[Federal Register Volume 68, Number 250 (Wednesday, December 31, 2003)]
[Notices]
[Pages 75572-75574]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 03-32160]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

[Docket No. 2003N-0268]


Agency Information Collection Activities; Submission for Office 
of Management and Budget Review; Comment Request; Biological Products: 
Reporting of Biological Product Deviations in Manufacturing

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing that a 
proposed collection of information has been submitted to the Office of 
Management and Budget (OMB) for review and clearance under the 
Paperwork Reduction Act of 1995.

DATES: Fax written comments on the collection of information by January 
30, 2004.

ADDRESSES: OMB is still experiencing significant delays in the regular 
mail, including first class and express mail, and messenger deliveries 
are not being accepted. To ensure that comments on the information 
collection are received, OMB recommends that written comments be faxed 
to the Office of Information and Regulatory Affairs, OMB, Attn: Fumie 
Yokota, Desk Officer for FDA, FAX: 202-395-6974.

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

SUPPLEMENTARY INFORMATION: In compliance with 44 U.S.C. 3507, FDA has 
submitted the following proposed collection of information to OMB for 
review and clearance.

Biological Products: Reporting of Biological Product Deviations in 
Manufacturing--(OMB Control Number 0910-0458)--Extension

    Under section 351 of the Public Health Service Act (42 U.S.C. 262), 
all biological products, including human blood and blood components, 
offered for sale in interstate commerce must be licensed and meet 
standards designed to ensure the continued safety, purity, and potency 
of such products. In addition, section 501 of the Federal Food, Drug, 
and Cosmetic Act (the act) (21 U.S.C. 351) provides that drugs and 
devices (including human blood and blood components) are adulterated if 
they do not conform with current good manufacturing practice (CGMP) 
assuring that they meet the requirements of the act. All establishments 
manufacturing human blood and blood components are required to register 
with FDA, and comply with the CGMP regulations for human blood and 
blood components (parts 211 and 606 (21 CFR parts 211 and 606)). 
Transfusion services are required under 42 CFR 493.1273(a) to comply 
with part 606 and 21 CFR part 640 as they pertain to the performance of 
manufacturing activities. FDA regards biological product deviation 
reporting to be an essential tool in its directive to protect public 
health by establishing and maintaining surveillance programs that 
provide timely and useful information. Section 600.14 (21 CFR 600.14) 
requires the licensed manufacturer who holds the biological product 
license, for other than human blood and blood components, and who had 
control over the product when the deviation occurred, to report to the 
Center for Biologics Evaluation and Research (CBER) as soon as possible 
but not to exceed 45 calendar days after acquiring information 
reasonably suggesting that a reportable event has occurred. Section 
606.171 requires a licensed manufacturer of human blood and blood 
components, including Source Plasma; an unlicensed registered blood 
establishment; or a transfusion service who had control over the 
product when the deviation occurred, to report to CBER as soon as 
possible but not to exceed 45 calendar days after acquiring information 
reasonably suggesting that a reportable event has occurred. Respondents 
to this collection of information are the licensed manufacturers of 
biological products other than human blood and blood components, 
unlicensed registered blood establishments, and transfusion services. 
Based on information from CBER's databases for fiscal year (FY) 2002, 
there were 115 licensed manufacturers of biological products other than 
human blood and blood components, 207 licensed manufacturers of human 
blood and blood components, including Source Plasma, and 2,800 
unlicensed registered blood establishments and 3,221 transfusion 
services. However, not all manufacturers or establishments may have any 
submissions in a given year and some may have multiple submissions. In 
the same FY, CBER's database also showed that the licensed 
manufacturers of biological products other than human blood and blood 
components submitted 476 biological product deviation reports (BPDRs) 
under Sec.  600.14, the licensed manufacturers of human blood and blood 
components, including Source Plasma submitted 27,000 BPDRs under Sec.  
606.171, and the unlicensed registered blood establishments and 
transfusion services submitted a total of 6,446 BPDRs. The number of 
total annual responses is based on the number of BPDRs CBER received in 
FY 2002. The rate of submission is not expected to change significantly 
in the next few years. Based on information from industry, the 
estimated average time to complete a deviation report is 2 hours. The 
availability of the standardized report FDA Form 3486, and the ability 
to submit this report electronically further streamlines the report 
submission process. Activities such as investigating, changing standard 
operating procedures (SOPs) or processes, and followup are currently 
required under parts 211 (approved under OMB control numbers 0910-0139

[[Page 75573]]

and 0910-0353), 606 (approved under OMB control number 0910-0116), and 
820 (21 CFR part 820) (approved under OMB control number 0910-0073) 
and, therefore, are not included in the burden calculation for the 
separate requirement of submitting a deviation report to FDA.
    In the Federal Register of June 30, 2003 (68 FR 38712), FDA 
published a 60-day notice requesting public comment on the information 
collection provisions. We received two comments.
    In response to whether the proposed collection of information is 
necessary, comment one stated that we should harmonize the biological 
product deviation reporting requirements (Sec.  600.14) with the NDA 
field alert reports under 21 CFR 314.81(b)(1) and, therefore, revoke 
Sec.  600.14. The comment stated the adoption of the new drug 
application (NDA) field alert regulations for all biologics would 
streamline compliance activities, and facilitate and align the recent 
transfer of biotechnology products from CBER to the Center for Drug 
Evaluation and Research (CDER). The comment also stated that revocation 
of Sec.  600.14 would reduce the reporting burden while continuing to 
support the industry in making good, risk based quality decisions.
    The NDA field alert regulations (approved under OMB control number 
0910-0001) are applicable only to those products that are approved for 
marketing under the provisions of part 314 (21 CFR part 314) (including 
those few products that CBER regulates even though they were approved 
under the NDA provisions of part 314). The NDA field alert regulations 
do not apply to biological drug products subject to licensing under the 
Public Health Service (PHS) Act, including licensed products that CDER 
now regulates. FDA has harmonized a number of regulations for certain 
biotechnology products where products regulated as biological products 
subject to licensure are similar to products subject to regulation as 
new drugs (see 65 FR 66621 at 66625, November 7, 2000). The products 
recently transferred from CBER to CDER are still regulated as 
biological products under the PHS Act. However, we recently stated in 
our CBER Web site that the biological product deviation reports for 
those transferred products are now to be sent to CDER. CBER will 
continue to monitor and assess its biological product deviation 
reporting program. If the level of reporting or the needs of the agency 
change, FDA will consider whether to harmonize its reporting 
requirements. The comment's suggestion that FDA adopt the NDA field 
alert regulations in Sec.  314.81(b)(1) and revoke Sec.  600.14 seeks a 
regulatory change that is outside the scope of FDA's current request 
for OMB renewal of the information collection in the existing 
regulations. Consequently, we decline to adopt the comment's 
recommendations.
    Comment two, in response to the necessity of the proposed 
regulation, recommended revisions to the regulation regarding the 
submission of reports regarding post-donation information, and argued 
that only a small percentage of those reports were forwarded to 
District Offices for further investigation and that the reporting 
burden has resulted in little tangible outcome. FDA uses those reports 
for reasons other than initiating further investigation or product 
recalls. For example, some reports of post-donation information 
revealed to FDA that the manufacturers had flaws in their donor 
screening procedures, which FDA communicated to the companies. In 
addition, information from biological product deviation reports has 
been valuable to FDA in crafting guidances for industry that improve 
product quality and reduce manufacturing problems generally. However, 
we will continue to monitor and assess our biological product deviation 
reporting program, including the review of these type of reports. 
Consequently, we decline to adopt the comment's recommendations at this 
time.
    In response to FDA's burden estimate, comment one questioned the 
estimated hours per response to submit a report to FDA and stated that 
FDA's estimate did not factor in the time to completely process the 
report. The comment provided an estimation of burden hours to submit a 
report 10 times FDA's estimate. In addition, the comment stated that 
additional time is required to update SOPs associated with the 
regulation and to perform ongoing training.
    Based on comments received in response to the burden hours 
published in the proposed rule of September 23, 1997 (62 FR 49642), FDA 
revised the burden hours (hours per response) in the final rule (65 FR 
66621 at 66632, November 7, 2000) to the current estimate. In response 
to the comments on the proposed rule, we stated the revised estimate 
was based in part on information from industry representatives about 
typical procedures, and the availability of a standardized report form. 
Activities such as investigating, changing SOPs or processes, and 
followup are required under parts 211, 606, and 820, and therefore, are 
not included in the burden estimate for the separate requirement of 
submitting to FDA a biological product deviation report. In the final 
rule, we estimated the hours as a one-time burden, in part, for 
establishing and making adjustments to SOPs and staff training. 
Continuance of these activities would be considered as part of normal 
business practice or covered by other regulations. We, therefore, 
decline to revise the burden hours.
    Comment two questioned FDA's estimate that the rate of submissions 
was not expected to change significantly in the next few years. The 
comment stated that there was a large increase in the number of reports 
from the previous year.
    We realize that the number of reports increased in the first couple 
of years after issuance of the final rule as industry adjusted to the 
new reporting requirements. However, we expect the numbers of reports 
to level off after this adjustment period, and therefore, we estimate 
that the rate of submission will not significantly increase in the next 
few years. If the number of reports significantly increases 
unexpectedly in the next few years, we will adjust the estimates at the 
next interval for approval of the information collection. Consequently, 
we decline to revise the estimates at this time.
    In response to ways of minimizing the collection burden, comment 
one stated that we should notify manufacturers when a report is 
submitted that is not deemed to meet the threshold for reporting. The 
comment also stated that firms are not comfortable with filing 
submissions electronically because there are inadequate safeguards to 
ensure against false reports.
    For reports submitted electronically, we notify the manufacturer of 
those reports that do not meet the threshold for reporting. For those 
submitted in hard copy, we notify the manufacturer if a trend of a 
particular type of unnecessary report is detected. We currently have an 
approximate rate of 45 percent of reports submitted electronically with 
the majority being submitted by the blood industry. Because the system 
is designed with a user name and password that is associated with the 
establishment, we believe there are adequate safeguards for submitting 
the information electronically.
    Comment two responded to ways of minimizing the collection burden 
by recommending that post-donation information be reported in summary 
format not to exceed annually. Although, as mentioned previously, FDA 
has made valuable use of

[[Page 75574]]

promptly-reported post-donation information, we will continue to 
monitor and assess our biological product deviation reporting program 
and make adjustments accordingly.
    FDA estimates the burden of this collection of information as 
follows:

                                 Table 1.--Estimated Annual Reporting Burden\1\
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                                                     Annual Frequency   Total Annual    Hours per
  21 CFR Section     Form No.   No. of Respondents     per Response       Responses     Response     Total Hours
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600.14                   3,486          115                   4.1           476            2             952
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606.171\2\               3,486          207                 130.4        27,000            2          54,000
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606.171\3\               3,486        6,021                   1.1         6,446            2          12,892
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Total                                                                                                 67,844
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\1\ There are no capital costs or operating and maintenance costs associated with this collection of
  information.
\2\ Licensed manufacturers of human blood and blood components, including Source Plasma.
\3\ Unlicensed registered blood establishments and transfusion services (2,800 + 3,221 = 6,021).


    Dated: December 16, 2003.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. 03-32160 Filed 12-30-03; 8:45 am]
BILLING CODE 4160-01-S