physician.
(b) Initial medical examinations. (1) Each donor shall be examined
by a qualified licensed physician on the day of the first donation or no
more than 1 week before the first donation and at subsequent intervals
of no longer than 1 year.
(2)(i) A donor who is to be immunized for the production of high-
titer plasma shall be examined by a qualified licensed physician. The
medical examination shall be performed within no more than 1 week before
the first immunization injection. The medical examination for
plasmapheresis need not be repeated, if the first donation occurs within
3 weeks after the first injection.
(ii) A donor who is an active participant in a plasmapheresis
program, and has been examined in accordance with paragraph (b)(1) of
this section, need not be reexamined before immunization for the
production of high-titer plasma.
(3) Each donor shall be certified to be in good health by the
examining physician. The certification of good health shall be on a form
supplied by the licensed establishment and shall indicate that the
certification applies to the suitability of the individual to be a
plasmapheresis donor and, when applicable, an immunized donor.
(c) Qualification of donor. Donors shall be in good health on the
day of donation, as indicated in part by:
(1) Normal temperature;
(2) Demonstration that systolic and diastolic blood pressures are
within normal limits, unless the examining physician is satisfied that
an individual with blood pressures outside these limits is an otherwise
qualified donor under the provisions of this section;
(3) A blood hemoglobin level of no less than 12.5 grams of
hemoglobin per 100 milliliters of blood;
(4) A normal pulse rate;
(5) A total serum protein of no less than 6.0 grams per 100
milliliters of serum;
(6) Weight, which shall be at least 110 pounds;
(7) Freedom from acute respiratory diseases;
(8) Freedom from any infectious skin disease at the site of
phlebotomy and from any such disease generalized to such an extent as to
create a risk of contamination of the plasma;
(9) Freedom from any disease, other than malaria, transmissible by
blood transfusion, insofar as can be determined by history and
examinations indicated in this section;
(10) Freedom of the arms and forearms from skin punctures or scars
indicative of addiction to self-injected narcotics;
(11) Freedom from a history of viral hepatitis;
(12) Freedom from a history of close contact within six months of
donation with an individual having viral hepatitis;
(13) Freedom from a history of having received, within six months,
human blood or any derivative of human blood which the Food and Drug
Administration has advised the licensed establishment is a possible
source of viral hepatitis, except for specific immunization performed in
accordance with Sec. 640.66 of this part.
(d) General. Any donor who, in the opinion of the interviewer,
appears to be under the influence of any drug, alcohol, or for any
reason does not appear to be providing reliable answers to medical
history questions, shall not be considered a suitable donor.
(e) Failure to return red blood cells. Any donor who has not had the
red blood cells returned from a unit of
[[Page 132]]
blood collected during a plasmapheresis procedure or who has been a
donor of a unit of whole blood shall not be subjected to plasmapheresis
for a period of 8 weeks, unless:
(1) The donor has been examined by a qualified licensed physician
and certified by the physician to be acceptable for further
plasmapheresis before expiration of the 8-week period;
(2) The donor possesses an antibody that is (i) transitory, (ii) of
a highly unusual or infrequent specificity, or (iii) of an unusually
high titer; and
(3) The special characteristics of the antibody and the need for
plasmapheresing the donor are documented.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10768, Mar. 12, 1976;
43 FR 9805, Mar. 10, 1978; 43 FR 12311, Mar. 24, 1978; 46 FR 57480, Nov.
24, 1981; 50 FR 4140, Jan. 29, 1985]
Sec. 640.64 Collection of blood for Source Plasma.
(a) Supervision. All blood for the collection of Source Plasma shall
be drawn from the donor by a qualified licensed physician or by persons
under his supervision trained in the procedure.
(b) Blood containers. Blood containers and donor sets shall be
pyrogen-free, sterile and identified by lot number. The amount of
anticoagulant required for the quantity of blood to be collected shall
be in the blood container when it is sterilized.
(c) The anticoagulant solution. The anticoagulant solution shall be
sterile and pyrogen-free. One of the following formulas shall be used in
the indicated volumes, except that a different formula may be used for
plasma for manufacture into noninjectable products if prior written
approval is obtained from the Director of the Center for Biologics
Evaluation and Research at the time of licensing or in the form of a
supplement to the Source Plasma product license.
(1) Anticoagulant citrate dextrose solution (ACD).
Tri-sodium citrate (Na3C6H5O72H2O).
Citric acid (C6H8O7H2O)........ 8.0 grams.
Dextrose (C6H12O6H2O).................... 24.5 grams.
Water for injection (U.S.P.) to make..... 1,000 milliliters.
Volume per 100 milliliters blood......... 15 milliliters.
(2) Anticoagulant citrate phosphate dextrose solution (CPD).
Tri-sodium citrate (Na3C6H5O72H2O).
Citric acid (C6H8OH2O)......... 3.27 grams.
Dextrose (C6H12O6H2O).................... 25.5 grams.
Monobasic sodium phosphate (NaH2PO4H2O).
Water for injection (U.S.P.) to make..... 1,000 milliliters.
Volume per 100 milliliters blood......... 14 milliliters.
(3) Anticoagulant sodium citrate solution.
Tri-sodium citrate (Na3C6H5O72H2O).
Water for injection (U.S.P.) to make..... 1,000 milliliters.
Volume per 100 milliliters of blood...... 10 milliliters.
(d) Donor identification. Each unit of blood and plasma shall be so
marked or identified by number or other symbol so as to relate it
directly to the donor.
(e) Prevention of contamination of the blood and plasma. The skin of
the donor at the site of phlebotomy shall be prepared thoroughly and
carefully by a method that gives maximum assurance of a sterile
container of blood. The blood shall be collected, the plasma separated,
and the cells returned to the donor by aseptic methods in a sterile
system which may be closed, or may be vented if the vent protects the
blood cells and plasma against contamination.
[38 FR 32089, Nov. 20, 1973; 39 FR 13632, Apr. 16, 1974, as amended at
41 FR 10768, Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan.
29, 1985; 55 FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]
Sec. 640.65 Plasmapheresis.
(a) Procedure-general. The plasmapheresis procedure is a procedure
in which, during a single visit to the establishment, blood is removed
from a donor, the plasma separated from the formed elements, and at
least the red blood cells returned to the donor. This procedure shall be
described in detail in the product license application.
(b) Procedures-specific requirements. The plasmapheresis procedure
shall meet the following requirements:
(1)(i) A sample of blood shall be drawn from each donor on the day
of the first medical examination or plasmapheresis, whichever comes
first and at least every 4 months thereafter by a qualified licensed
physician or by persons under his supervision and trained in such
procedure. A serologic test for
[[Page 133]]
syphilis, a total plasma or serum protein determination, and a plasma or
serum protein electrophoresis or quantitative immuno-diffusion test or
an equivalent test to determine immunoglobulin composition of the plasma
or serum shall be performed on the sample.
(ii) A repeat donor who does not return for plasmapheresis at the
time the 4-month sample is due to be collected may be plasmapheresed on
the day he appears: Provided, That no longer than 6 months has elapsed
since the last sample was collected, and the physician on the premises
approves the plasmapheresis procedure and so indicates by signing the
donor's record before such procedure is performed. The sample for the 4-
month tests shall be collected on the day of the donor's return.
(iii) A repeat donor from whom the plasmapheresis center is unable
to obtain a sample for testing as prescribed in paragraph (b)(1)(i) of
this section for a total period exceeding 6 months shall be processed as
a new donor.
(2)(i) The accumulated laboratory data, including tracings, if any,
of the plasma or serum protein electrophoresis pattern, the calculated
values of each component, and the collection records shall be reviewed
by a qualified licensed physician within 21 days after the sample is
drawn to determine whether or not the donor may continue in the program.
The review shall be signed by the reviewing physician. If the protein
composition is not within normal limits established by the testing
laboratory, or if the total protein is less than 6.0 grams per 100
milliliters of samples, the donor shall be removed from the program
until these values return to normal.
(ii) A donor with a reactive serologic test for syphilis shall not
be plasmapheresed again until the donor's serum is tested and found to
be nonreactive to a serologic test for syphilis, except as provided in
paragraph (b)(2) (iii) and (iv) of this section.
(iii) A donor whose serum is determined to have a biologic false-
positive reaction to a serologic test for syphilis may be
plasmapheresed: Provided, That the donor's file identifies the serologic
test for syphilis and results used to confirm the biologic false-
positive reaction and indicates that the physician on the premises has
determined the false-positive reaction is not the result of an
underlying disorder that would disqualify the donor from participation
in the plasmapheresis program. If the serologic test for syphilis is
performed at a facility other than the plasmapheresis center, all
applicable provisions of Sec. 640.71 shall be met.
(iv) A donor with a reactive serologic test for syphilis may be
plasmapheresed only to obtain plasma to be used for further
manufacturing into control serum for the serologic test for syphilis:
Provided, That the physician on the premises approves the donation, the
donor's file contains a signed statement from a physician or clinic
establishing that treatment for syphilis has been initiated and that
continuance in the plasmapheresis program will not interfere with or
jeopardize the treatment of the syphilitic donor.
(3) A donor identification system shall be established that
positively identifies each donor and relates such donor directly to his
blood and its components as well as to his accumulated records and
laboratory data. Such system shall include either a photograph of each
donor which shall be used on each visit to confirm the donor's identity,
or some other method that provides equal or greater assurance of
positively identifying the donor.
(4) The amount of whole blood, not including anticoagulant, removed
from a donor during a plasmapheresis procedure or in any 48-hour period
shall not exceed 1,000 milliliters unless the donor's weight is 175
pounds or greater, in which case the amount of whole blood, not
including anticoagulant, removed from the donor during a plasmapheresis
procedure or in any 48-hour period shall not exceed 1,200 milliliters.
(5) The amount of whole blood, not including anticoagulant, removed
from a donor within a seven-day period shall not exceed 2,000
milliliters unless the donor's weight is 175 pounds or greater, in which
case the amount of whole blood, not including anticoagulant, removed
from the donor during a seven-day period shall not exceed 2,400
milliliters.
[[Page 134]]
(6) No more than 500 milliliters of whole blood shall be removed
from a donor at one time, unless the donor's weight is 175 pounds or
greater, in which case no more than 600 milliliters of whole blood shall
be removed from the donor at one time.
(7) The plasma shall be separated from the red blood cells
immediately after blood collection. The maximum feasible volume of red
blood cells shall be returned to the donor before another unit is
collected.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976]
Sec. 640.66 Immunization of donors.
If specific immunization of a donor is to be performed, the
selection and scheduling of the injection of the antigen, and the
evaluation of each donor's clinical response, shall be by a qualified
licensed physician or physicians. The administration of the antigen may
be performed by a licensed physician or a trained person under his
supervision. Any material used for immunization shall be either a
product licensed under section 351 of the Public Health Service Act for
such purpose or one specifically approved by the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration.
Immunization procedures shall be on file at each plasmapheresis center
where immunizations are performed.
[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 640.67 Laboratory tests.
(a) Hepatitis B surface antigen. Each unit of Source Plasma shall be
nonreactive to a test for hepatitis B surface antigen as prescribed in
Secs. 610.40 and 610.41 of this chapter, except insofar as permitted in
Sec. 610.40(d)(1) and (d)(2) of this chapter.
(b) Antibody to HIV. Each unit of Source Plasma shall be negative by
a test for antibody to HIV as prescribed in Sec. 610.45 of this chapter,
except as provided in Sec. 610.45(c) of this chapter.
[53 FR 117, Jan. 5, 1988, as amended at 57 FR 10814, Mar. 31, 1992]
Sec. 640.68 Processing.
(a) Sterile system. All administration and transfer sets inserted
into blood containers used for processing Source Plasma intended for
manufacturing into injectable or noninjectable products and all interior
surfaces of plasma containers used for processing Source Plasma intended
for manufacturing into injectable products shall be sterile, pyrogen-
free, nontoxic, and compatible with the contents under normal conditions
of use. Only Sodium Chloride Injection USP shall be used as a red blood
cell diluent. If the method of separation of the plasma intended for
injectable products involves a system in which an airway must be
inserted into the plasma container, the airway shall be sterile and
constructed so as to exclude microorganisms and maintain a sterile
system.
(b) Final containers. Final containers used for Source Plasma,
whether integrally attached or separated from the original blood
container, shall not be entered prior to issuance for any purpose except
for filling with the plasma. Such containers shall be uncolored and
hermetically sealed, and shall permit clear visibility of the contents.
Final containers and their components shall not interact with the plasma
contents under conditions of storage and use so as to alter the safety,
quality, purity, or potency of the plasma and shall provide adequate
protection against external factors that may cause deterioration or
contamination. Prior to filling, the final container shall be marked or
identified by number or other symbol which will relate it directly to
the donor.
(c) Preservative. Source Plasma shall not contain a preservative.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976;
50 FR 4140, Jan. 29, 1985]
Sec. 640.69 General requirements.
(a) Pooling. Two units of Source Plasma from the same donor may be
pooled if such units are collected during one plasmapheresis procedure:
Provided, That the pooling is done by a procedure that does not
introduce a risk of contamination of the red blood cells and, for plasma
intended for injectable
[[Page 135]]
products, gives maximum assurance of a sterile container of plasma.
(1) The pooling of plasma from two or more donors is not permitted
in the manufacture of Source Plasma intended for manufacturing into
injectable products.
(2) The pooling of plasma from two or more donors by the
manufacturer of Source Plasma intended for manufacturing into
noninjectable products is permitted: Provided, That the plasma from two
or more donors is pooled after the plasma has been removed from the red
blood cells, and after the red blood cell containers are sealed.
(b) Storage. Immediately after filling, plasma intended for
manufacturing into injectable products shall be stored at a temperature
not warmer than --20 deg. C., except for plasma collected as provided in
Sec. 640.74. Plasma intended for manufacturing into noninjectable
products may be stored at temperatures appropriate for the intended use
of the final product, provided these temperatures are included in the
Source Plasma license application.
(c) Inspection. Source Plasma intended for manufacturing into
injectable products shall be inspected for evidence of thawing at the
time of issuance, except that inspection of individual plasma containers
need not be made if the records of continuous monitoring of the storage
temperature establish that the temperature remained at --20 deg. C or
colder. If there is evidence that the storage temperature has not been
maintained at --20 deg. C or colder, the plasma may be relabeled and
issued as provided in Sec. 640.76(a).
(d) Pilot samples. If pilot samples are provided, they shall meet
the following standards:
(1) Prior to filling, all pilot samples shall be marked or
identified so as to relate them directly to the donor of that unit of
plasma.
(2) All pilot samples shall be filled at the time the final product
is prepared by the person who prepares the final product.
(3) All pilot samples shall be representative of the contents of the
final product.
(4) All pilot samples shall be collected in a manner that does not
contaminate the contents of the final container.
[38 FR 32089, Nov. 20, 1973, as amended at 41 FR 10769, Mar. 12, 1976;
41 FR 14367, Apr. 5, 1976; 50 FR 4140, Jan. 29, 1985]
Sec. 640.70 Labeling.
(a) In addition to the labeling requirements of Sec. 610.62 of this
chapter, and in lieu of the requirements in Secs. 606.121, 610.60, and
610.61 of this chapter, the following information shall appear on the
label affixed to each container of Source Plasma:
(1) The proper name of the product.
(2) The statement ``Caution: For Manufacturing Use Only'' for
products intended for further manufacturing into injectable products, or
the statement, ``Caution: For Use In Manufacturing Noninjectable
Products Only'', for products intended for further manufacturing into
noninjectable products. The statement shall follow the proper name in
the same size and type of print as the proper name.
(3) The statement ``Store at --20 deg. C. or colder'': Provided,
That where plasma is intended for manufacturing into noninjectable
products, this statement may be omitted if replaced by a statement of
the temperature appropriate for the final product to be prepared from
the plasma.
(4) The total volume or weight of plasma and total quantity and type
of anticoagulant used.
(5) The donor number or individual bleed number, or both. If plasma
is pooled from two or more donors, either all donor numbers, all bleed
numbers, or a pool number that is traceable to each individual unit
comprising the pool.
(6) The expiration date of the plasma. If plasma intended for
manufacturing into noninjectable products is pooled from two or more
donors the expiration date is determined from the collection date of the
oldest unit in the pool, and the pooling records shall show the
collection date for each unit constituting the pool.
(7) A statement as to whether the plasma was collected from normal
donors or from immunized donors. In the case of immunized donors, the
label shall state the immunizing antigen.
[[Page 136]]
(8) The test for hepatitis B surface antigen used for the results,
or the statement ``Nonreactive for HBsAg by FDA required test''.
(9) When plasma collected from a donor is reactive for the serologic
test for syphilis, a statement that the plasma is reactive and must be
used only for the manufacturing of positive control reagents for the
serologic test for syphilis.
(10) Name, address, and license number of the manufacturer.
(11) The statement ``Negative by a test for antibody to HIV'', or
equivalent statement.
(b) Source Plasma diverted for Source Plasma Salvaged shall be
relabeled ``Source Plasma Salvaged'' as prescribed in Sec. 640.76.
Immediately following the proper name of the product, the labeling shall
conspicuously state as applicable, ``STORAGE TEMPERATURE EXCEEDED --
20 deg. C'' or ``SHIPPING TEMPERATURE EXCEEDED --5 deg. C''.
[41 FR 10770, Mar. 12, 1976, as amended at 41 FR 27034, July 1, 1976; 41
FR 35062, Aug. 19, 1976; 47 FR 30969, July 16, 1982; 50 FR 4140, Jan.
29, 1985; 50 FR 35471, Aug. 30, 1985; 53 FR 117, Jan. 5, 1988]
Sec. 640.71 Manufacturing responsibility.
(a) All steps in the manufacture of Source Plasma, including donor
examination, blood collection, plasmapheresis, laboratory testing,
labeling, storage, and issuing shall be performed by personnel of the
establishment licensed to manufacture Source Plasma, except that the
following tests may be performed by personnel of an establishment
licensed for blood or blood derivatives under section 351(a) of the
Public Health Service Act, or by a clinical laboratory that meets the
standards of the Clinical Laboratories Improvement Act of 1967 (CLIA)
(42 U.S.C. 263a): Provided, The establishment or the clinical laboratory
is qualified to perform the assigned test(s).
(1) The test for hepatitis B surface antigen.
(2) The total plasma or serum protein and the quantitative test for
plasma or serum proteins or for immunoglobulins.
(3) The serologic test for syphilis.
(4) A test for antibody to HIV.
(b) Such testing shall not be considered divided manufacturing,
which requires two product licenses for Source Plasma: Provided, That
(1) The results of such tests are maintained by the establishment
licensed for Source Plasma whereby such results may be reviewed by a
licensed physician as required in Sec. 640.65(b)(2) and by an authorized
representative of the Food and Drug Administration.
(2) The Source Plasma manufacturer has obtained a written agreement
that the testing laboratory will permit authorized representatives of
the Food and Drug Administration to inspect its testing procedures and
facilities during reasonable business hours.
(3) The testing laboratory will participate in any proficiency
testing programs undertaken by the Center for Biologics Evaluation and
Research, Food and Drug Administration.
[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 53 FR 117, Jan. 5, 1988; 55 FR 11013, Mar. 26,
1990]
Sec. 640.72 Records.
(a) In addition to the recordkeeping requirements of this
subchapter, the following records shall be maintained:
(1) Documentation compiled every 3 months establishing that the
shipping temperature requirements of Sec. 600.15 of this title and
Sec. 640.74(b)(2) are being met for Source Plasma intended for
manufacture into injectable products.
(2) For each donor, a separate and complete record of all initial
and periodic examinations, tests, laboratory data, interviews, etc.,
undertaken pursuant to Secs. 640.63, 640.65, 640.66, and 640.67, except
that negative test results for hepatitis B surface antigen, negative
test results for antibody to HIV, and the volume or weight of plasma
withdrawn from a donor need not be kept on the individual donor record:
Provided, That such information is maintained on the premises of the
plasmapheresis center where the donor's plasma has been collected.
(3) The original or a clear copy of the donor's written consent for
participation in the plasmapheresis program or for immunization.
[[Page 137]]
(4) The certification of the donor's good health as prescribed in
Sec. 640.63(b)(3).
(5) If plasma that is reactive to a serologic test for syphilis is
issued as prescribed in Sec. 640.65(b)(2)(iv), the distribution records
shall indicate by number those units that are reactive.
(b) Each donor record must be directly cross-referenced to the
unit(s) of Source Plasma associated with the donor.
(c) If a repeat donor is rejected or a donor's plasma is found
unsuitable, the donor's record shall contain a full explanation for the
rejection.
(d) If a donor has a reaction while on the plasmapheresis premises,
or a donor reaction is reported to the center after the donor has left
the premises, the donor's record shall contain a full explanation of the
reaction, including the measures taken to assist the donor and the
outcome of the incident.
(Collection of information requirements approved by the Office of
Management and Budget under control number 0910-0227)
[41 FR 10770, Mar. 12, 1976, as amended at 50 FR 4140, Jan. 29, 1985; 53
FR 117, Jan. 5, 1988]
Sec. 640.73 Reporting of fatal donor reactions.
If a donor has a fatal reaction which, in any way, may be associated
with plasmapheresis the Director of the Center for Biologics Evaluation
and Research shall be notified by telephone as soon as possible. If the
facility is located outside of the continental United States,
notification by cable or telegram shall be acceptable.
[41 FR 10770, Mar. 12, 1976, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 640.74 Modification of Source Plasma.
(a) Upon approval by the Director, Center for Biologics Evaluation
and Research, Food and Drug Administration, of a supplement to the
product license for Source Plasma, a manufacturer may prepare Source
Plasma as a liquid product for a licensed blood derivative manufacturer
who has indicated a need for a liquid product.
(b) Source Plasma Liquid shall meet all standards of the frozen
Source Plasma except:
(1) Source Plasma Liquid shall be stored in nonleachable containers
so that the containers and their components will not interact with the
plasma contents under conditions of storage and use so as to alter the
safety, quality, purity, or potency of the plasma and shall provide
adequate protection against external factors that may cause
deterioration or contamination.
(2) Source Plasma Liquid shall be shipped, stored and labeled for
storage at a temperature of 10 deg.C. or colder. An exception to the
shipping or storage temperature shall be approved by the Director,
Center for Biologics Evaluation and Research, Food and Drug
Administration, based upon his receipt of substantial evidence to
support another temperature. Such evidence may be submitted by either
the product licensee of the Source Plasma Liquid or the manufacturer of
the final blood derivative product who has requested the Source Plasma
Liquid.
(3) The label for the Source Plasma Liquid shall be easily
distinguished from that of the frozen product. Color coding shall not be
used for this purpose.
(4) The label affixed to each container of Source Plasma Liquid
shall contain, in addition to the information required by Sec. 640.70(a)
but excluding Sec. 640.70(a)(3), the name of the manufacturer of the
final blood derivative product for whom it was prepared.
(5) Source Plasma Liquid shall be inspected immediately prior to
issuance. If the color or physical appearance is abnormal, or there is
any indication or suspicion of microbial contamination, the unit of
Source Plasma Liquid shall not be issued.
[38 FR 32089, Nov. 20, 1973. Redesignated and amended at 41 FR 10770,
Mar. 12, 1976; 49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55
FR 11013, Mar. 26, 1990; 59 FR 49351, Sept. 28, 1994]
Sec. 640.76 Products stored or shipped at unacceptable temperatures.
(a) Storage temperature. (1) Except as provided in paragraph (a)(2)
of this section, Source Plasma intended for manufacture into injectable
products that
[[Page 138]]
is inadvertently exposed (i.e., an unforeseen occurrence in spite of
compliance with good manufacturing practice) to a storage temperature
warmer than -20 deg. C and colder than +10 deg. C may be issued only if
labeled as ``Source Plasma Salvaged.'' The label shall be revised before
issuance, and appropriate records shall be maintained identifying the
units involved, describing their disposition, and explaining fully the
conditions that caused the inadvertent temperature exposure.
(2) Source Plasma intended for manufacture into injectable products
that is exposed inadvertently (i.e., an unforeseen occurrence in spite
of compliance with good manufacturing practice) to one episode of
storage temperature fluctuation that is warmer than -20 deg. C and
colder than -5 deg. C for not more than 72 hours is exempt from the
labeling requirements of paragraph (a)(1) of this section, provided that
the plasma has been and remains frozen solid. Appropriate records shall
be maintained identifying the units involved, describing their
disposition, explaining fully the conditions that caused the inadvertent
temperature exposure, and documenting that the episode of temperature
elevation did not exceed 72 hours, that the temperature did not rise to
warmer than -5 deg. C in storage, and that the plasma remained frozen
solid throughout the period of elevated temperature. When requested,
copies of the records shall be provided to the plasma derivative
manufacturer.
(b) Shipping temperature. If Source Plasma for manufacture into
injectable products is exposed inadvertently (i.e., an unforeseen
occurrence in spite of compliance with good manufacturing practice) to a
shipping temperature warmer than -5 deg. C and colder than +10 deg. C,
the plasma derivative manufacturer shall label it ``Source Plasma
Salvaged.'' Appropriate records shall be maintained identifying the
units involved, describing their disposition, and explaining fully the
conditions that caused the inadvertent temperature exposure.
(c) Relabeling. If Source Plasma is required to be relabeled as
``Source Plasma Salvaged'' under paragraph (a)(1) or (b) of this
section, the person responsible for the relabeling shall cover the
original label with either (1) a complete new label containing the
appropriate information or (2) a partial label affixed to the original
label and containing the appropriate new information, which covers the
incorrect information regarding storage temperature.
[45 FR 80501, Dec. 5, 1980, as amended at 50 FR 4140, Jan. 29, 1985]
Subpart H--Albumin (Human)
Sec. 640.80 Albumin (Human).
(a) Proper name and definition. The proper name of the product shall
be Albumin (Human). The product is defined as a sterile solution of the
albumin component of human blood.
(b) Source material. The source material of Albumin (Human) shall be
blood, plasma, serum or placentas from human donors determined at the
time of donation to have been free from disease-causative agents that
are not destroyed or removed by the processing method, as determined by
the medical history of the donor and from such physical examination and
clinical tests as may appear necessary for each donor at the time the
blood was obtained. Where source material is a product for which
additional standards are effective, the requirements of those additional
standards shall determine the propriety of the source material for use
in the production of Albumin (Human). Where no additional standards are
effective with respect to source material for the production of Albumin
(Human), such source material shall:
(1) Be collected by a procedure which is designed to assure the
integrity and to minimize the risk of contamination of the source
material. The manufacturer of Albumin (Human) shall ensure that the
collection procedure shall be as described in its license.
(2) Be identified to relate it accurately to the individual donor
and the dates of collection.
(3) Not contain a preservative.
(4) Be stored and transported in a manner designed to prevent
contamination by microorganisms, pyrogens, or other impurities.
(c) Additives in source material. Source material shall not contain
an additive unless it is shown that the processing method yields a final
product free of
[[Page 139]]
the additive to such extent that the continued safety, purity, potency,
and effectiveness of the final product will not be adversely affected.
[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985]
Sec. 640.81 Processing.
(a) Date of manufacture. The date of manufacture shall be the date
of final sterile filtration of a uniform pool of bulk solution.
(b) Processing method. The processing method shall not affect the
integrity of the product, and shall have been shown to yield
consistently a product which is safe for intravenous injection.
(c) Microbial contamination. All processing steps shall be conducted
in a manner to minimize the risk of contamination from either
microorganisms or other deleterious matter. Preservatives to inhibit
growth of microorganisms shall not be used during processing.
(d) Storage of bulk fraction. Bulk concentrate to be held more than
1 week prior to further processing shall be stored in clearly identified
closed vessels at a temperature of --5 deg. C or colder. Any other bulk
form of the product, exclusive of the sterile bulk solution, to be held
more than 1 week prior to further processing shall be stored in clearly
identified closed vessels at a temperature of 5 deg. C or colder. Any
bulk fraction to be held one week or less prior to further processing
shall be stored in clearly identified closed vessels at a temperature of
5 deg. C or colder.
(e) Heat treatment. Heating of the final containers of Albumin
(Human) shall begin within 24 hours after completion of filling. Heat
treatment shall be conducted so that the solution is heated for not less
than 10 or more than 11 hours at an attained temperature of
60 deg.plus-minus0.5 deg. C.
(f) Stabilizer. Either 0.16 millimole sodium acetyltryptophanate, or
0.08 millimole sodium acetyltryptophanate and 0.08 millimole sodium
caprylate shall be added per gram of albumin as a stabilizer.
(g) Incubation. All final containers of Albumin (Human) shall be
incubated at 20 deg. to 35 deg. C for at least 14 days following the
heat treatment prescribed in paragraph (e) of this section. At the end
of this incubation period, each final container shall be examined and
all containers showing any indication of turbidity or microbial
contamination shall not be issued. The contents of turbid final
containers shall be examined microscopically and tested for sterility.
If growth occurs, organisms shall be identified as to genus, and the
material from such containers shall not be used for further
manufacturing.
[42 FR 27582, May 31, 1977, as amended at 50 FR 4140, Jan. 29, 1985]
Sec. 640.82 Tests on final product.
Tests shall be performed on the final product to determine that it
meets the following standards:
(a) Protein content. Final product shall conform to one of the
following concentrations: 4.0plus-minus0.25 percent;
5.0plus-minus0.30 percent; 20.0plus-minus1.2 percent; and
25.0plus-minus1.5 percent solution of protein.
(b) Protein composition. At least 96 percent of the total protein in
the final product shall be albumin, as determined by a method that has
been approved for each manufacturer by the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration.
(c) Hydrogen ion concentration. The pH shall be
6.9plus-minus0.5 when measured in a solution of the final product
diluted to a concentration of 1 percent protein with 0.15 molar sodium
chloride.
(d) Sodium content. The sodium content of the final product shall be
130 to 160 milliequivalents per liter.
(e) Heme content. The absorbance at 403 nanometers of a solution of
the final product diluted to a concentration of 1 percent protein in a
cell with a 1-centimeter light path shall not exceed 0.25.
(f) Heat stability. A final container sample of Albumin (Human)
shall remain unchanged, as determined by visual inspection, after
heating at 57 deg. C for 50 hours, when compared to its control
consisting of a sample, from the same lot, which has not undergone this
heating.
[42 FR 27582, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 50
FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26, 1990]
[[Page 140]]
Sec. 640.83 General requirements.
(a) Preservative. The final product shall not contain a
preservative.
(b) Storage of bulk solution. After all processing steps have been
completed, the sterile bulk solution shall be stored in a manner that
will ensure the continued sterility of the product, and at a temperature
that shall not exceed the recommended storage temperature of the final
product prescribed in Sec. 610.53 of this chapter.
[42 FR 27582, May 31, 1977]
Sec. 640.84 Labeling.
In addition to the labeling requirements of Secs. 610.60, 610.61,
and 610.62 of this chapter,
(a) The container and package labels shall contain the following
information:
(1) The osmotic equivalent in terms of plasma, and the sodium
content in terms of a value or a range in milliequivalents per liter;
(2) The cautionary statement placed in a prominent position on the
label, ``Do Not Use if Turbid. Do Not Begin Administration More Than 4
Hours After the Container Has Been Entered.'';
(3) The need for additional fluids when 20 percent or 25 percent
albumin is administered to a patient with marked dehydration;
(4) The protein content, expressed as a 4 percent, 5 percent, 20
percent, or 25 percent solution.
(b) The type of source material, expressed as venous plasma,
placental plasma, or both, used to manufacture the final product shall
appear on either the container or package label or in the package
insert.
[42 FR 27582, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984]
Subpart I--Plasma Protein Fraction (Human)
Source: 42 FR 27583, May 31, 1977, unless otherwise noted.
Sec. 640.90 Plasma Protein Fraction (Human).
(a) Proper name and definition. The proper name of the product shall
be Plasma Protein Fraction (Human). The product is defined as a sterile
solution of protein composed of albumin and globulin, derived from human
blood.
(b) Source material. The source material of Plasma Protein Fraction
(Human) shall be blood, plasma, or serum from human donors determined at
the time of donation to have been free from disease-causative agents
that are not destroyed or removed by the processing method, as
determined by the medical history of the donor and from such physical
examination and clinical tests as may appear necessary for each donor at
the time the blood was obtained. When source material is a product for
which additional standards are effective, the requirements of those
additional standards shall determine the propriety of the material for
use in the production of Plasma Protein Fraction (Human). When no
additional standards are effective with respect to source material for
the production of Plasma Protein Fraction (Human), such source material
shall:
(1) Be collected by a procedure which is designed to assure the
integrity and to minimize the risk of contamination of the source
material. The manufacturer of Plasma Protein Fraction (Human) shall
ensure that the collection procedure shall be as described in its
license;
(2) Be identified to relate it accurately to the individual donor
and to the dates of collection;
(3) Not contain a preservative; and
(4) Be stored and transported in a manner designed to prevent
contamination by microorganisms, pyrogens, or other impurities.
(c) Additives in source material. Source material shall not contain
an additive unless it is shown that the processing method yields a final
product free of the additive to such extent that the continued safety,
purity, potency, and effectiveness of the final product will not be
adversely affected.
Sec. 640.91 Processing.
(a) Date of manufacture. The date of manufacture shall be the date
of final sterile filtration of a uniform pool of bulk solution.
(b) Processing method. The processing method shall not affect the
integrity of
[[Page 141]]
the product, and shall have been shown to yield consistently a product
which:
(1) After the heating prescribed in paragraph (e) of this section
does not show an increase in the components with electrophoretic
mobility similar to that of alpha globulin that amounts to more than 5
percent of the total protein.
(2) Contains less than 5 percent protein with a sedimentation
coefficent greater than 7.0 S.
(3) Is safe for intravenous injection.
(c) Microbial contamination. All processing steps shall be conducted
in a manner to minimize the risk of contimination from either
microorganisms or other deleterious matter. Preservatives to inhibit
growth of microorganisms shall not be used during processing.
(d) Storage of bulk fraction. Bulk concentrate to be held more than
1 week prior to further processing shall be stored in clearly identified
closed vessels at a temperature of --5 deg. C or colder. Any other bulk
form of the product (exclusive of the sterile bulk solution) to be held
more than 1 week prior to further processing, shall be stored in clearly
identified closed vessels at a temperature of 5 deg. C or colder. Any
bulk fraction to be held one week or less prior to further processing
shall be stored in clearly identified closed vessels at a temperature of
5 deg. C or colder.
(e) Heat treatment. Heating of the final containers of Plasma
Protein Fraction (Human) shall begin within 24 hours after completion of
filling. Heat treatment shall be conducted so that the solution is
heated for not less than 10 or more than 11 hours at an attained
temperature of 60 deg.plus-minus0.5 deg. C.
(f) Stabilizer. Either 0.16 millimole sodium acetyltryptophanate, or
0.08 millimole sodium acetyltryptophanate and 0.08 millimole sodium
caprylate shall be added per gram of protein as a stabilizer.
(g) Incubation. All final containers of Plasma Protein Fraction
(Human) shall be incubated at 20 deg. to 35 deg. C for at least 14 days
following the heat treatment prescribed in paragraph (e) of this
section. At the end of this incubation period, each final container
shall be examined and all containers showing any indication of turbidity
or microbial contamination shall not be issued. The contents of turbid
final containers shall be examined microscopically and tested for
sterility. If growth occurs, the types of organisms shall be identified
as to genus and the material from such containers shall not be used for
further manufacturing.
Sec. 640.92 Tests on final product.
Tests shall be performed on the final product to determine that it
meets the following standards:
(a) Protein content. The final product shall be a
5.0plus-minus0.3 percent solution of protein.
(b) Protein composition. The total protein in the final product
shall consist of at least 83 percent albumin, and no more than 17
percent globulins. No more than 1 percent of the total protein shall be
gamma globulin. The protein composition shall be determined by a method
that has been approved for each manufacturer by the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration.
(c) Hydrogen ion concentration. The pH shall be
7.0plus-minus0.3 when measured in a solution of the final product
diluted to a concentration of 1 percent protein with 0.15 molar sodium
chloride.
(d) Sodium content. The sodium content of the final product shall be
130 to 160 milliequivalents per liter.
(e) Potassium content. The potassium content of the final product
shall not exceed 2 milliequivalents per liter.
(f) Heat stability. A final container sample of Plasma Protein
Fraction (Human) shall remain unchanged, as determined by visual
inspection, after heating at 57 deg. C for 50 hours, when compared to
its control consisting of a sample, from the same lot, which has not
undergone this heating.
[42 FR 27583, May 31, 1977, as amended at 49 FR 23834, June 8, 1984; 55
FR 11013, Mar. 26, 1990]
Sec. 640.93 General requirements.
(a) Preservative. The final product shall not contain a
preservative.
(b) Storage of bulk solution. After all processing steps have been
completed, the sterile bulk solution shall be stored in a manner that
will ensure the continued sterility of the product, and at a
[[Page 142]]
temperature that shall not exceed the recommended storage temperature of
the final product prescribed in Sec. 610.53 of this chapter.
Sec. 640.94 Labeling.
In addition to the labeling requirements of Secs. 610.60, 610.61,
and 610.62 of this chapter, the container and package labels shall
contain the following information:
(a) The osmotic equivalent in terms of plasma, and the sodium
content in terms of a value or a range in milli- equivalents per liter.
(b) The cautionary statement placed in a prominent position on the
label, ``Do Not Use if Turbid. Do Not Begin Administration More than 4
Hours After the Container Has Been Entered.''
[42 FR 27583, May 31, 1977, as amended at 49 FR 2244, Jan. 19, 1984]
Subpart J--Immune Globulin (Human)
Sec. 640.100 Immune Globulin (Human).
(a) Proper name and definition. The proper name of this product
shall be Immune Globulin (Human). The product is defined as a sterile
solution containing antibodies derived from human blood.
(b) Source material. The source of Immune Globulin (Human) shall be
blood, plasma or serum from human donors determined at the time of
donation to have been free of causative agents of diseases that are not
destroyed or removed by the processing methods, as determined by the
donor's history and from such physical examination and clinical tests as
appear necessary for each donor at the time the blood was obtained. The
source blood, plasma or serum shall not contain a preservative and shall
be stored in a manner that will prevent contamination by microorganisms,
pyrogens or other impurities.
(c) Additives in source material. Source blood, plasma or serum
shall contain no additives other than citrate or acid citrate dextrose
anticoagulant solution, unless it is shown that the processing method
yields a product free of the additive to such an extent that the safety,
purity and potency of the product will not be affected adversely.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985]
Sec. 640.101 General requirements.
(a) Heat stability test. Approximately 2 ml. of completely processed
material of each lot shall not show any visible sign of gelation after
heating in a 12 x 75 mm. stoppered glass tube at 57 deg. C. for 4 hours.
(b) Hydrogen ion concentration. The pH of final container material
shall be 6.8plus-minus0.4 when measured in a solution diluted to 1
percent protein with 0.15 molar sodium chloride.
(c) Turbidity. The product shall be free of turbidity as determined
by visual inspection of final containers.
(d) Date of manufacture. The date of manufacture is the date of
initiating the last valid measles or poliomyelitis antibody test
(Sec. 640.104(b) (2) and (3)) whichever date is earlier.
(e) Labeling. In addition to complying with all applicable labeling
required in this subchapter, labeling shall indicate that:
(1) There is no prescribed potency for viral hepatitis antibodies.
(2) The product is not recommended for intravenous administration.
(3) The lot is or is not suitable for use with Measles Virus Vaccine
Live.
(4) The lot is or is not recommended for poliomyelitis.
(f) Samples and protocols. For each lot of Immune Globulin (Human)
the following material shall be submitted to the Director, Center for
Biologics Evaluation and Research, Food and Drug Administration, 8800
Rockville Pike, Bethesda, MD 20892:
(1) A 50 ml. sample of the final product.
(2) All protocols relating to the history of each lot and all
results of all tests prescribed in these additional standards.
[38 FR 32089, Nov. 20, 1973; 48 FR 13026, Mar. 29, 1983, as amended at
49 FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 51 FR 15611, Apr.
25, 1986; 55 FR 11013, Mar. 26, 1990]
Sec. 640.102 Manufacture of Immune Globulin (Human).
(a) Processing method. The processing method shall be one that has
been
[[Page 143]]
shown: (1) To be capable of concentrating tenfold from source material
at least two different antibodies; (2) not to affect the integrity of
the globulins; (3) to consistently yield a product which is safe for
subcutaneous and intramuscular injection and (4) not to transmit viral
hepatitis.
(b) Microbial contamination. Low temperatures or aseptic techniques
shall be used to minimize contamination by microorganisms. Preservatives
to inhibit growth of microorganisms shall not be used during processing.
(c) Bulk storage. The globulin fraction may be stored in bulk prior
to further processing provided it is stored in clearly identified
hermetically closed vessels. Globulin as either a liquid concentrate or
a solid and containing alcohol or more than 5 percent moisture shall be
stored at a temperature of --10 deg. C. or lower. Globulin as a solid
free from alcohol and containing less than 5 percent moisture, shall be
stored at a temperature of 0 deg. C. or lower.
(d) Determination of the lot. Each lot of Immune Globulin (Human)
shall represent a pooling of approximately equal amounts of material
from not less than 1,000 donors.
(e) Sterilization and heating. The final product shall be sterilized
promptly after solution. At no time during processing shall the product
be exposed to temperatures above 45 deg.C. and after sterilization the
product shall not be exposed to temperatures above 30 deg. to 32 deg. C.
for more than 72 hours.
[38 FR 32089, Nov. 20, 1973, as amended at 50 FR 4140, Jan. 29, 1985]
Sec. 640.103 The final product.
(a) Final solution. The final product shall be a
16.5plus-minus1.5 percent solution of globulin containing 0.3 molar
glycine and a preservative.
(b) Protein composition. At least 90 percent of the globulin shall
have an electrophoretic mobility not faster than -2.8 x 10-5
centimeters2 per volt per second, when measured at a 1 percent
protein concentration in sodium diethylbarbiturate buffer at pH 8.6 and
0.1 ionic strength.
Sec. 640.104 Potency.
(a) Antibody levels and tests. Each lot of final product shall
contain at least the minimum levels of antibodies for diphtheria,
measles, and for at least one type of poliomyelitis. In the event the
final bulk solution is stored at a temperature above 5 deg. C. the
antibody level tests shall be performed after such storage with a sample
of the stored material.
(b) Minimum levels. The minimum antibody levels are as follows:
(1) No less than 2 units of diphtheria antitoxin per ml.
(2) A measles neutralizing antibody level of no less than 0.50 times
the level of the Reference Immune Serum Globulin, except that when
recommended for use with Measles Virus Vaccine Live, the measles
antibody level shall be as prescribed in Sec. 640.114.
(3) A poliomyelitis neutralizing antibody level of no less than 1.0
for Type 1, 1.0 for Type 2, and 2.5 for Type 3, times the antibody level
of the Reference Immune Serum Globulin.
(c) Reference materials. The following reference materials shall be
obtained from the Center for Biologics Evaluation and Research:
(1) Reference Immune Serum Globulin for correlation of measles
antibody titers.
(2) Reference Immune Serum Globulin for correlation of poliomyelitis
antibody titers, Types 1, 2, and 3.
[38 FR 32089, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974; 49
FR 23834, June 8, 1984; 50 FR 4140, Jan. 29, 1985; 55 FR 11013, Mar. 26,
1990]
Subpart K--Measles Immune Globulin (Human)
Sec. 640.110 Measles Immune Globulin (Human).
(a) Proper name and definition. The proper name of the product shall
be Measles Immune Globulin (Human). It shall consist of a sterile
solution of 10 to 18 percent globulin derived from human blood, having
the same measles antibody level as the Reference Measles Immune
Globulin. Measles Immune Globulin shall be made from a sterile 16.5
plus-minus1.5 percent solution of human globulin.
[[Page 144]]
(b) Source material. The source of Measles Immune Globulin (Human)
shall be blood, plasma or serum from human donors determined at the time
of donation to have been free of causative agents of diseases that are
not destroyed or removed by the processing method, as determined by the
donor's history and from such physical examination and clinical tests as
appear necessary for each donor at the time the blood was obtained. The
source blood, plasma or serum shall not contain a preservative and shall
be stored in a manner that will prevent contamination by microorganisms,
pyrogens or other impurities.
(c) Additives in source material. Source blood, plasma or serum
shall contain no additives other than citrate or acid citrate dextrose
anticoagulant solution, unless it is shown that the processing method
yields a product free of the additive to such an extent that the safety,
purity and potency of the product will not be affected adversely.
[38 FR 32089, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974]
Sec. 640.111 General requirements.
(a) Heat stability test. Approximately 2 ml of final container
material of each lot shall not show any visible sign of gelation after
heating in a 12 x 75 mm. stoppered glass tube at 57 deg. C. for four
hours.
(b) Hydrogen ion concentration. The pH of final container material
shall be 6.8plus-minus0.4 when measured in a solution diluted to 1
percent protein with 0.15 molar sodium chloride.
(c) Turbidity. The product shall be free of turbidity as determined
by visual inspection of final containers.
(d) Date of manufacture. The date of manufacture is the date of
initiating the last valid measles antibody test as required in
Sec. 640.114.
(e)--(f) [Reserved]
(g) Samples and protocols. For each lot of globulin, the following
materials shall be submitted to the Director, Center for Biologics
Evaluation and Research, Food and Drug Administration, 8800 Rockville
Pike, Bethesda, MD 20892.
(1) 30 ml of final product.
(2) All protocols relating to the history of the manufacture of each
lot and all results of all tests prescribed in these additional
standards.
[38 FR 32089, Nov. 20, 1973, as amended at 49 FR 23834, June 8, 1984; 51
FR 15611, Apr. 25, 1986; 55 FR 11013, Mar. 26, 1990]
Sec. 640.112 Manufacture of Measles Immune Globulin (Human).
(a) Processing method. The globulin shall be prepared by a
processing method that (1) has been shown to be capable of concentrating
tenfold from source material at least two different antibodies, (2) does
not affect the integrity of the globulins and is capable of consistently
yielding a product which is safe for subcutaneous and intramuscular
injections and (3) will not transmit viral hepatitis.
(b) Reference materials. The following reference material shall be
obtained from the Center for Biologics Evaluation and Research:
Reference Measles Immune Globulin for correlation of measles antibody
titers with globulin products.
(c) Microbial contamination. Low temperatures or aseptic techniques
shall be used to minimize contamination by microorganisms. Preservatives
to inhibit growth of microorganisms shall not be used during processing.
(d) Bulk storage. The globulin fraction may be stored in bulk prior
to further processing provided it is stored in well-marked hermetically
closed vessels. Purified globulin as either a liquid concentrate or a
solid and containing alcohol or more than 5 percent moisture shall be
stored at a temperature not to exceed -10 deg. C. Purified globulin as a
solid free from alcohol and containing less than 5 percent moisture,
shall be stored at temperatures not to exceed 0 deg. C.
(e) Determination of the lot. Each lot of Measles Immune Globulin
(Human) shall represent a pooling of material from not less than 1,000
donors.
(f) Sterilization and dilution. The product shall be prepared
initially as a 16.5 percent solution and this preparation shall be
sterilized promptly after solution. After sterilization the product
shall not be exposed to temperatures above 45 deg. C. for more than a
total of 72 hours. Dilution of this sterile globulin
[[Page 145]]
solution shall be made only to adjust the required measles antibody
level.
[38 FR 32089, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974; 49
FR 23834, June 8, 1984; 55 FR 11013, Mar. 26, 1990]
Sec. 640.113 The final product.
(a) Final solution. The final product shall be a 10 to 18 percent
solution of globulin containing 0.3 molar glycine and a preservative.
(b) Protein composition. No less than 90 percent of the globulin
shall have an electrophoretic mobility not faster than -2.8 x 10-5
centimeters2 per volt per second, when measured at a 1 percent
protein concentration in sodium diethylbarbiturate at pH 8.6 and 0.1
ionic strength.
Sec. 640.114 Potency.
Antibody levels and tests. Each lot of final product shall contain
no less than the minimum levels of antibodies for diphtheria and measles
as follows:
(a) The product shall contain no less than 2 units of diphtheria
antitoxin per ml, adjusted for dilution from the 16.5 percent solution.
(b) Each lot of final product shall contain the same measles
antibody level as the Reference Measles Immune Globulin. The measles
antibody potency shall be determined by simultaneous determinations of
the neutralizing antibody titers of the globulin on tests and of a
reference preparation against 100 TCID50 (50-500 TCID50 when
based upon a single test) of measles virus in a tissue culture system.
The potency test shall also include a determination of virus titer and
controls for globulin toxicity and cell culture viability. Twofold
serial dilutions of the globulin under test and of the reference
preparation shall be employed in this determination. In applying these
requirements a plus or minus variation of one twofold dilution is
acceptable.
[38 FR 32089, Nov. 20, 1973, as amended at 39 FR 9661, Mar. 13, 1974]
Subpart L--Alternative Procedures
Sec. 640.120 Alternative procedures.
(a) The Director, Center for Biologics Evaluation and Research, may
approve an exception or alternative to any requirement in subchapter F
of chapter I of title 21 of the Code of Federal Regulations regarding
blood, blood components, or blood products. Requests for such exceptions
or alternatives should ordinarily be made in writing. However, in
limited circumstances such requests may be made orally and permission
may be given orally by the Director. Oral requests and approvals must be
followed by written requests and written approvals. Approval of a
request for an exception or alternative must be obtained from the
Director prior to the distribution of any affected blood, blood
component, or blood product.
(b) FDA will publish a list of approved alternative procedures and
exceptions periodically in the Federal Register.
[55 FR 10423, Mar. 21, 1990]