[Federal Register Volume 65, Number 216 (Tuesday, November 7, 2000)]
[Rules and Regulations]
[Pages 66621-66635]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-28133]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 600 and 606

[Docket No. 97N-0242]


Biological Products: Reporting of Biological Product Deviations 
in Manufacturing

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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    Summary: The Food and Drug Administration (FDA) is amending the 
regulation requiring licensed

[[Page 66622]]

manufacturers of biological products to report errors and accidents in 
manufacturing that may affect the safety, purity, or potency of a 
product. FDA also is amending the current good manufacturing practice 
(CGMP) regulations for blood and blood components to require 
establishments involved in the manufacture of blood and blood 
components, including licensed manufacturers, unlicensed registered 
establishments and transfusion services, to report biological product 
deviations in manufacturing. The final rule requires licensed 
manufacturers, unlicensed registered blood establishments, and 
transfusion services who had control over the product when a deviation 
occurred to report to FDA the biological product deviation if the 
product has been distributed. The final rule also establishes a 45-day 
reporting period. FDA is issuing the final rule as part of a 
retrospective review under Executive Order 12866 of significant FDA 
regulations to improve the effectiveness of FDA's regulatory program.

DATES: This rule is effective May 7, 2000.

FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for 
Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852, 
301-827-6210.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of September 23, 1997 (62 FR 49642), FDA 
published a proposed rule to amend the requirements for reporting 
errors and accidents in manufacturing biological products in 
Sec. 600.14 (21 CFR 600.14). The proposed rule would also have added 
Sec. 606.171 and expanded the requirement for reporting of errors and 
accidents in the manufacturing of biological products to include 
unlicensed registered blood establishments and transfusion services. 
FDA provided 90 days for comments on the proposed rule.
    FDA is extending a reporting requirement to establishments defined 
in 21 CFR 607.3(c) that manufacture blood and blood components. Such 
establishments include unlicensed registered blood establishments and 
transfusion services (hereinafter referred to as ``unlicensed blood 
establishments''). FDA believes this action is necessary because it has 
observed an increase in the number of product recalls initiated by 
unlicensed blood establishments due to biological product deviations in 
manufacturing that were not reported voluntarily to the agency. FDA is 
also narrowing the scope of the reporting requirement as discussed in 
section II of this document to those reports that are necessary to 
protect the public health, while relieving industry of some reporting 
burden. FDA also believes the reporting requirement will address 
concerns, identified by the Office of Inspector General of the 
Department of Health and Human Services, that: (1) Error and accident 
reports required under Sec. 600.14 were not being submitted in a timely 
manner; and (2) unlicensed blood establishments were not obligated to 
submit such reports.

II. Highlights of the Final Rule

    In response to comments received on the proposed rule, FDA has 
revised several substantive provisions of the proposed rule. FDA has 
replaced the term ``error and accident''with the term ``biological 
product deviation.'' In Secs. 600.14(b) and 606.171(b), the final rule 
more clearly describes the types of events, now termed ``biological 
product deviations,'' that must be reported to FDA. These are events 
which may affect the safety, purity, or potency of a distributed 
biological product and which represent either a deviation from CGMP, 
applicable regulations, applicable standards, or established 
specifications, or are unforeseen or unexpected.
    In an effort to reduce the reporting burden on both industry and 
the agency, while protecting the public health, FDA has changed the 
threshold for when a deviation must be reported. As proposed, a 
licensed manufacturer or unlicensed blood establishment would have 
reported deviations related to products ``made available for 
distribution.'' The final rule focuses on deviations involving 
distributed products only, because such deviations may involve products 
administered to patients, and therefore present the greatest risk to 
public health.
    FDA defines the terms ``distributed'' and ``control'' to make clear 
that the reporting requirement applies only to distributed product. The 
final rule defines ``distributed'' as meaning the biological product 
has left the control of the licensed manufacturer or unlicensed blood 
establishment; or the licensed manufacturer has provided Source Plasma 
or any other blood component for use in the manufacture of a licensed 
product. ``Control'' is defined as having responsibility for 
maintaining a product's continued safety, purity, and potency, and 
compliance with applicable product and establishment standards and CGMP 
requirements.
    If the product never leaves the control of the licensed 
manufacturer or unlicensed blood establishment, no biological product 
deviation report (BPDR) should be filed. However, the licensed 
manufacturer or unlicensed blood establishment who discovers a 
biological product deviation before the product has left its control 
must investigate the deviation. Such an obligation exists independent 
of this rule. For example, under CGMP, a licensed manufacturer must 
thoroughly investigate unexplained discrepancies and batch failures, 
including the failure of a product to meet specifications, and must 
document the discovery, investigation, and followup taken (parts 211 
and 820 (21 CFR parts 211 and 820)). Manufacturers of in vitro products 
licensed under section 351 of the Public Health Service Act (PHS Act) 
(42 U.S.C. 262) must investigate the cause of nonconformities related 
to product, processes, and the quality system, and identify the action 
needed to correct and prevent recurrence of nonconforming product and 
other quality problems ( Sec. 820.100). The CGMP regulations applicable 
to licensed and unlicensed blood establishments provide, ``A thorough 
investigation, including the conclusions and follow-up, of any 
unexplained discrepancy or the failure of a lot or unit to meet any of 
its specifications shall be made and recorded'' (Sec. 606.100(c) (21 
CFR 606.100(c))). FDA will monitor internal quality assurance (QA) 
procedures through routine inspections.
    In Sec. 600.14(a)(2)(i), FDA has limited the exception to the 
reporting requirement for manufacturers of in vitro diagnostic products 
to manufacturers who only manufacture in vitro diagnostic products that 
are not licensed under section 351 of the PHS Act. Manufacturers of 
such products continue to have reporting obligations under 21 CFR part 
803. Establishments that manufacture both in vitro diagnostic products 
licensed under section 351 of the PHS Act and unlicensed medical 
devices will be required to report under Sec. 600.14 only those events 
which may affect the safety, purity, or potency of the licensed 
product.
    In Sec. 600.14(a)(2)(iii), FDA is clarifying the reporting 
requirement for licensed manufacturers of biological products when the 
manufacturer, as part of its license application, is approved to 
manufacture Source Plasma or any other blood component for further 
manufacture of other biological products. When a biological product 
deviation occurs during the manufacture of the Source Plasma or

[[Page 66623]]

any other blood component, the BPDR must be submitted under 
Sec. 606.171. When a biological product deviation occurs after the 
manufacture of that Source Plasma or any other blood component and 
during the manufacture of another biological product, the BPDR is 
submitted under Sec. 600.14. When a licensed manufacturer provides 
Source Plasma or any other blood component for use in the manufacture 
of another licensed biological product, such Source Plasma or any other 
blood component has been distributed under Sec. 606.3(k).
    FDA also is clarifying the reporting responsibilities of licensed 
manufacturers and unlicensed blood establishments who contract out 
certain manufacturing steps. A manufacturer who contracts with another 
person to perform any manufacturing step but who retains control over 
the product is still responsible for reporting under the rule even if 
the deviation occurred or was discovered at the contract establishment. 
Sections 600.14(a)(1) and 606.171(a)(1) make explicit that licensed 
manufacturers and unlicensed blood establishments must establish, 
maintain, and follow a procedure for receiving from their contractors 
the information necessary to fulfill their reporting requirements.
    FDA is retaining the proposed 45-day reporting time in the final 
rule but is clarifying that the 45-day time period runs from the date 
that the manufacturer, its agent, or another person performing a 
manufacturing, holding, or distribution step under the manufacturer's 
control, first discovers information reasonably suggesting a reportable 
event has occurred. FDA is also adding a requirement in Secs. 600.14(d) 
and 606.171(d) that licensed manufacturers and unlicensed blood 
establishments use Form FDA-3486 to report biological product 
deviations. This form is available in paper form and also on the 
Internet. Sections 600.14(e) and 606.171(e) indicate where and how the 
BPDR form should be submitted.
    Finally, FDA has written the final rule using plain language in 
accordance with the presidential memorandum on plain language in 
government writing, dated June 1, 1998. FDA has adopted the plain 
language approach to make its written communications with the public 
more accessible and understandable. As a result, FDA is expanding 
Sec. 600.14 and 606.171 in the final rule to address the following: (1) 
Who must report, (2) What must be reported, (3) When must the report be 
submitted, (4) How must the report be submitted, and (5) Where must the 
report be sent?

III. Comments on the Proposed Rule and FDA Responses

    FDA received 98 comments on the proposed rule. The comments were 
submitted by manufacturers, blood establishments, trade associations, 
professional associations, Department of Defense, and individuals. In 
addition, the Office of Management and Budget (OMB) forwarded to FDA a 
number of comments it received on the proposed rule. Thirty-two 
comments supported FDA's goal of creating a standardized reporting 
system to identify biological product deviations in manufacturing and 
recognized the importance to blood safety of requiring prompt reporting 
of biological product deviations in the manufacture of blood and blood 
components. Fifteen comments objected to the proposed rule. Several 
comments, mostly those from transfusion services and pharmaceutical 
entities, objected to a mandatory reporting requirement being applied 
to them. Several expressed concerns that the reporting burden would be 
overwhelming.
    In general, the comments expressed specific concerns about the 
scope and content of the proposed rule and requested clarification of 
certain definitions. FDA summarizes and responds to each of the 
received comments in the following sections.

A. General Comments

    (Comment 1) Twenty-one comments questioned the public health 
benefit of the proposed rule and asked FDA to further define its public 
health and safety objective. Many of the comments suggested that the 
reporting system overlapped existing QA programs and was, therefore, 
unnecessary.
    The objectives of the biological product deviation reporting 
requirement are to: (1) Enable FDA to respond when public health may be 
at risk, (2) expedite reporting of biological product deviations in 
manufacturing, (3) provide FDA with uniform data to track trends that 
may indicate broader threats to the public health, (4) create a uniform 
reporting requirement that can be enforced against noncomplying 
entities, and (5) help ensure licensed manufacturers and unlicensed 
blood establishments are taking appropriate actions to investigate and 
correct biological product deviations.
    The reporting system will enable the agency to evaluate and monitor 
blood establishments in response to detected deviations, and regularly 
alert field staff and blood establishments with trend analysis of the 
types of deviations reported. Under the existing rule, there were two 
impediments to the success of the reporting process: (1) Error and 
accident reports were not being submitted in a timely manner by 
establishments, and (2) there was no assurance that unlicensed blood 
establishments were submitting reports.
    The reporting system is not intended to overlap QA programs. 
Instead, it provides FDA with information that an individual 
establishment's QA program may not detect. For example, if an event 
occurs once a year in every establishment, it may not appear 
significant to any single establishment. The reporting system will 
allow FDA to recognize the significance of that event in a timely 
fashion and to take appropriate action to protect the public health. 
Reporting of biological product deviations will enable FDA to identify 
areas in which further regulation or guidance is needed to assist 
licensed manufacturers and unlicensed blood establishments in 
decreasing the occurrence of these events.
    (Comment 2) Fifty comments wanted to know how FDA will use or 
analyze the information and what procedure FDA will use to respond to 
reports received under the rule. Two comments stated that the reports 
should not be used as a basis for issuing a Form FDA-483.
    A BPDR alone will not be a basis for issuing a Form FDA-483. Form 
FDA-483 is a list a list of observations noted during an FDA inspection 
and issued to the firm at the conclusion of the inspection. The firm is 
expected to respond to the observations and make the necessary 
corrections. First, this information will aid FDA, licensed 
manufacturers, and unlicensed blood establishments in appropriately 
targeting QA efforts to improve product quality and reduce 
manufacturing problems. In addition to reviewing reports upon receipt 
at FDA, FDA will review all reports during routine inspections and 
examine all manufacturing deviations, not merely reportable deviations, 
to ensure that the establishment has followed all established standard 
operating procedures (SOP's) related to investigation, followup, and 
reporting of deviations. Secondly, the BPDR's will inform FDA about 
specific problems licensed manufacturers and unlicensed blood 
establishments encounter in the manufacture of biological products. FDA 
intends to provide this data to industry, in accordance with its 
responsibility to safeguard trade secrets and confidential commercial 
information. FDA already provides this kind of data in fiscal quarter 
summaries, available to the public by mail, facsimile, and Internet. 
Thirdly, these

[[Page 66624]]

reports will identify areas needing future guidance from the agency. 
FDA will issue such guidance in accordance with its good guidance 
practices (GGP's).
    A BPDR alone will not be a basis for issuing a Form FDA-483. 
However, a documented failure to follow CGMP or other regulatory 
compliance problem connected to a deviation may become an observation 
on a Form FDA-483. For example, an investigator may include an 
observation under one of the following conditions: (1) The deviation 
reoccurs because of inadequate corrective action, (2) investigation of 
the deviation is inadequate, or (3) the deviation represents an 
underlying systemic problem in the operation. Significant CGMP 
deficiencies related to a BPDR may also become the subject of a Form 
FDA-483 observation. Of course, an investigator may include the failure 
to file a BPDR as an observation on a Form FDA-483.
    (Comment 3) Several comments expressed concern that FDA would not 
have the resources to handle the reports submitted under the proposed 
rule.
    After reviewing the comments to the proposed rule, FDA has worked 
actively to reduce the burden of reporting on licensed manufacturers, 
unlicensed blood establishments, and the agency under the final rule. 
FDA has refocused the final rule to require reports only for 
distributed products. FDA is also developing a standardized format for 
reporting, which will not only streamline the process for the reporter, 
but also allow FDA to process the reports more efficiently. FDA 
believes that the reporting requirement under the final rule will not 
present an undue burden on licensed manufacturers, unlicensed blood 
establishments, or the agency.
    (Comment 4) Three comments asked how FDA would enforce the proposed 
rule.
    In 1983, through a memorandum of understanding (MOU), the 
Healthcare Financing Administration (HCFA) and FDA coordinated all 
federally authorized inspections of unlicensed blood establishments in 
order to minimize duplication of effort and to reduce the burden on 
affected facilities. HCFA and FDA will use their usual enforcement 
tools available under the Federal Food, Drug, and Cosmetic Act (the 
act) (21 U.S.C. 301 et seq.) and the PHS Act (42 U.S.C. 201 et seq.). 
The agencies will review compliance with the reporting requirements 
during inspections. If upon inspection of a licensed manufacturer or 
unlicensed blood establishment, the inspecting agency discovers the 
establishment is not complying with the biological product deviation 
reporting requirement, or the requirements for investigation and 
followup, the inspecting agency may take further enforcement action, as 
warranted.
    (Comment 5) One comment questioned whether biological product 
deviation reports would be subject to the Freedom of Information Act 
(FOIA) and, accordingly, available to the media or public and whether 
reporting could cause disclosure of confidential information.
    BPDR's would be subject to disclosure under the provisions of the 
FOIA and the implementing regulations in 21 CFR part 20. FDA will 
appropriately purge all nondisclosable information prior to the release 
of the reports.
    (Comment 6) Seven comments requested that FDA obtain additional 
data and hold a public meeting before implementing a final rule. One 
comment suggested proceeding with a demonstration project first.
    In addition to following the normal rulemaking process, FDA has 
discussed the rule in various public forums. FDA believes interested 
parties have been given ample opportunity to express their views on the 
proposed rule. A ``demonstration program'' is unnecessary because this 
is not a new program, but a revision and updating of an existing 
program with which most licensed manufacturers have experience. 
However, FDA may engage in further public discussion to provide 
guidance to industry concerning what constitutes a reportable deviation 
within the parameters of the final rule.
    (Comment 7) Three comments requested that FDA develop guidance for 
the proposed rule.
    FDA agrees that guidance to industry would be helpful. FDA has 
developed draft guidance regarding those events it would expect to be 
reported under this rule. The draft guidance recognizes that licensed 
manufacturers and unlicensed blood establishments may shoulder a wide 
range of responsibilities in manufacturing. A manufacturer of licensed 
biological products would be in control of the product for more steps 
in manufacturing than a small hospital transfusion service. 
Accordingly, the draft guidance describes specific guidance for each 
type of licensed manufacturer and unlicensed blood establishment. The 
notice of availability for the draft guidances specific for licensed 
manufacturers of products other than blood and blood components, and 
licensed and unlicensed blood establishments will issue in the Federal 
Register in the near future.
    (Comment 8) FDA received several comments from industry that 
extending the reporting requirement to unlicensed entities in proposed 
Sec. 606.171 imposed an unnecessary burden on these entities.
    FDA indicated in proposing this regulation that one of its primary 
objectives was to make the biological product deviation reporting 
requirement applicable to all blood establishments, whether licensed 
manufacturers, unlicensed registered blood establishments, or 
transfusion services. In the proposed rule, FDA stated that reports 
from the full spectrum of establishments engaged in manufacturing and 
distribution of blood and blood components were necessary to 
effectively evaluate and monitor the blood industry. FDA continues to 
believe that a mandatory reporting requirement is necessary for all 
establishments involved in blood and blood product manufacturing and is 
establishing the biological deviation reporting requirement as part of 
the CGMP regulations, which these establishments must follow.

B. Scope

    (Comment 9) One comment recommended FDA adopt a single mechanism 
for reporting all errors and accidents, adverse events, etc., for all 
blood products, medical devices and all drugs, and eliminate all other 
reporting programs, voluntary or mandatory.
    FDA recognizes that the reporting programs for biological products, 
human drugs, and medical devices have varying requirements. What is 
reported, and how it is reported, are different under the different 
systems. These differences are intentional. For example, the adverse 
event reporting (AER) and medical device reporting systems focus on 
patient impact. The starting point for reporting, therefore, is often 
patient reaction to a product. In contrast, biological product 
deviation reporting focuses on the manufacturing process as it may 
affect the safety, purity, and potency of the product. FDA anticipates 
that information submitted in BPDR's will improve product quality and 
may help reduce the incidence of adverse patient outcomes without undue 
burden on licensed manufacturers and unlicensed blood establishments.
    (Comment 10) Five comments stated that the proposed rule should 
apply only to blood and blood products and should not extend to 
biotechnology products. These comments argued that the need to revise 
error and accident regulations for biotechnology products is not clear 
because there does not exist a pattern of recalls for these products. 
The comments stated that the recall

[[Page 66625]]

guidelines in part 7 (21 CFR part 7) and the AER system (21 CFR 600.80) 
are adequate to ensure the safety and quality of biotechnology 
products.
    The regulatory scheme for biotechnology products has always 
included recall guidelines (part 7), AER, and error and accident 
reporting ( Sec. 600.14). These three programs, each designed to serve 
different objectives, have worked together to ensure the safety and 
quality of biotechnology products. Adverse experience reporting focuses 
on patient outcomes. Consequently, the type and specificity of the 
information reported as adverse experiences differs substantially from 
that required in biological product deviation reports. Under the recall 
provisions of part 7, manufacturers notify FDA when they voluntarily 
remove products from the marketplace that are in violation of the laws 
administered by FDA. The biological product deviation regulations are 
designed to gather information about the events that give rise to 
defective or potentially defective products and provide FDA with an 
essential tool to monitor potential risks to public health and to 
facilitate a response when necessary.
    Section 600.14, in its current form, requires error and accident 
reporting by all licensed biological product manufacturers, including 
manufacturers of biotechnology products. This rule would not impose new 
requirements on such manufacturers. In fact, by limiting reporting to 
biological product deviations involving distributed products, the new 
rule would decrease the preexisting burden on such manufacturers. FDA 
believes the revised reporting requirement is necessary to ensure that 
all manufacturers understand their reporting requirements, to expedite 
biological product deviation reporting, and to enable FDA to monitor 
accurately the safety of biological products.
    (Comment 11) Ten comments requested that transfusion centers not be 
regulated to the same extent as blood collection centers and the 
pharmaceutical industry under the proposed rule. Of these, five 
comments proposed that the reporting guidelines themselves be specific 
to each type of establishment. Six comments called for definitions or 
examples specific to transfusion service practice and two comments 
called for separate data collection forms.
    FDA believes that in order to achieve an accurate overview of the 
industry, it is most useful to impose the same reporting requirement on 
all blood establishments, including transfusion centers. However, FDA 
recognizes that different regulated entities may need specific guidance 
on how the biological deviation reporting requirement will apply to 
them. FDA is issuing guidance to support the final rule that will 
include examples specific to blood and source plasma collection 
centers, pharmaceutical and biological device manufacturers, and 
transfusion services. FDA also developed a biological product deviation 
reporting form. FDA believes one form for all the entities covered 
under the rule will facilitate processing of the reports and will aid 
reporters in providing the necessary information. The agency will 
provide separate instructions on completing and submitting the 
biological product deviation reporting form.
    (Comment 12) Eight comments asked how the biological product 
deviation reporting requirement will affect the new drug application 
(NDA) Field Alert Report regulations under 21 CFR 314.81(b)(1) and 
several comments recommended harmonizing these regulations.
    The BPDR's will have little, if any affect on the NDA Field Alert 
regulations. The NDA Field Alert regulations are applicable only to 
those products that are approved for marketing under the provisions of 
part 314 (21 CFR part 314), and not to drug products subject to 
licensing under the PHS Act. 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 Sec. 601.2(c) (21 CFR 601.2(c)) 
for a list of such biotechnology products and Sec. 314.70(g), 
601.2(c)(1) and (c)(2), and 601.12 (21 CFR 601.12) for examples of 
harmonization.
    For these biotechnology products, a total of 13 error and accident 
reports were submitted under Sec. 600.14 in the fiscal year (FY) 1999. 
Because FDA believes this is a very small burden to industry, FDA has 
determined that reports for such biotechnology products should continue 
to be submitted consistent with the requirements for other biological 
products under Sec. 600.14 of the final rule. This will allow the 
Center for Biologics Evaluation and Research (CBER) to keep all reports 
in a single data base and will facilitate the overall assessment of its 
biological product deviation reporting program. If the level of 
reporting or the needs of the agency change, FDA will reconsider 
whether to harmonize its reporting requirements for biotechnology 
products.
    (Comment 13) Twenty-two comments recommended developing a tiered 
system of reporting based on the severity of the deviation in which 
serious errors or accidents would be reported and all other errors and 
accidents would be handled through internal QA programs.
    FDA considers any biological product deviation that may affect the 
safety, purity, and potency of a product to be ``serious.'' However, 
deviations that are discovered before distribution pose less of a 
threat to the public health because no patient would receive the 
product, and because the licensed manufacturer or unlicensed blood 
establishment's QA procedures worked to prevent the distribution of 
product subject to that biological product deviation. Accordingly, FDA 
has established an approach to reporting biological product deviations 
that limits reporting to events that involve distributed products and 
that may affect the safety, purity, or potency of the product.
    (Comment 14) Eighteen comments recommended adopting an alternative 
reporting system such as the medical event reporting system for 
transfusion medicine (MERS-TM).
    MERS-TM, a voluntary reporting system, was designed as a standard 
method for collection and analysis of event reports for blood 
establishments to implement as part of their QA system. The MERS-TM is 
designed to capture all manufacturing errors and accidents, including 
those ``near miss'' events that may be discovered by the blood 
establishment prior to distribution of the product. While FDA believes 
that the MERS-TM system is useful in reporting ``near miss'' events on 
a voluntary basis, FDA is limiting the requirement for reporting to 
biological product deviations affecting distributed products.

C. Definitions

    (Comment 15) Forty-five comments requested clarification of the 
definition of the terms ``errors and accidents'' in proposed 
Secs. 600.3(hh) and 606.3(k). Several of these comments suggested 
alternative language.
    FDA is clarifying the regulations by eliminating the terms ``error 
and accident.'' The classification of events as an ``error'' or 
``accident'' is immaterial to the purposes underlying the rule and 
appears to have caused confusion. Consequently, FDA has revised the 
rule to focus the reporting requirement on events that represent a 
deviation from CGMP, applicable regulations, applicable standards or 
established specifications, or represent unexpected or unforeseeable 
events,

[[Page 66626]]

which may affect the safety, purity, or potency of a distributed 
product. Such events are reportable regardless of whether or not they 
are considered ``errors'' or ``accidents.'' In the final rule, FDA has 
termed such events ``biological product deviations'' and described what 
constitutes a biological product deviation in Secs. 600.14(b) and 
606.171(b).
    (Comment 16) Three comments suggested that the reporting 
requirement in proposed Secs. 600.3(hh)(1) and 606.3(k)(1) should be 
limited to deviations from CGMP and that extending it to ``applicable 
standards'' or ``established specifications'' was beyond the FDA's 
jurisdiction.
    FDA disagrees with the suggestion that such matters are beyond 
FDA's jurisdiction. As set out in Secs. 600.14(b) and 606.171(b), 
licensed manufacturers and unlicensed blood establishments must submit 
a BPDR only if the deviation ``may affect the safety, purity, or 
potency'' of a product, and if other reporting criteria are met. Events 
affecting the safety, purity, and potency of biological products fall 
squarely within FDA's jurisdiction. Moreover, the PHS Act requires FDA 
to consider ``standards designed to assure that the biological product 
continues to be safe, pure, and potent'' (42 U.S.C. 
262(a)(2)(B)(i)(II)).
    (Comment 17) Thirty-two comments requested clarification of the 
definition of ``made available for distribution'' in proposed 
Secs. 600.3(ii) and 606.3(l). Thirty-seven comments requested that the 
definition be amended to limit the scope of the proposed rule to 
reporting of deviations which occur after a product has been 
distributed, and six comments asked that ``made available for 
distribution'' be defined by each facility based on their established 
process controls.
    FDA agrees with the comments that suggested that the scope be 
limited to those products that have been distributed and has written 
the final rule to reflect this. FDA considers all events that may 
affect the safety, purity, or potency of a biological product to be 
significant, whether prior to or after distribution. Limiting the 
reporting requirement to distributed products will reduce the burden of 
reporting on licensed manufacturers, unlicensed blood establishments, 
and on FDA, while not sacrificing public safety.
    Licensed manufacturers and unlicensed blood establishments remain 
obligated to document, investigate and followup any event that may 
affect the safety, purity, or potency of a biological product under 
CGMP regulations, whether the event is reportable under this rule or 
not. FDA will continue to monitor both reportable and nonreportable 
events and corrective actions through inspections.
    (Comment 18) One comment stated the term ``made available for 
distribution'' in proposed Secs. 600.3(ii) and 606.3(l) is ambiguous in 
relation to intermediates since at each intermediate state the product 
may be released for further processing.
    FDA has clarified the final rule by limiting reporting of 
biological product deviations to distributed products, i.e., they have 
left the licensed manufacturer or unlicensed blood establishment who 
controlled the product at the time the deviation occurred; or the 
licensed manufacturer has provided Source Plasma or any other blood 
component for use in the manufacture of a licensed product.

D. Who Must Report?

    (Comment 19) One comment asked for clarification on how FDA will 
apply this regulation to cooperative manufacturing arrangements, 
including shared and contract manufacturers.
    Under Sec. 600.14, it is the licensed manufacturer who must report 
biological product deviations. That is because, up until the time the 
product is distributed, it is the license holder who is responsible for 
maintaining the continued safety, purity, and potency of the biological 
product, for compliance with applicable product and establishment 
standards, and for compliance with CGMP. If the license holder arranges 
for another manufacturer to perform a manufacturing step, that 
manufacturing step is performed under the license holder's control, and 
the license holder must report biological product deviations that occur 
during that manufacturing step. In shared manufacturing situations, 
where two or more manufacturers operate under their own license, each 
manufacturer would report a biological product deviation that occurred 
when the product was in its control; i.e., when the first shared 
manufacturer completes his manufacturing step and sends the product to 
the second shared manufacturer for additional manufacturing, the 
product is considered distributed by the first shared manufacturer.
    Section 606.171 applies to all blood establishments, including 
licensed establishments, unlicensed registered blood establishments, 
and transfusion services. The rule requires the blood establishment 
that has control over a product when a blood product deviation occurs 
to report to FDA. If a blood establishment contracts a manufacturing 
step to another facility, or enters into a shared manufacturing 
agreement, the establishment responsible for maintaining the continued 
safety, purity, and potency of the product and for compliance with 
applicable product and establishment standards, and for compliance with 
CGMP, must submit a BPDR for any deviation occurring while the 
biological product is under its control.
    (Comment 20) One comment suggested FDA require both the blood bank 
or transfusion service who receives a defective product from a licensed 
manufacturer and the licensed manufacturer to report biological product 
deviations to ensure the effectiveness of the reporting process.
    In the final rule, FDA has attempted to eliminate duplicate 
reporting by regulated entities. The licensed manufacturer or 
unlicensed blood establishment who had control over the product when 
the deviation occurred is in the best position to provide the necessary 
information to FDA. Therefore, under the final rule, the licensed 
manufacturer or unlicensed blood establishment who had control over the 
product when the deviation occurred is responsible for reporting. 
Consignees should report product deficiencies to the licensed 
manufacturer or unlicensed blood establishment and assist in the 
investigation of the product's deficiencies, if necessary.
    Example 1: An unlicensed blood establishment pools 10 units of 
cryoprecipitate and affixed an incorrect, extended expiration date. The 
unlicensed blood establishment issues the pooled cryoprecipitate to a 
patient. The unlicensed blood establishment would be required to submit 
a BPDR to FDA because: (1) The product did not meet CGMP; (2) the 
unlicensed blood establishment had control of the product when the 
deviation occurred; (3) the deviation may have affected the safety, 
purity, and potency of the product for the patient; and (4) the product 
was distributed.
    Example 2: An unlicensed blood establishment receives a unit of 
irradiated red blood cells from a licensed manufacturer and issues the 
product to a patient requiring irradiated red blood cells. The licensed 
manufacturer of the blood product subsequently notifies the unlicensed 
blood establishment that the unit was improperly irradiated. The 
licensed manufacturer, not the unlicensed blood establishment, is 
required to submit a BPDR to FDA because: (1) The product did not meet 
CGMP; (2) the deviation

[[Page 66627]]

occurred under the control of the licensed manufacturer; (3) the 
deviation may affect the safety, purity, and potency of the product; 
and (4) the licensed manufacturer distributed the product to the 
unlicensed blood establishment.

E. What Kind of Events Are Reportable?

    (Comment 21) Forty-two comments stated that FDA provided 
insufficient information about what events must be reported in proposed 
Secs. 600.14 and 606.171. Numerous comments also expressed concern 
regarding the examples of what events to report that FDA provided in 
the preamble to the proposed rule. Ten comments asked for information 
on what not to report. Seven comments asked FDA to provide specific 
examples of events to be reported by hospital-based transfusion 
services.
    In response to these comments, FDA has changed the final rule to 
limit reportable events to those involving distributed products. As 
discussed in comment seven of this document, FDA developed guidance 
that will provide specific examples of reportable events as those 
events relate to the various regulated entities. FDA considered these 
comments in developing its guidance.
    (Comment 22) Two comments asked whether the proposed rule was 
limited to manufacturing activities or whether it included 
nonmanufacturing events such as testing, storage, labeling, and 
recordkeeping.
    FDA disagrees with the interpretation that testing, storage, 
labeling, and recordkeeping are not manufacturing activities. The term 
``manufacture'' is defined in 21 CFR 600.3(u) as ``all steps in 
propagation or manufacture and preparation'' and includes, for example, 
filling, testing, labeling, packaging, and storage.
    The final rule further states in Secs. 600.14(b) and 606.171(b) 
that any event, and information relevant to the event, associated with 
manufacturing, to include testing, processing, packing, labeling, or 
storage, or with the holding, or distribution, must be reported if they 
meet the other criteria. If a recordkeeping error may have affected the 
safety, purity, and potency of the product and meets the other criteria 
in Secs. 600.14(b) and 606.171(b), it is reportable under the 
regulations.
    (Comment 23) One comment asked how a licensed manufacturer or 
unlicensed blood establishment would distinguish between an error and 
accident that would be reportable from any unexplained discrepancies or 
in-process or final specification investigations conducted under 
Sec. 211.192 or other regulation, which would not have to be reported.
    The requirements to investigate discrepancies under Sec. 211.192 
and to report product deviations under Secs. 600.14 and 606.171 are not 
mutually exclusive. Under Sec. 211.192, manufacturers are required to 
investigate any unexplained discrepancies or failure to meet in-process 
or final product specifications. The CGMP regulations applicable to 
blood establishments provide, ``A thorough investigation, including the 
conclusions and follow-up, of any unexplained discrepancy or the 
failure of a lot or unit to meet any of its specifications shall be 
made and recorded'' (Sec. 606.100(c)). If during the investigation the 
criteria described in Secs. 600.14(b) and 606.171(b) are met, a BPDR is 
required.
    (Comment 24) One comment asked whether the biological product 
deviation reporting requirement applied to validation batches submitted 
in support of a biologics license application (BLA), or to materials 
submitted under an investigative new drug application (IND).
    Under Secs. 600.14 and 606.171, biological product deviations 
related to products under an IND would not be reportable unless the 
product was licensed for another intended use. However, information 
related to the deviation may be required to be reported under the IND 
regulations in 21 CFR part 312. Biological product deviations related 
to validation batches would not be reportable unless the products were 
distributed after receipt of a biologics license.
    (Comment 25) One comment asked if the submission of a supplement 
for reprocessing would preclude the submission of a BPDR.
    The submission of a supplement for reprocessing would not preclude 
the submission of a BPDR. If a product has been distributed and a 
licensed manufacturer or unlicensed blood establishment determines that 
a biological product deviation has occurred, then the licensed 
manufacturer or unlicensed blood establishment must submit a BPDR 
whether or not it subsequently reprocesses the product. If the licensed 
manufacturer or unlicensed blood establishment discovers a biological 
product deviation before it distributes the product, and subsequently 
reprocesses and distributes the affected product, no BPDR would be 
required as long as the reprocessed product was unaffected by the 
original deviation.

F. What Type of Information Do Licensed Manufacturers and Unlicensed 
Blood Establishments Report?

    (Comment 26) Two comments requested that FDA delete any reference 
to ``disposition of the product'' from the information that is to be 
reported under the rule because this information would not be available 
within the 45-day time requirement.
    FDA believes licensed manufacturers and unlicensed blood 
establishments will usually know the disposition of the product within 
the 45-day reporting period. Licensed manufacturers and unlicensed 
blood establishments should know if the product was shipped to another 
facility, destroyed, quarantined, designated for reprocessing, disposed 
of in some other manner, or, in many cases, administered to a patient.
    (Comment 27) Seventeen comments recommended that if the product has 
been subject to recall, then the recall should be the instrument for 
reporting the disposition of the product.
    FDA disagrees. FDA believes information on the disposition of the 
product and retrieval efforts are important in analyzing the impact of 
reported deviations on the public and should be submitted in BPDR's. 
The information required for the BPDR is not as extensive as the recall 
information voluntarily provided to the district. The information 
regarding final disposition does not need to be complete by the time 
the BPDR is submitted. By obtaining as much information as possible on 
the disposition of a product at the time the report is submitted, FDA 
will be able to perform appropriate followup action. The draft guidance 
document will further describe the required information to be reported 
in the BPDR.
    (Comment 28) One comment asked if FDA would require licensed 
manufacturers and unlicensed blood establishments to consider previous 
and subsequent lots in investigating any lot that instigated a BPDR.
    The regulations in this final rule do not affect the manner in 
which a biological product deviation is investigated. The obligation to 
investigate a biological product deviation is part of the CGMP 
regulations for biological drug products and biological devices, 
including blood and blood components. The CGMP requirements for blood 
establishments, whether licensed or unlicensed, require blood 
establishments to thoroughly investigate discrepancies 
(Sec. 606.100(c)) and to maintain and make available to FDA appropriate 
records of such investigation, conclusions, and

[[Page 66628]]

followup (Secs. 606.100(c) and 606.160(b)(7)(iii) (21 CFR 
606.160(b)(7)(iii))). Licensed manufacturers subject to drug CGMP 
(Secs. 211.192 and 211.198) and medical device manufacturers (see 
Sec. 820.100) are similarly obligated to investigate, correct, and 
record findings related to biological product deviations. Under these 
existing regulations FDA expects the licensed manufacturer or 
unlicensed blood establishment to determine what impact the deviation 
may have had on other product lots and take appropriate corrective 
action. These regulations do not mandate the manner of investigation by 
a licensed manufacturer or unlicensed blood establishment but require 
that the investigation be complete.

G. When to Report

    (Comment 29) Twenty-three comments stated that 45-calendar days to 
report a biological product deviation as proposed in Secs. 600.14(a) 
and 606.171 is not enough time since licensed manufacturers and 
unlicensed blood establishments must analyze and correct the deviation 
prior to reporting. One comment suggested that fewer than 45 days to 
report would be better.
    In adopting a 45-day time requirement, FDA looked at the history of 
reporting under the prior regulations and determined that 45 days was a 
reasonable period given the importance of timely reporting. The agency 
reviewed the reports submitted during FY 1997 through 1999 and an 
average of 73 percent of the reports was received within 45 days.
    Licensed manufacturers and unlicensed blood establishments should 
not wait to report biological product deviations until after completing 
their corrective actions. Rather, licensed manufacturers and unlicensed 
blood establishments should submit BPDR's as soon as possible but no 
later than 45 days after the date that the licensed manufacturer or 
unlicensed blood establishment, its agent, or another person performing 
a manufacturing, holding, or distribution step under the manufacturer's 
or establishment's control, first discovers information reasonably 
suggesting a reportable event has occurred. The reports should include 
information on the intended followup to be taken if followup is not 
completed prior to submission of the report. To facilitate timely 
reporting by licensed manufacturers and unlicensed blood 
establishments, FDA is providing guidance on how to report as well as a 
standardized form for reporting.
    (Comment 30) Fourteen comments requested clarification as to when 
the 45-day reporting time limit begins. Several of these comments 
offered various possible starting dates.
    In response to these comments, FDA has clarified the 45-day time 
requirement in the final rule. The 45 days commence on ``the date (the 
licensed manufacturer or unlicensed blood establishment, its agent, or 
another person who performs a manufacturing, holding, or distribution 
step under the control of the licensed manufacturer or unlicensed 
establishment) acquire(s) information reasonably suggesting that a 
reportable event has occurred.'' For example, if a manufacturer 
contracted with a third party to receive and process its customer 
complaints, that third party would be the manufacturer's agent for 
purposes of this rule, and the 45 days would begin to run upon the 
agent's receipt of information reasonably suggesting a reportable event 
has occurred.
    (Comment 31) Four comments recommended adopting a hierarchy for 
when to report based on the potential risk of the deviation. For 
example, one comment suggested errors with substantial risk be reported 
within 45 days, errors with moderate risk be reported when the internal 
investigation is complete and errors with minimal risk be reported in 
an annual report.
    FDA has adopted a simpler approach based on the potential public 
health risk of the event. Biological product deviations involving 
distributed products must be reported within 45 days. Biological 
product deviations that are discovered before the product leaves the 
control of the licensed manufacturer or unlicensed blood establishments 
are nonreportable, but reviewable during routine inspections, because 
such events present significantly less public health risk.

H. How to Report

    (Comment 32) Forty-seven comments requested a standardized format 
for reporting biological product deviations and several of these 
submitted a proposed form. Fourteen comments requested one form for 
hospital-based transfusion centers and a separate form for blood 
collection centers and pharmaceutical manufacturers. Seventeen comments 
requested FDA to develop means for electronic reporting. One comment 
suggested FDA supply forms to blood suppliers.
    FDA recognizes the need for a standardized method for reporting 
biological product deviations. FDA has developed a form for licensed 
manufacturers and unlicensed blood establishments to use to report 
under the final rule and is issuing guidance including instructions for 
completing the biological product deviation reporting form. FDA also 
has developed an electronic format for reporting. The agency has taken 
into consideration the comments and sample forms submitted in devising 
the biological product deviation reporting form. The agency also is 
requesting comments to the docket from the public on the report form 
and the instructions for preparing the report in accordance with the 
Paperwork Reduction Act of 1995. The agency is making the form 
available in various ways, including the FDA website at http://www.fda.gov/cber and the CBER FAX information system at 1-888-CBER-FAX.

IV. Analysis of Impacts

    FDA has examined the impacts of the final rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612) (as 
amended by subtitle D of the Small Business Regulatory Fairness Act of 
1996 (Public Law 104-121)), and the Unfunded Mandates Reform Act of 
1995 (Public Law 104094). Executive Order 12866 directs agencies to 
assess all costs and benefits of available regulatory alternatives and, 
when regulation is necessary, to select regulatory approaches that 
maximize net benefits (including potential economic, environmental, 
public health and safety, and other advantages; distributive impacts; 
and equity). The Regulatory Flexibility Act requires agencies to 
analyze whether a rule may have a significant impact on a substantial 
number of small entities and, if it does, to analyze regulatory options 
that would minimize the impact. Section 202(a) of the Unfunded Mandates 
Reform Act requires that agencies prepare a written statement of 
anticipated costs and benefits before proposing any rule that may 
result in an expenditure by State, local, and tribal governments, in 
the aggregate, or by the private sector, of $100 million (adjusted 
annually for inflation) in any one year.
    The agency has determined that the final rule is a significant 
action as defined in section 3, paragraph (f)(4) of Executive Order 
12866. We have also determined that this rule will not result in 
aggregate expenditures for State, local, and tribal governments, or the 
private sector of $100 million in any one year. Based on FDA's analysis 
using available data, the agency does not anticipate that the rule will 
result in a significant impact on a substantial number of small 
entities.

[[Page 66629]]

A. Estimated Economic Impact

    The rule will have an impact on licensed manufacturers and 
unlicensed blood establishments as described in table 1 of this 
document. All of these types of establishments will experience both a 
one-time cost impact to make changes to their recordkeeping systems and 
reporting procedures, as well as an annual cost impact associated with 
the ongoing reporting of product deviations that are encountered. Table 
1 below summarizes these two components of cost impact. The rule is 
estimated to have an aggregate one-time cost impact of $8,131,648 and 
an annual cost impact of $340,319. These estimates are detailed in the 
discussion that follows.

                             Table 1.--Summary of Estimated Cost Impact of the Rule
----------------------------------------------------------------------------------------------------------------
                                                                                  Total One-Time   Total Annual
                                Industry Affected                                      Cost            Cost
----------------------------------------------------------------------------------------------------------------
                         Licensed Manufacturers (Other than Blood and Blood Components)
----------------------------------------------------------------------------------------------------------------
111 Manufacturers of biologics                                                          $348,096     ($1,803)\1\
Subtotal for manufacturers of biologics                                                 $348,096     ($1,803)\1\
----------------------------------------------------------------------------------------------------------------
                                              Blood Establishments
----------------------------------------------------------------------------------------------------------------
Licensed blood establishments                                                           $727,552   ($286,395)\1\
2,800 Registered blood establishment                                                  $4,390,400         $95,397
3,400 Transfusion services                                                            $2,665,600        $533,120
Subtotal for blood establishments                                                     $7,783,552        $342,122
Total Cost Impact                                                                     $8,131,648       $340,319
----------------------------------------------------------------------------------------------------------------
\1\Use of parenthesis indicates savings.

    Based on the agency's registration data base, there are an 
estimated 111 licensed biologics manufacturers, 232 licensed blood 
establishments, and 2,800 unlicensed registered blood establishments. 
Based on data from the HCFA, there are estimated to be 3,400 
transfusion services currently in operation. Such manufacturers and 
establishments currently conduct some QA activities. The impact of the 
final rule reflects the change in these ongoing activities that would 
be required by the rule.

B. One-Time Costs for Affected Establishments

    Licensed biologics manufacturers must comply with part 211 or part 
820; and licensed and unlicensed blood establishments must comply with 
parts 211 and 606 (21 CFR part 606), which encompasses a variety of QA 
activities embodied in CGMP's, to include investigating problems, 
performing followup, and recordkeeping.
    The proposed rule stated that FDA had no precise estimates of the 
one-time cost for preparation and/or revision of the SOP, staff 
training, and time spent making the report. The agency expected that 
such activities would require an average of 2 hours to create an SOP 
for submitting error and accident reports, and approximately 1 hour to 
review and update existing SOP's at the establishments that have been 
reporting. The majority of the comments from industry stated that the 
estimates were underestimated. However, only a couple of comments, 
based on their experience, suggested a range of timeframes from 20 
hours to a few days to develop and implement a new SOP. FDA has 
reassessed the time for staff review of the requirements of the rule, 
establishing or making adjustments to current systems and procedures, 
and for staff training. These estimates are discussed below.
    Licensed biologics manufacturers currently have recordkeeping 
systems and QA systems in place. These establishments are estimated to 
incur a one-time cost for staff review of the requirements of the rule, 
and accompanying modifications to current systems and procedures, and 
for staff training in the use of modified procedures. FDA estimates 
that these activities may require a total of 80 hours of staff time. 
Using an estimated hourly wage rate of $39.20,\1\ the total one-time 
cost for these manufacturers is estimated to be $348,096 ($39.20  x  80 
 x  111).
---------------------------------------------------------------------------

    \1\This estimated wage rate is based on the rate of $37.98 used 
in the proposed rule published in 1997, inflation-adjusted to 1999.
---------------------------------------------------------------------------

    For blood establishments, the changes made in response to the rule 
are expected to vary according to whether the establishment is 
currently licensed. The 232 licensed blood establishments are currently 
required to report the product deviations under Sec. 606.14. These 
facilities are likely to have systems in place for keeping record of 
product deviations, and will not be expected to have to establish a new 
reporting system. However, the licensed blood establishments are also 
likely to handle the majority of product deviation reports, because 
these facilities account for an estimated 90 percent of the total 
volume of U.S. blood collections. The licensed blood establishments 
will need to allocate staff time for a one-time review of the rule and 
some modifications to their current recordkeeping system and reporting 
procedures. In addition, these facilities will allocate a few hours of 
training time to review the reporting changes with staff who will be 
involved in the reporting of product deviations to FDA. FDA estimates 
that these activities may require a total of 80 hours of staff time. 
Using an estimated hourly wage rate of $39.20, the total one-time cost 
for these manufacturers is estimated to be $727,552 ($39.20 x 80 x 
232).
    The 2,800 registered blood establishments that are not licensed are 
estimated to account for about 10 percent of total U.S. blood 
collections, and currently perform product deviation reporting on a 
voluntary but less consistent basis. It is anticipated that the 
registered blood establishments will allocate staff time to establish a 
recordkeeping system for reportable product deviations involving 
products. In addition, the registered blood establishments will 
allocate staff time to modify current SOP's to comply with the 
biological product deviation reporting required by the rule, and to 
review the SOP changes with the staff who will be involved in reporting 
these deviations to FDA. FDA estimates that these activities will 
require an average of 40 hours of staff time per facility. Using an 
estimated hourly wage rate of $39.20, the total one-time cost for these 
establishments is estimated to be $4,390,400 ($39.20 x 40 x 2,800).

[[Page 66630]]

    Transfusion services currently perform a variety of QA activities, 
but report product deviations to FDA on a voluntary and very limited 
basis. Transfusion services currently must comply with 42 CFR 
493.1273(a). This regulation requires transfusion services to comply 
with parts 606 and 640 (21 CFR part 640) provisions, which includes 
keeping records of errors and accidents, transfusion reaction reports 
and complaints, with a record of investigation and followup. These 
establishments are expected to allocate staff time to review the 
requirements of the rule, modify current SOP's to comply with the 
biological product deviation reporting requirements, and train 
appropriate staff in using the modified procedures. This one-time 
effort is estimated to involve approximately 20 hours of staff time per 
facility, yielding an estimated cost of $2,665,600 ($39.20 x 20 x 
3,400) for transfusion services. Based on the estimates for licensed 
and unlicensed blood establishments, the total one-time cost for blood 
and blood component manufacturers is $7,783,552 ($727,552 + $4,390,400 
+ $2,665,600).

C. Annual Costs for Affected Establishments

    In addition to the cost of establishing modified systems and 
procedures, unlicensed blood establishments will experience some annual 
costs associated with ongoing reporting of product deviations that fit 
the criteria specified in the rule. Those costs are estimated below.
    Licensed manufacturers and unlicensed blood establishments will be 
required to report to FDA product deviations when: (1) The event is 
associated with the manufacturing, to include testing, processing, 
packing, labeling, and storage, or with the holding or distribution of 
a licensed biological product, or a licensed or unlicensed blood or 
blood component; (2) the deviation occurs in the licensed manufacturer 
or unlicensed blood establishment's facility or in another facility 
while the product remains in the control of the licensed manufacturer 
or unlicensed blood establishment; (3) the deviation may affect the 
safety, purity, or potency of that product, and either represents a 
deviation from CGMP, applicable regulations, applicable standards, or 
established specifications; or represents an unexpected or 
unforeseeable event; and (4) the deviation involves a distributed 
product.
    When a manufacturer becomes aware of a reportable product 
deviation, the manufacturer investigates the deviation, records the 
deviation, and performs followup. FDA estimates that the establishment 
will allocate an additional 2 hours of staff time to prepare and submit 
a report to FDA. In the comments on the proposed rule, FDA received one 
comment that suggested the agency's estimate of 30 minutes to file a 
report was reasonable for the filing task itself, but would not cover 
the time needed to prepare the report. Other comments stated that their 
establishments average 4, 6, or 8 hours to prepare a report, but some 
comments also explained that these hours included investigations, 
followup, and SOP revision. FDA agrees that 30 minutes would not 
reflect the anticipated time for preparing, in addition to filing, the 
report. The reporting to FDA required in this rule does not introduce 
additional requirements for recordkeeping, investigation, and followup 
of manufacturing problems and deviations beyond what is required under 
CGMP requirements. Therefore, the estimated time for complying with 
this final rule does not include recordkeeping, investigation, and 
followup of a biological product deviation.
    Licensed manufacturers already report a broad range of product 
deviations to FDA. This range includes all deviations in products made 
available for distribution, and has not previously been limited to 
those products actually distributed. Under the existing regulation, a 
total of 93 biologics manufacturing deviations were reported to FDA in 
1999. Since the new rule limits the criteria for reporting, FDA 
estimates that reporting will be 25 percent reduced, yielding an 
estimated total of 70 reports (93 x (1090.25)) rather than the current 
93 reports. Based on the estimate of 2 hours to complete and file a 
report, FDA estimates a total savings of $1,803 ((93-70)  x  2  x  
$39.20).
    Under the current rule, a total of 14,611 blood and blood component 
errors and accidents were reported by licensed blood establishments to 
FDA in FY 1999. These facilities are also estimated to account for 
approximately 90 percent of all blood and plasma collections, totaling 
approximately 26 million units, or 23,400,000 (0.90 x 26,000,000) units 
processed by licensed blood establishments. The current rate of 
reporting per unit of blood collected and processed is thus 6.24 
((14,611/23,400,000) x 10,000) per 10,000 units. Under the final rule, 
FDA estimates that reporting for these facilities will be reduced by 25 
percent, reducing the total reports to 10,958 ((1090.25) x 14,611) or a 
rate of 4.68 (10,958/23,400,000 x 10,000) per 10,000 units of 
collection. This translates to a projected savings of $286,395 
((14,611-10,958)  x  2  x  $39.20)).
    Assuming a deviation reporting rate of 4.68 per 10,000 units for 
those unlicensed registered blood establishments that account for 
approximately 10 percent of the total blood collections of 26 million 
units, the agency estimates that unlicensed registered blood 
establishments will incur new annual costs of $95,397 (0.10 x 
26,000,000 x (4.68/10,000) x 2 x $39.20) to make an estimated 1,217 
reports. This translates to an increased annual cost of approximately 
$34.07 ($95,397/2,800) per unlicensed registered blood establishment.
    Transfusion services will be newly required to report product 
deviations that meet the criteria specified in the rule. The annual 
cost to transfusion services for this reporting requirement is based on 
the voluntary annual reporting rate of transfusion services for FY 99, 
i.e., two reports per transfusion service. This reporting rate is 
supported by the estimate of BPDR's per hospital per year by bedsize 
calculated in table 2 of this document. The reporting by the 
transfusion service is estimated to involve approximately 2 hours of 
staff time at the transfusion facility. As noted earlier, this rule 
does not require new investigations of such reports. Records of 
investigations and followup to address problems with the manufacturing 
process are already required as part of the CGMP for blood and blood 
components. FDA therefore estimates the total cost of annual reporting 
by transfusion services to be $533,120 (3,400 x 2 x 2 x $39.20). This 
translates to an increased annual cost of approximately $156.80 per 
transfusion service.
    In summary, the annual cost impact of the rule is estimated to be 
$342,122 (($95,397 + $533,120)--$286,395) for licensed and unlicensed 
blood establishments, and a net savings of $1,803 for licensed 
manufacturers of biological products other than blood and blood 
components.

D. Impact on Small Entities

    The agency does not anticipate that the final rule will have a 
significant impact on a substantial number of small business 
establishments. However, because of the limits of available data, the 
agency is uncertain about the number of small entities affected and the 
actual extent of current product deviations at these facilities that 
would trigger reporting and determine the cost impact. Since the agency 
received no comments supported by data regarding the estimated impact 
on small entities in the proposed rule, the following

[[Page 66631]]

analysis is based on the limited data available.
    The licensed manufacturers and unlicensed blood establishments 
affected by the final rule are included under the major Standard 
Industrial Code (SIC) group 80 for providers of health services. 
According to section 601 of the Regulatory Flexibility Act of 1980, the 
term ``small entity'' encompasses the terms ``small business,'' ``small 
organization,'' and ``small governmental jurisdiction.'' According to 
the Small Business Administration (SBA), a small business within the 
blood industry is an enterprise with less than $5 million in annual 
receipts. A small organization is a not-for-profit enterprise which is 
independently owned and operated and is not dominant in its field. A 
``small governmental jurisdiction'' generally means governments of 
cities, counties, towns, townships, villages, school districts, or 
special districts, with a population of less than 50,000. Because the 
rule would reduce reporting requirements for currently licensed 
facilities, FDA has focused the following small business analysis on 
those blood collection facilities and transfusion services that will be 
newly required to report these product deviations, and are therefore 
expected to incur new costs.

E. Impact on Small Blood and Blood Component Manufacturers

    The FDA registry of blood establishments does not provide an 
indication of the size of the registered entities. Although uncertain, 
it is likely that some smaller facilities may experience significant 
costs as a result of compliance with the final rule. According to the 
1996 directory of the American Association of Blood Banks (AABB), only 
34 regional and community blood centers have annual revenues of less 
than $5 million and each collect no more than 30,000 donations per 
year. With an estimated rate of 4.68 product deviation reports per 
10,000 units collected [see annual cost estimates in section IV.C of 
this document], this would imply an estimated 14 product deviation 
reports (4.68 x 3) per smaller blood center per year, and associated 
cost of $1,098 ($39.20 x 2 x 14 reports). The one-time cost for these 
facilities is expected to be similar to the unlicensed registered blood 
establishments estimate involving 40 hours of staff time, thus $1,568 
($39.20 x 40) per facility.

F. Impact on Small Transfusion Service Facilities

    Hospital transfusion services are expected to be the primary entity 
affected by the requirements, but the extent of the small business 
impact is uncertain. Although the details of manufacturing activities 
at transfusion services are not available, FDA examined other data to 
develop a preliminary assessment of small business impact. The size of 
U.S. hospitals varies substantially. The 1998 American Hospital 
Association (AHA) survey data indicate a total of 5,134 U.S. registered 
community hospitals grouped into 8-bedsize categories. The average 
annual revenues for facilities in these bedsize categories range from 
approximately $5.5 million to $513 million. However, since many 
hospitals are not-for-profit or are operated by State and local 
governments, the SBA annual receipt criteria for small businesses would 
not apply to these facilities. Of the 5,134 U.S. community hospitals 
included in the AHA report 1,330 are under the control of State and 
local government, 3,045 are nonprofit institutions and the remaining 
759 are reported to be investor-owned.
    The number of hospitals that would meet at least one of the various 
SBA definitions for small entities is uncertain. According to the AHA 
statistics for 1998, the smallest reported hospital size category 
includes 262 hospitals with 6 to 24 beds, and total gross revenues of 
$1.43 billion, yielding average revenues of $5.46 million. FDA assumes 
that the 11 facilities reported to be investor-owned within this 
bedsize category could qualify as small entities. Although it is 
possible that all nonprofit hospitals may qualify as small entities, it 
appears that a number of facilities might be excluded from that 
definition because they are reported to be hospitals in a system. 
According to the AHA survey definition, ``hospitals in a system'' refer 
to those ``hospitals belonging to a corporate body that owns and/or 
manages health provider facilities or health-related subsidiaries; the 
system may also own non-health-related facilities.'' The AHA currently 
has record of 1,592 hospitals that are nonfederal and nonprofit 
(including State and local government controlled) that are hospitals in 
a system. If these facilities were excluded, FDA estimates that 2,783 
[1,330 State & local + 3,045 nonprofit--1,592 in-a-system] nonfederal, 
nonprofit hospitals may qualify as small entities. Thus, a total of 
2,794 [2,783 + 11] hospitals might qualify as small entities.
    The following analysis of potential impact by size of hospital 
suggests that, regardless of hospital size, the cost impact of product 
deviation reporting will be limited if the number of deviation reports 
per facility is proportionate to the utilization of blood transfusions 
implied by relative number of inpatient surgeries performed by 
hospitals in different size categories. Table 2 of this document 
estimates the percentage of all inpatient hospital surgeries, based on 
the number of inpatient surgeries reported to AHA as performed by 
hospitals in different bedsize categories. This percentage is used to 
estimate a share of the total reports that would be made by hospitals 
in each category. The estimated number of product deviation reports per 
hospital within a bedsize category is based on the total projected 
number of reports and the percentage of inpatient surgeries reported 
for hospitals within each size category.

                     Table 2.--Estimates of BPDR's per Hospital per Year by Bedsize category
----------------------------------------------------------------------------------------------------------------
                                                                                     Estimated
                                                                     Estimated    Share of 1,217     Estimated
                Bedsize Category                    Nonfederal        Percent         Product       Reports per
                                                     Hospitals       Inpatient       Deviation      Hospital\1\
                                                                     Surgeries        Reports
----------------------------------------------------------------------------------------------------------------
6 to 24                                               262               0.21            2.6             0
25 to 49                                              906               2.02           24.6             0
150 to 99                                           1,128               6.03           73.3             0
100 to 199                                          1,338              19.38          235.9             0
200 to 299                                            692              20.99          255.4             0
300 to 399                                            361              16.24          197.6             1
400 to 499                                            196              12.17          148.1             1
500 +                                                 251              22.97          279.5            1
----------------------------------------------------------------------------------------------------------------
\1\Rounded to the nearest whole number.


[[Page 66632]]

    The cost impact of product deviation reporting is based on the 
table 2 estimates of reports per hospital and the earlier estimate of 
one-time cost of $784 (20 hours x $39.20) per hospital to modify 
systems and SOP's for recordkeeping and reporting. Based on the low 
expected volume of reports per hospital, the agency found that the 
estimated annual reporting cost, as a percentage of average annual 
facility revenues, approached zero for hospitals in every bedsize 
category. This suggests that the relative cost impact may be quite 
limited, across hospitals of different sizes, if the number of BPDR's 
required per hospital is proportionate to the number of inpatient 
surgeries performed by hospitals in different size categories.

G. Expected Benefits of the Rule

    As described in the preamble, the benefits of the rule relate to 
the safety of biological products and protection of the public health. 
The final rule focuses on the subset of risk events in which the 
product is actually distributed and the cause of the problem is related 
to steps in the manufacturing process, that may affect the safety, 
purity, and potency of the product. FDA needs to receive timely reports 
of such events in order to quickly address problems, and provide 
updated industry guidance to assure continued product safety and good 
manufacturing practice. The requirements provide FDA with the ability 
to detect broader risks that extend beyond the reach of a single 
manufacturer or hospital's QA systems and staff resources.
    In addition to these public health benefits, the final rule 
benefits licensed manufacturers in terms of a reduced level of 
reporting and streamlining the reporting process by providing a 
standardized report form that may be submitted electronically. 
Reporting requirements are now focused more narrowly on product 
deviations that represent more immediate risks.

V. The Paperwork Reduction Act of 1995

    This final rule contains information collection requirements that 
are subject to review by OMB under the Paperwork Reduction Act of 1995 
(the PRA) (44 U.S.C. 3501-3520). The title, description, and respondent 
description of the information collection provisions are shown below 
with an estimate of the annual reporting and recordkeeping burden. 
Included in the estimate is the time for reviewing instructions, 
searching existing data sources, gathering and maintaining the data 
needed, and completing and reviewing each collection of information.
    Title: Biological Products: Reporting of Biological Product 
Deviations in Manufacturing.
    Description: FDA is amending the current regulations that require 
licensed manufacturers of biological products to report to FDA errors 
and accidents in manufacturing; and adding regulations requiring 
unlicensed blood establishments to report certain biological product 
deviations in the manufacture of blood and blood components. Under this 
final rule, a licensed manufacturer or unlicensed blood establishment 
must submit a report to FDA based on the following criteria: (1) The 
event is associated with the manufacturing, to include testing, 
processing, packing, labeling, and storage, or with the holding or 
distribution, of a licensed biological product, or a licensed or 
unlicensed blood or blood component; (2) the deviation occurs in the 
licensed manufacturer or unlicensed blood establishment's facility or 
in another facility while the product remains in the control of the 
licensed manufacturer or unlicensed blood establishment; (3) the 
deviation may affect the safety, purity, or potency of that product and 
either represents deviation from CGMP, applicable regulations, 
applicable standards, or established specifications; or represents an 
unexpected or unforeseeable event; and (4) the deviation involves a 
distributed product. The agency is requiring a 45-calendar day 
reporting timeframe and is making available to industry a standardized 
format for reporting biological deviations in manufacturing that may be 
submitted either by hard copy or electronically.
    Authority is given to the agency to issue regulations for the 
efficient enforcement of the act under section 701 of the act (21 
U.S.C. 371) and to inspect all establishments responsible for 
manufacturing biological products (section 704 of the act (21 U.S.C. 
374) and 42 U.S.C. 262). 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.
    Description of Respondents: Licensed manufacturers of biological 
products, unlicensed registered blood establishments, and transfusion 
services.
    As required by section 3506(c)(2)(B) of the PRA, FDA provided an 
opportunity for public comment on the information collection 
requirements of the proposed rule (62 FR 49642). Nine letters of 
comment on the information collection requirements were submitted to 
OMB. Most of the comments submitted to OMB were the same as those 
submitted directly to FDA in response to the proposed rule. FDA's 
responses to these comments are found in section III of this document. 
Responses to additional comments in the letters received by OMB that 
were not addressed in section III of this document are addressed in the 
following paragraphs.
    (Comment 33) One comment to OMB and 24 comments submitted to the 
docket state that the estimated time of 0.5 hours to complete a 
deviation report is underestimated. Several of these comments further 
state that their establishments currently average about 4 to 6, or 6 to 
8 hours for preparing a deviation report under Sec. 600.14. One comment 
states that ``[A] single investigation in our institution may take four 
hours per incident as we thoroughly investigate, report, change SOP's 
or processes if indicated, and follow-up to ensure that changes were 
implemented and work as intended.''
    FDA agrees that the burden is underestimated and is adjusting the 
``hours per response'' estimate in table 3 from 0.5 hours to 2 hours 
based on: (1) Information from industry representatives about typical 
reporting procedures, (2) the issuance of guidance that will assist 
industry in identifying reportable events, and (3) the availability of 
a standardized report form. The standardized report form, and the 
ability to submit a report electronically, should streamline the 
process and improve the quality of time. Activities such as 
investigating, changing SOP's or processes, and followup are currently 
required under parts 211, 606, and 820 and, therefore, are not included 
in the burden calculation for the separate requirement of submitting to 
FDA a deviation report.
    (Comment 34) Two comments state that in determining the estimated 
time for completing and submitting a deviation report, FDA may not have 
met its statutory obligations under the PRA because it used anecdotal 
evidence, that is not representative of current practices.
    When FDA seeks information from industry to estimate burden for a 
proposed rule, the agency ordinarily contacts fewer than 10 
representatives. If FDA requested information from 10 or more industry 
representatives, the agency would be required to prepare a separate 
burden analysis and seek OMB approval before it could ask for such 
information. Although less than 10

[[Page 66633]]

persons usually do not represent the majority of the industry, the 
comment period for the proposed rule provides the opportunity for all 
interested persons to comment on the estimated burden. For this final 
rule, FDA considered all of the comments received regarding the 
estimated burden numbers and, in response, adjusted the estimates.
    (Comment 35) Another comment states that the added hourly burden of 
generating these reports may compromise the ability of hospitals to 
provide optimal technical support for blood transfusion activities.
    The requirement for reporting has not changed for licensed 
manufacturers. Licensed manufacturers are currently required to report 
errors and accidents under Sec. 600.14, and the agency recommended 
reporting of errors and accidents by unlicensed blood establishments in 
a memorandum to registered blood establishments dated March 20, 1991. 
Unlicensed registered blood establishments and transfusion services are 
required under 42 CFR 493.1273(a) to comply with CGMP regulations set 
forth at parts 606 and 640, and specifically with Sec. 606.100(c) for 
the investigation and followup of any unexplained discrepancy or the 
failure of a lot or unit to meet any of its specifications, and with 
Sec. 606.160(b)(7)(iii) for recordkeeping requirements for errors and 
accidents. The only additional requirement under this final rule is 
that the unlicensed registered blood establishment or transfusion 
service submit a report based on this recordkeeping of deviations. FDA 
estimates that preparing and submitting one report would involve only 2 
hours, and that only two reports would be submitted per year by an 
unlicensed registered blood establishment or transfusion service. The 
estimated total burden per year is only 4 hours per establishment. 
Therefore, FDA concludes that the final rule should not affect a 
hospital's ability to provide optimal technical support for blood 
transfusion activities.
    (Comment 36) One comment notes that the paper-based reporting 
system that is now being used by FDA does not provide a format from 
which reported information can be entered into a usable data base 
without a great deal of difficulty and expense.
    FDA agrees with the comment and has prepared a standardized form 
for reporting deviations in manufacturing a biological product (BPDR, 
Form FDA-3486) that may be downloaded from CBER's website or received 
by facsimile. After completion, the form is sent to the identified 
address in Sec. 600.14(e). In an effort to expedite and simplify 
reporting, FDA also is providing to industry the opportunity to 
complete and submit a Form FDA-3486 electronically. The establishment 
may insert the requested information into the appropriate fields online 
and submit the report through the Internet.
    (Comment 37) One comment notes that FDA estimates that there are no 
capital costs or operation and maintenance costs associated with the 
proposed rule. The comment noted that these terms are undefined.
    The agency considers capital costs or operation and maintenance 
costs to be costs other than those needed for usual and customary 
business practice. FDA believes there are no capital costs or operation 
and maintenance costs associated with the maintenance of files and 
records because respondents should have the facilities and the 
infrastructure for recordkeeping and retention as part of their usual 
and customary practice. The final rule provides for the use of a 
standardized reporting form, which will be available for convenience on 
CBER's website. For those establishments that do not have access to the 
Internet, the form may also be accessed and submitted by facsimile or 
mail. Therefore, the purchase of computer equipment and Internet access 
would not be necessary in order to comply with this rule.

A. Estimated Annual Reporting Burden

    The 54,208 total hours estimated in table 3 of this document are 
based on information from FDA's data bases and CBER's annual summary on 
error and accident reporting for FY 1999. In calculating the reporting 
burden for the revised Sec. 600.14 in this final rule, FDA found that 
approximately 111 licensed manufacturers of biological products other 
than blood and blood components submitted 93 error and accident reports 
in FY 1999 under the current Sec. 600.14. In calculating the reporting 
burden for Sec. 606.171 under this final rule, FDA found that 
approximately 232 licensed manufacturers of blood and blood components, 
including Source Plasma, submitted 14,611 error and accident reports.
    In calculating the burden for unlicensed registered blood 
establishments and transfusion services under the new Sec. 606.171, FDA 
found that 48 establishments of the estimated 2,800 unlicensed 
registered blood establishments voluntarily submitted 94 error and 
accident reports; and 15 of the estimated 3,400 transfusion services 
voluntarily submitted 28 error and accident reports. Based on this 
voluntary reporting rate, each of the 6,200 unlicensed blood 
establishment is expected to submit no more than 2 reports annually, 
totaling 12,400 reports annually.
    Licensed manufacturers of blood and blood components collect 90 
percent of the nation's blood supply. Accordingly, the estimated total 
number of reports submitted annually by each licensed blood 
establishment is greater than the total number of reports submitted by 
each unlicensed blood establishment.
    In the proposed rule, the agency estimated that industry would 
expend 58,393.5 hours to submit approximately 116,787 total annual 
responses. In the final rule, FDA estimates that it will take 54,208 
hours to submit 27,104 total annual responses. The decrease in total 
reports submitted annually is due to the more narrow scope in the final 
rule, which requires BPDR's only for distributed products.

B. Estimated One-Time Burden for Implementation of Rule

    FDA has estimated a total of 207,440 hours as a one-time burden for 
performing the following activities: Staff review of the requirements 
of the rule, establishing or making adjustments to current systems and 
SOP's, and staff training. As previously discussed in section IV.B of 
this document, the estimated one-time burden to perform these 
activities would be 80 hours for each licensed manufacturer of 
biological products and licensed manufacturer of blood and blood 
components, 40 hours for each unlicensed registered blood 
establishment, and 20 hours for each transfusion service.

                                 Table 3.--Estimated Annual Reporting Burden\1\
----------------------------------------------------------------------------------------------------------------
                                                                 Annual
                                                    No. of     Frequency      Total      Hours per
                 21 CFR Section                  Respondents      per         Annual      Response   Total Hours
                                                                Response    Responses
----------------------------------------------------------------------------------------------------------------
600.14\2\                                                111          0.8           93            2          186

[[Page 66634]]

 
606.171\3\                                               232         62.9       14,611            2       29,222
606.171\4\                                             6,200            2       12,400            2       24,800
Total                                                  6,543                    27,104                    54,208
----------------------------------------------------------------------------------------------------------------
            One-Time Burden\5\
----------------------------------------------------------------------------------------------------------------
Licensed manufacturers\2\                                111            1          111           80        8,880
Licensed manufacturers\3\                                232            1          232           80       18,560
Unlicensed registered blood establishments             2,800            1        2,800           40      112,000
Transfusion services                                   3,400            1        3,400           20       68,000
Total                                                                                                   207,440
----------------------------------------------------------------------------------------------------------------
\1\There are no capital costs or operating and maintenance costs associated with this collection of information.
 
\2\Licensed manufacturers of biological products other than blood and blood components
\3\1ALicensed manufacturers of blood and blood components, including Source Plasma
\4\Unlicensed registered blood establishments and transfusion services
\5\One-time burden activities: Staff review of the requirements of the rule, establishing or making adjustments
  to current systems and SOP's, and staff training

    The information collection requirements of the final rule have been 
submitted to OMB for review. Prior to the effective date of the final 
rule, FDA will publish a document in the Federal Register announcing 
OMB's decision to approve, modify, or disapprove the information 
collection requirements in the final rule. An agency may not conduct or 
sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.

VI. Environmental Impact

    The agency has determined under 21 CFR 25.30(j) that this action is 
of a type that does not individually or cumulatively have a significant 
effect on the human environment. Therefore, neither an environmental 
assessment nor an environmental impact statement is required.

VII. Federalism

    FDA has analyzed this final rule in accordance with the principles 
set forth in Executive Order 13132. FDA has determined that the rule 
does not contain policies that have substantial direct effects on the 
States, on the relationship between the National Government and the 
States, or on the distribution of power and responsibilities among the 
various levels of government. Accordingly, the agency has concluded 
that the rule does not contain policies that have federalism 
implications as defined in the order and, consequently, a federalism 
summary impact statement is not required.

List of Subjects

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

21 CFR Part 606

    Blood, Labeling, Laboratories, Reporting and recordkeeping 
requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, 21 CFR parts 600 and 606 are amended as 
follows:

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    1. The authority citation for 21 CFR part 600 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371, 
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.
    2. Amend Sec. 600.3 by adding paragraphs (hh) and (ii) to read as 
follows:


Sec. 600.3  Definitions.

* * * * *
    (hh) Distributed means the biological product has left the control 
of the licensed manufacturer.
    (ii) Control means having responsibility for maintaining the 
continued safety, purity, and potency of the product and for compliance 
with applicable product and establishment standards, and for compliance 
with current good manufacturing practices.
    3. Revise Sec. 600.14 to read as follows:


Sec. 600.14  Reporting of biological product deviations by licensed 
manufacturers.

    (a) Who must report under this section? (1) You, the manufacturer 
who holds the biological product license and who had control over the 
product when the deviation occurred, must report under this section. If 
you arrange for another person to perform a manufacturing, holding, or 
distribution step, while the product is in your control, that step is 
performed under your control. You must establish, maintain, and follow 
a procedure for receiving information from that person on all 
deviations, complaints, and adverse events concerning the affected 
product.
    (2) Exceptions:
    (i) Persons who manufacture only in vitro diagnostic products that 
are not subject to licensing under section 351 of the Public Health 
Service Act do not report biological product deviations for those 
products under this section but must report in accordance with part 803 
of this chapter;
    (ii) Persons who manufacture blood and blood components, including 
licensed manufacturers, unlicensed registered blood establishments, and 
transfusion services, do not report biological product deviations for 
those products under this section but must report under Sec. 606.171 of 
this chapter;
    (iii) Persons who manufacture Source Plasma or any other blood 
component and use that Source Plasma or any other blood component in 
the further manufacture of another licensed biological product must 
report:
    (A) Under Sec. 606.171 of this chapter, if a biological product 
deviation occurs during the manufacture of that Source Plasma or any 
other blood component; or
    (B) Under this section, if a biological product deviation occurs 
after the manufacture of that Source Plasma or

[[Page 66635]]

any other blood component, and during manufacture of the licensed 
biological product.
    (b) What do I report under this section? You must report any event, 
and information relevant to the event, associated with the 
manufacturing, to include testing, processing, packing, labeling, or 
storage, or with the holding or distribution, of a licensed biological 
product, if that event meets all the following criteria:
    (1) Either:
    (i) Represents a deviation from current good manufacturing 
practice, applicable regulations, applicable standards, or established 
specifications that may affect the safety, purity, or potency of that 
product; or
    (ii) Represents an unexpected or unforeseeable event that may 
affect the safety, purity, or potency of that product; and
    (2) Occurs in your facility or another facility under contract with 
you; and
    (3) Involves a distributed biological product.
    (c) When do I report under this section? You should report a 
biological product deviation as soon as possible but you must report at 
a date not to exceed 45-calendar days from the date you, your agent, or 
another person who performs a manufacturing, holding, or distribution 
step under your control, acquire information reasonably suggesting that 
a reportable event has occurred.
    (d) How do I report under this section? You must report on Form 
FDA-3486.
    (e) Where do I report under this section? You must send the 
completed Form FDA-3486 to the Director, Office of Compliance and 
Biologics Quality (HFM-600), Center for Biologics Evaluation and 
Research, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-1448, by 
either a paper or an electronic filing:
    (1) If you make a paper filing, you should identify on the envelope 
that a BPDR (biological product deviation report) is enclosed; or
    (2) If you make an electronic filing, you may submit the completed 
Form FDA-3486 electronically through CBER's website at www.fda.gov/cber.
    (f) How does this regulation affect other FDA regulations? This 
part supplements and does not supersede other provisions of the 
regulations in this chapter. All biological product deviations, whether 
or not they are required to be reported under this section, should be 
investigated in accordance with the applicable provisions of parts 211 
and 820 of this chapter.

PART 606--CURRENT GOOD MANUFACTURING PRACTICE FOR BLOOD AND BLOOD 
COMPONENTS

    4. The authority citation for 21 CFR part 606 continues to read as 
follows:

    Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 360j, 371, 
374; 42 U.S.C. 216, 262, 263a, 264.

    5. Amend Sec. 606.3 by adding paragraphs (k) and (l) to read as 
follows:


Sec. 606.3  Definitions.

* * * * *
    (k) Distributed means:
    (1) The blood or blood components have left the control of the 
licensed manufacturer, unlicensed registered blood establishment, or 
transfusion service; or
    (2) The licensed manufacturer has provided Source Plasma or any 
other blood component for use in the manufacture of a licensed 
biological product.
    (l) Control means having responsibility for maintaining the 
continued safety, purity, and potency of the product and for compliance 
with applicable product and establishment standards, and for compliance 
with current good manufacturing practices.
    6. Amend Sec. 606.160 by revising paragraph (b)(7)(iii) to read as 
follows:


Sec. 606.160  Records.

* * * * *
    (b) * * *
    (7) * * *
    (iii) Biological product deviations.
* * * * *
    7. Add Sec. 606.171 to subpart I to read as follows:


Sec. 606.171  Reporting of product deviations by licensed 
manufacturers, unlicensed registered blood establishments, and 
transfusion services.

    (a) Who must report under this section? You, a licensed 
manufacturer of 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, must report 
under this section. If you arrange for another person to perform a 
manufacturing, holding, or distribution step, while the product is in 
your control, that step is performed under your control. You must 
establish, maintain, and follow a procedure for receiving information 
from that person on all deviations, complaints, and adverse events 
concerning the affected product.
    (b) What do I report under this section? You must report any event, 
and information relevant to the event, associated with the 
manufacturing, to include testing, processing, packing, labeling, or 
storage, or with the holding or distribution, of both licensed and 
unlicensed blood or blood components, including Source Plasma, if that 
event meets all the following criteria:
    (1) Either:
    (i) Represents a deviation from current good manufacturing 
practice, applicable regulations, applicable standards, or established 
specifications that may affect the safety, purity, or potency of that 
product; or
    (ii) Represents an unexpected or unforeseeable event that may 
affect the safety, purity, or potency of that product; and
    (2) Occurs in your facility or another facility under contract with 
you; and
    (3) Involves distributed blood or blood components.
    (c) When do I report under this section? You should report a 
biological product deviation as soon as possible but you must report at 
a date not to exceed 45-calendar days from the date you, your agent, or 
another person who performs a manufacturing, holding, or distribution 
step under your control, acquire information reasonably suggesting that 
a reportable event has occurred.
    (d) How do I report under this section? You must report on Form 
FDA-3486.
    (e) Where do I report under this section? You must send the 
completed Form FDA-3486 to the Director, Office of Compliance and 
Biologics Quality (HFM-600), 1401 Rockville Pike, suite 200N, Rockville 
MD, 20852-1448 by either a paper or electronic filing:
    (1) If you make a paper filing, you should identify on the envelope 
that a BPDR (biological product deviation report) is enclosed; or
    (2) If you make an electronic filing, you may submit the completed 
Form FDA-3486 electronically through CBER's website at www.fda.gov/cber.
    (f) How does this regulation affect other FDA regulations? This 
part supplements and does not supersede other provisions of the 
regulations in this chapter. All biological product deviations, whether 
or not they are required to be reported under this section, should be 
investigated in accordance with the applicable provisions of parts 211, 
606, and 820 of this chapter.

    Dated: June 8, 2000.
Margaret M. Dotzel
Associate Commissioner for Policy
[FR Doc. 00-28133 Filed 11-3-00; 8:45 am]
BILLING CODE 4160-00-F