[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