[Federal Register Volume 70, Number 118 (Tuesday, June 21, 2005)]
[Notices]
[Pages 35680-35683]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 05-12180]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2005N-0220]


Agency Information Collection Activities; Proposed Collection; 
Comment Request; Current Good Manufacturing Practices and Related 
Regulations for Blood and Blood Components; and Requirements for Donor 
Testing, Donor Notification, and ``Lookback''

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing an 
opportunity for public comment on the proposed collection of certain 
information by the agency. Under the Paperwork Reduction Act of 1995 
(the PRA), Federal agencies are required to publish notice in the 
Federal Register concerning each proposed collection of information, 
including each proposed extension of an existing collection of 
information, and to allow 60 days for public comment in response to the 
notice. This notice solicits comments on the information collection 
requirements contained in FDA's current good manufacturing practice 
(CGMP) and related regulations for blood and blood components; and 
requirements for donor testing, donor notification, and ``lookback''.

DATES: Submit written or electronic comments on the collection of 
information by August 22, 2005.

ADDRESSES: Submit electronic comments on the collection of information 
to: http://www.fda.gov/dockets/ecomments. Submit written comments on 
the collection of information to the Division of Dockets Management 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852. All comments should be identified with the docket 
number found in brackets in the heading of this document.

FOR FURTHER INFORMATION CONTACT: Jonna Capezzuto, Office of Management 
Programs (HFA-250), Food and Drug Administration, 5600 Fishers Lane, 
Rockville, MD 20857, 301-827-4659.

SUPPLEMENTARY INFORMATION: Under the PRA (44 U.S.C. 3501-3520), Federal 
agencies must obtain approval from the Office of Management and Budget 
(OMB) for each collection of information they conduct or sponsor. 
``Collection of information'' is defined in 44 U.S.C. 3502(3) and 5 CFR 
1320.3(c) and includes agency requests or requirements that members of 
the public submit reports, keep records, or provide information to a 
third party. Section 3506(c)(2)(A) of the PRA (44 U.S.C. 3506(c)(2)(A)) 
requires Federal agencies to provide a 60-day notice in the Federal 
Register concerning each proposed collection of information, including 
each proposed extension of an existing collection of information, 
before submitting the collection to OMB for approval. To comply with 
this requirement, FDA is publishing notice of the proposed collection 
of information set forth in this document.
    With respect to the following collection of information, FDA 
invites comments on these topics: (1) Whether the proposed collection 
of information is necessary for the proper performance of FDA's 
functions, including whether the information will have practical 
utility; (2) the accuracy of FDA's estimate of the burden of the 
proposed collection of information, including the validity of the 
methodology and assumptions used; (3) ways to enhance the quality, 
utility, and clarity of the information to be collected; and (4) ways 
to minimize the burden of the collection of information on respondents, 
including through the use of automated collection techniques, when 
appropriate, and other forms of information technology.

Current Good Manufacturing Practices and Related Regulations for Blood 
and Blood Components; and Requirements for Donor Testing, Donor 
Notification, and ``Lookback'' (OMB Control Number 0910-0116)--
Extension

    Under the statutory requirements contained in section 351 of the 
Public Health Service Act (PHS Act) (42 U.S.C. 262), no blood, blood 
component, or derivative may move in interstate commerce unless: (1) It 
is propagated or manufactured and prepared at an establishment holding 
an unsuspended and unrevoked license; (2) the product complies with 
regulatory standards designed to ensure safety, purity, and potency; 
and (3) it bears a label plainly marked with the product's proper name, 
manufacturer, and expiration date. In addition, under the biologics 
licensing and quarantine provisions in sections 351-361 of the PHS Act 
(42 U.S.C. 262-264) and the general administrative provisions under 
sections 501-503, 505-510, and 701-704 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 351-353, 355-360, and 371-374), FDA has the 
authority to issue and enforce regulations designed to protect the 
public from unsafe or ineffective biological products and to issue 
regulations necessary to prevent the introduction, transmission, or 
spread of communicable diseases between States or possession or from 
foreign countries into the States or possession. The CGMP and related 
regulations implement FDA's statutory authority to ensure the safety, 
purity, and potency of blood and blood components. The ``lookback'' 
requirements are intended to help ensure the continued safety of the 
blood supply by providing necessary information to users of blood and 
blood components and appropriate notification of recipients of 
transfusion who are at increased risk for transmitting human 
immunodeficiency virus (HIV) infection. The public health objective in 
testing human blood donors for evidence of infection due to 
communicable disease agents and in donor notification is to prevent the 
transmission of communicable disease.
    The information collection requirements in the CGMP, donor testing, 
donor notification, and ``lookback'' regulations provide FDA with the 
necessary information to perform its duty to ensure the safety, purity, 
and potency of blood and blood components. These requirements establish 
accountability and traceability in the processing and handling of blood 
and blood components and enables FDA to conduct meaningful inspections. 
The recordkeeping requirements serve preventative and remedial 
purposes. The disclosure requirements identify the various blood and 
blood components and important properties of the product, demonstrate 
that the CGMP requirements have been met, and facilitate the tracing of 
a product back to its original source. The reporting requirements 
inform FDA of any deviations that occur and that may require immediate 
corrective action.
    Under the reporting requirements, Sec.  606.170(b) (21 CFR 
606.170(b)) requires that fatal complications of blood collection and 
transfusions be reported to FDA as soon as possible and that a written 
report shall be submitted within 7 days. Section 610.40(c)(1)(ii) (21 
CFR 610.40(c)(1)(ii)) requires each dedicated donation be labeled as 
required under 21 CFR 606.121 and with a label entitled ``INTENDED 
RECIPIENT INFORMATION LABEL'' containing the name and identifying 
information of the recipient. Section

[[Page 35681]]

610.40(g)(2) requires an establishment to obtain written approval from 
FDA to ship human blood or blood components for further manufacturing 
use prior to completion of testing. Section 610.40(h)(2)(ii)(A) 
requires an establishment to obtain written approval from FDA to use or 
ship human blood or blood components found to be reactive by a 
screening test for evidence of a communicable disease agent(s) or 
collect from a donor with a record of a reactive screening test. 
Sections 610.40(h)(2)(ii)(C) and (h)(2)(ii)(D) require an establishment 
to label reactive human blood and blood components with the appropriate 
screening test results, and, if they are intended for further 
manufacturing use into injectable products, with a statement indicating 
the exempted use specifically approved by FDA. Section 610.40(h)(2)(vi) 
requires each donation of human blood or blood component that tests 
reactive by a screening test for syphilis and is determined to be a 
biological false positive be labeled with both test results. Section 
610.42(a) (21 CFR 610.42(a)) requires a warning statement, including 
the identity of the communicable disease agent, on medical devices 
containing human blood or blood components found to be reactive by a 
screening test for evidence of infection due to a communicable disease 
agent(s) or syphilis. Section 610.46(a) (21 CFR 610.46(a)) requires 
blood establishments to notify consignees, within 72 hours, of 
repeatedly reactive test results so that previously collected blood and 
blood components are appropriately quarantined. Section 610.46(b) 
requires blood establishments to notify consignees of licensed, more 
specific test results for HIV within 30 calendar days after the donors' 
repeatedly reactive test. Section 610.47(b) (21 CFR 610.47(b)) requires 
transfusion services not subject to the Centers for Medicare and 
Medicaid Services (CMS) regulations to notify physicians of prior 
donation recipients or to notify recipients themselves of the need for 
HIV testing and counseling. Section 630.6(a) (21 CFR 630.6(a)) requires 
an establishment to make reasonable attempts to notify any donor who 
has been deferred as required by Sec.  610.41 (21 CFR 610.41), or who 
has been determined not to be eligible as a donor. Section 630.6(d)(1) 
requires an establishment to provide certain information to the 
referring physician of an autologous donor who is deferred based on the 
results of tests as described in Sec.  610.41.
    Under the recordkeeping requirements, section 606.100(b) (21 CFR 
606.100(b)) requires that written standard operating procedures (SOPs) 
be maintained for the collection, processing, compatibility testing, 
storage, and distribution of blood and blood components used for 
transfusion and manufacturing purposes. Section 606.100(c) requires the 
review of all pertinent records to a lot or unit of blood prior to 
release. Any unexplained discrepancy or failure of a lot or unit of 
final product to meet any of its specifications must be thoroughly 
investigated, and the investigation, including conclusions and 
followup, must be recorded. Section 606.110(a) (21 CFR 606.110(a)) 
requires a physician to certify in writing that the donor's health 
permits plateletpheresis or leukapheresis if a variance from additional 
regulatory standards for a specific product is used when obtaining the 
product from a specific donor for a specific recipient. Section 
606.110(b) requires establishments to request prior Center for 
Biologics Evaluation and Research (CBER) approval for plasmapheresis of 
donors who do not meet donor requirements. The information collection 
requirements for Sec.  606.110(b) are reported and approved under OMB 
control number 0910-0338 which expires August 31, 2005. Section 
606.151(e) (21 CFR 606.151(e)) requires that records of expedited 
transfusions in life-threatening emergencies be maintained. So that all 
steps in the collection, processing, compatibility testing, storage and 
distribution, quality control, and transfusion reaction reports and 
complaints for each unit of blood and blood components can be clearly 
traced, Sec.  606.160 (21 CFR 606.160) requires that legible and 
indelible contemporaneous records of each significant step be made and 
maintained for no less than 5 years. Section 606.160(b)(1)(ix) requires 
a facility to maintain records of notification of donors deferred or 
determined not to be eligible for donation, including appropriate 
followup if the initial notification attempt fails. Section 
606.160(b)(1)(xi) requires an establishment to maintain records of 
notification of the referring physician of a deferred autologous donor, 
including appropriate followup if the initial notification attempt 
fails. Section 606.165 (21 CFR 606.165) requires that distribution and 
receipt records be maintained to facilitate recalls, if necessary. 
Section 606.170(a) (21 CFR 606.170(a)) requires records to be 
maintained of any reports of complaints of adverse reactions as a 
result of blood collection or transfusion. Each such report must be 
thoroughly investigated, and a written report, including conclusions 
and followup, must be prepared and maintained. Section 610.40(g)(1) 
requires an establishment to appropriately document a medical emergency 
for the release of human blood or blood components prior to completion 
of required testing.
    In addition to the CGMPs in part 606 (21 CFR part 606), there are 
regulations in part 640 (21 CFR part 640) that require additional 
standards for certain blood and blood components as follows: Sections 
640.3(a)(1), (a)(2), and (f); 640.4(a)(1) and (a)(2); 640.25(b)(4) and 
(c)(1); 640.27(b); 640.31(b); 640.33(b); 640.51(b); 640.53(b) and (c); 
640.56(b) and (d); 640.61; 640.63(b)(3), (e)(1), and (e)(3); 
640.65(b)(2); 640.66; 640.71(b)(1); 640.72; 640.73; and 640.76(a) and 
(b). The information collection requirements and estimated burdens for 
these regulations are included in the part 606 burden estimates, as 
described in Tables 1 and 2 of this document.
    Respondents to this collection of information are licensed and 
unlicensed blood establishments that collect blood and blood 
components, including Source Plasma and Source Leukocytes inspected by 
FDA, and other transfusion services inspected by CMS. Based on 
information received from CBER's database systems, there are 
approximately 81 licensed Source Plasma collection establishments with 
multiple locations and 1,628 registered Whole Blood collection 
establishments for a total of 1,709 establishments. There are 
approximately 2,156 registered blood establishments inspected by FDA. 
Of these establishments, approximately 773 perform plateletpheresis and 
leukopheresis. These establishments annually collect approximately 28 
million units of Whole Blood, blood components including Source Plasma, 
and Source Leukocytes and are required to follow FDA ``lookback'' 
procedures, and approximately 134 are registered transfusion services 
that are not subject to CMS's ``lookback'' regulations. Based on CMS 
records, there are an estimated 4,980 transfusion services approved for 
Medicare reimbursement.
    The following reporting and recordkeeping estimates are based on 
information provided by industry, CMS, and FDA experience. Based on 
information received from industry, we estimate that there are an 
average of 13 million donations of Source Plasma from approximately 2 
million donors and 15 million donations of Whole Blood, including 
300,000 (2 percent of 15 million) autologous, from approximately 8 
million donors.

[[Page 35682]]

Assuming each autologous donor makes an average of 2 donations, FDA 
estimates that there are approximately 150,000 autologous donors.
    FDA estimates that approximately 5 percent (12,000) of the 240,000 
donations that are donated specifically for the use of an identified 
recipient would be tested under the dedicated donors testing provisions 
in Sec.  610.40(c)(1)(ii).
    Under Sec.  610.40(g)(2) and (h)(2)(ii)(A), the only product 
currently shipped prior to completion of testing is a licensed product, 
Source Leukocytes, used in the manufacture of interferon, which 
requires rapid preparation from blood. Shipments of Source Leukocytes 
are preapproved under a biologics license application and each shipment 
does not have to be reported to the agency. Based on information from 
CBER's database system, FDA receives an estimated 1 application per 
year from manufacturers of Source Leukocytes.
    Under Sec.  610.40(h)(2)(ii)(C) and (h)(2)(ii)(D), FDA estimates 
that each manufacturer would ship an estimated 1 human blood or blood 
component per month (12 per year) that would require two labels; one as 
reactive for the appropriate screening test under Sec.  
610.40(h)(2)(ii)(C), and the other stating the exempted use 
specifically approved by FDA under Sec.  610.40(h)(2)(ii)(D). According 
to CBER's database system, there are an estimated 40 licensed 
manufacturers that ship known reactive human blood or blood components.
    Based on information we received from industry, we estimate that 
approximately 18,000 donations annually test reactive by a screening 
test for syphilis, and are determined to be biological false positives 
by additional testing and labeled accordingly (Sec.  610.40(h)(2)(vi)).
    Human blood or a blood component with a reactive screening test, as 
a component of a medical device, is an integral part of the medical 
device, e.g., a positive control for an in vitro diagnostic testing 
kit. It is usual and customary business practice for manufacturers to 
include on the container label a warning statement that identifies the 
communicable disease agent. In addition, on the rare occasion when a 
human blood or blood component with a reactive screening test is the 
only component available for a medical device that does not require a 
reactive component, then a statement of warning is required to be 
affixed to the medical device. To account for this rare occasion under 
Sec.  610.42(a), we estimate that the warning statement would be 
necessary no more than once a year.
    Based on information received from industry, we estimate that there 
are approximately 4,424 repeat donors that will test reactive on a 
screening test for HIV with 159 confirmed positive. We estimate that 
each repeat donor has donated two previous times and an average of 
three components were made from each donation. Under Sec.  610.46(a) 
and (b), this estimate results in 26,544 (4,424 x 2 x 3) notifications 
of the HIV screening test results to consignees by collecting 
establishments for the purpose of quarantining affected blood and blood 
components, and another 26,544 (4,424 x 2 x 3) notifications to 
consignees of subsequent test results.
    Under Sec.  610.47(b), based also on the information received from 
industry, we estimate that 80 percent of the 159 (127) confirmed HIV 
positive were from repeat donors of Whole Blood donations.
    Industry estimates that approximately 13 percent of 10 million 
potential donors (1.3 million donors) who come to donate annually are 
determined not to be eligible for donation prior to collection because 
of failure to satisfy eligibility criteria. It is the usual and 
customary business practice of 1,709 collecting establishments to 
notify onsite and to explain the reason why the donor is determined not 
to be suitable for donating. Based on such available information, we 
estimate that two-thirds of the 1,709 collecting establishments 
provided onsite additional information and counseling to a donor 
determined not to be eligible for donation as usual and customary 
business practice. Consequently, we estimate that only one-third or 570 
collection establishments would need to provide, under Sec.  630.6(a), 
additional information and counseling onsite to the estimated 433,333 
(one-third of 1.3 million) ineligible donors.
    It is estimated that another 4.5 percent of 10 million donors 
(450,000 donors) are deferred annually based on test results. We 
estimate that currently 95 percent of the establishments that collect 
98 percent of the blood and blood components notify donors who have 
reactive test results for HIV, Hepatitis B Virus (HBV), Hepatitis C 
Virus (HCV), Human T-Lymphotropic Virus (HTLV), and syphilis as usual 
and customary business practice. Consequently, 5 percent (85) of the 
industry (1,709) collecting 2 percent (9,000) of the deferred donors 
(450,000) would notify donor under Sec.  630.6(a).
    As part of usual and customary business practice, collecting 
establishments notify an autologous donor's referring physician of 
reactive test results obtained during the donation process required 
under Sec.  630.6(d)(1). However, we estimate that 5 percent of the 
1,628 blood collection establishments (81) may not notify the referring 
physicians of the estimated 2 percent of 150,000 autologous donors with 
reactive test results (3,000) as their usual and customary business 
practice.
    The recordkeeping chart reflects the estimate that 95 percent of 
the recordkeepers, which collect 98 percent of the blood supply, had 
developed SOPs as part of their customary and usual business practice. 
Establishments may minimize burdens associated with CGMP and related 
regulations by using model SOPs developed by industries' accreditation 
organizations. These accreditation organizations represent almost all 
registered blood establishments.
    Under Sec.  606.160(b)(1)(ix), we estimate the total annual records 
based on the 1.3 million donors determined not to be eligible to donate 
and each of the 450,000 (1,300,000 + 450,000 = 1,750,000) donors 
deferred based on reactive test results for evidence of infection due 
to communicable disease agents. Under Sec.  606.160(b)(1)(xi), only the 
1,628 registered blood establishments collect autologous donations and, 
therefore, are required to notify referring physicians. We estimate 
that 4.5 percent of the 150,000 autologous donors (6,750) will be 
deferred under Sec.  610.41 and thus result in the notification of 
their referring physicians.
    FDA has concluded that the use of untested or incompletely tested 
but appropriately documented human blood or blood components in rare 
medical emergencies should not be prohibited. We estimate the 
recordkeeping under Sec.  610.40(g)(1) to be minimal with one or less 
occurrence per year. The reporting of test results to the consignee in 
Sec.  610.40(g) does not create a new burden for respondents because it 
is the usual and customary business practice or procedure to finish the 
testing and provide the results to the manufacturer responsible for 
labeling the blood products.
    The hours per response and hours per record are based on estimates 
received from industry or FDA experience with similar recordkeeping or 
reporting requirements.
    FDA estimates the burden of this collection of information as 
follows:

[[Page 35683]]



                                 TABLE 1.--Estimated Annual Reporting Burden\1\
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                                                      Annual
      21 CFR Section         No. of Respondents    Frequency per   Total Annual      Hours per      Total Hours
                                                     Response        Responses       Response
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606.170(b)\2\                                 82               1              82              20           1,640
610.40(c)(1)(ii)                           1,628               8          12,000            0.08             960
610.40(g)(2)                                   1               1               1               1               1
610.40(h)(2)(ii)(A)                            1               1               1               1               1
610.40(h)(2)(ii)(C) and                       40              12             480             0.2              96
 (h)(2)(ii)(D)
610.40(h)(2)(vi)                           1,628              11          18,000            0.08           1,440
610.42(a)                                      1               1               1               1               1
610.46(a)                                  1,709              16          26,544            0.17           4,512
610.46(b)                                  1,709              16          26,544            0.17           4,512
610.47(b)                                    134               1             134               1             134
630.6(a)\3\                                  570             760         433,333            0.08          34,667
630.6(a)\4\                                   85             106           9,000             1.5          13,500
630.6(d)(1)                                   81              37           3,000               1           3,000
Total                       ....................  ..............  ..............  ..............          64,464
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\The reporting requirement in Sec.   640.73, which addresses the reporting of fatal donor reactions, is
  included in the estimate for Sec.   606.170(b).
\3\Notification of donors determined not to be eligible for donation based on failure to satisfy eligibility
  criteria.
\4\Notification of donors deferred based on reactive test results for evidence of infection due to communicable
  disease agents.


                                                   TABLE 2.--Estimated Annual Recordkeeping Burden\1\
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                                                                  Annual Frequency per
              21 CFR Section                No. of Recordkeepers      Recordkeeping     Total Annual Records    Hours per Record         Total Hours
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606.100(b)\2\                                             249\5\                     1                   249                    24                 5,976
606.100(c)                                                249\5\                    10                 2,490                     1                 2,490
606.110(a)\3\                                              39\6\                     1                    39                   0.5                    20
606.151(e)                                                249\5\                    12                 2,988                 0.083                   248
606.160\4\                                                249\5\                 1,928               480,000                  0.75               360,000
606.160(b)(1)(ix)                                          1,709                 1,024             1,750,000                  0.05                87,500
606.160(b)(1)(xi)                                          1,628                     4                 6,750                  0.05                   338
606.165                                                   249\5\                 1,928               480,000                 0.083                39,840
606.170(a)                                                249\5\                    12                 2,988                     1                 2,988
610.40(g)(1)                                               1,628                     1                 1,628                   0.5                   814
Total                                       ....................  ....................  ....................  ....................              500, 214
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\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
\2\The recordkeeping requirements in Sec.  Sec.   640.3(a)(1), 640.4(a)(1), and 640.66, which address the maintenance of SOPs, are included in the
  estimate for Sec.   606.100(b).
\3\The recordkeeping requirements in Sec.   640.27(b), which address the maintenance of donor health records for the plateletpheresis, are included in
  the estimate for Sec.   606.110(a).
\4\The recordkeeping requirements in Sec.  Sec.   640.3(a)(2) and (f); 640.4(a)(2); 640.25(b)(4) and (c)(1); 640.31(b); 640.33(b); 640.51(b); 640.53(b)
  and (c); 640.56(b) and (d); 640.61; 640.63(b)(3), (e)(1), and (e)(3); 640.65(b)(2); 640.71(b)(1); 640.72; and 640.76(a) and (b), which address the
  maintenance of various records are included in the estimate for Sec.   606.160.
\5\Five percent of CMS transfusion services and FDA-registered blood establishments (0.05 X 4,980).
\6\Five percent of plateletpheresis and leukopheresis establishments (0.05 X 773).


    Dated: June 14, 2005.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 05-12180 Filed 6-20-05; 8:45 am]
BILLING CODE 4160-01-S