[Federal Register: November 3, 1997 (Volume 62, Number 212)]
[Corrections]
[Page 59386]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr03no97-92]
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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 Errors and Accidents in
Manufacturing
Correction
In proposed rule document 97-25129 beginning on page 49642, in the
issue of Tuesday, September 23, 1997, make the following correction:
On page 49642, in the second column, in the DATES section, in the
last line, ``March 23, 1998.'' should read ``180 days after its date of
publication in the Federal Register.''
BILLING CODE 1505-01-D
[Federal Register: September 23, 1997 (Volume 62, Number 184)]
[Proposed Rules]
[Page 49642-49648]
From the Federal Register Online via GPO Access [wais.access.gpo.gov]
[DOCID:fr23se97-25]
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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 Errors and Accidents in
Manufacturing
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the regulations requiring licensed manufacturers of biological products
to report errors and accidents in manufacturing that may affect the
safety, purity, or potency of a product. FDA is proposing to establish
a reporting period for licensed biological products; require that error
and accident reports be submitted for products that have been made
available for distribution, and amend the current good manufacturing
practice (CGMP) regulations for blood and blood components to require
error and accident reporting by unlicensed registered blood
establishments and transfusion services which are currently reporting
on a voluntary basis. The proposed reporting requirements are intended
to expedite reporting of errors and accidents in manufacturing of
biological products; provide FDA with a more accurate surveillance of
the nation's blood supply, thereby enabling FDA to monitor actions
taken in response to the errors and accidents detected for all
establishments involved in manufacturing of blood and blood components;
and facilitate a rapid response where the public health may be at risk.
DATES: Submit written comments on the proposed rule by December 22,
1997. Submit written comments on the information collection provisions
by October 23, 1997. The agency is proposing that any final rule that
may issue based upon this proposed rule become effective March 23,
1998.
ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,
Rockville, MD 20857. Submit written comments on the information
collection provisions to the Office of Information and Regulatory
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., Washington,
DC 20503. ATTN: Desk Officer for FDA.
FOR FURTHER INFORMATION CONTACT: Paula S. McKeever, Center for
Biologics Evaluation and Research (HFM-630), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-594-3074.
SUPPLEMENTARY INFORMATION:
I. Introduction
Establishments that engage in the manufacture, preparation,
propagation, compounding, or processing of drug and device products,
including biological products, must register with the FDA under section
510 of the Federal Food, Drug, and Cosmetic Act (the act) ( 21 U.S.C.
360), unless specifically exempted by regulation.
Establishments propagating or manufacturing and preparing
biological products for interstate commerce are subject to licensing
under the Public Health Service Act (PHS Act) (42 U.S.C. 262(a)). These
licenses are issued by FDA only upon a showing that the establishment
and the product for which a license is desired meet applicable
standards designed to ensure the continued safety, purity, and potency
of such products prescribed in the regulations (42 U.S.C. 262(d)(1)).
Blood and blood products are regulated as drugs under section
201(g) of the act (21 U.S.C. 321(g)) and biologicals are regulated
under 42 U.S.C. 262 of the PHS Act. Establishments manufacturing blood
and blood components are required to register with FDA and to comply
with the CGMP (parts 211 and 606 (21 CFR parts 211 and 606)).
Transfusion services which do not routinely collect or process blood
and blood components are exempted from registering as blood
establishments (Sec. 607.65(f) (21 CFR 607.65(f))), but are required
under 42 CFR 493.1273(a) to comply with parts 606 and 640 (21 CFR part
640) as they pertain to the performance of manufacturing activities,
such as compatibility testing, storage, labeling, and recordkeeping, or
any other process involving manufacturing.
A product is considered adulterated under the act when the methods
used in its manufacture, processing, packing, or holding do not conform
to the CGMP (section 501(a)(1) of the act (21 U.S.C. 351(a)(1))). By
applying the CGMP, firms assure that the products meet the requirements
for safety, have the identity and strength, and meet the quality and
purity characteristics which they purport or are represented to possess
(section 501(a)(2)(B) of the act). A product is also adulterated if its
strength differs from, or purity or quality falls below what it is
purported or represented to possess (section 501(c) of the act). A
product is considered misbranded if its labeling is false or misleading
in any particular (section 502(a) of the act (21 U.S.C. 352(a))) or if
the product is dangerous to health when used as labeled under section
502(j) of the act. The introduction or delivery for introduction of
adulterated and/or misbranded biological products into interstate
commerce is prohibited under section 301(a) of the act (21 U.S.C.
331(a)). It is also a prohibited act to adulterate and/or misbrand
biological products while held for sale after receipt of shipment in
interstate commerce (section 301(k) of the act). These prohibited acts
are punishable by prescribed penalties under the act.
[[Page 49643]]
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 the proposal to amend the error and accident reporting
regulations to be an essential tool in its directive to protect public
health by establishing and maintaining surveillance programs that
provide timely and useful information.
II. Background
Section 600.14 (21 CFR 600.14) requires that licensed manufacturers
of biological products notify the Director, Office of Compliance,
Center for Biologics Evaluation and Research (CBER), promptly of errors
or accidents in manufacturing that may affect the safety, purity, or
potency of any product. In addition, all blood establishments, whether
licensed or unlicensed, are required by the CGMP to thoroughly
investigate and make adequate corrections to their manufacturing
processes concerning errors and accidents (Sec. 606.100(c)) and to
maintain and make available to FDA appropriate records of such
investigations and corrections (Secs. 606.100(c) and
606.160(b)(7)(iii)). CBER has recommended to blood and blood component
establishments that error and accident reports be submitted to CBER
when the error or accident is associated with blood or blood components
that have been made available for distribution, whether or not actual
release or shipment has occurred. FDA believes this reporting standard
is appropriate for ensuring the safety of the nations blood supply and
proposes to codify it in the regulations.
In a memorandum to all registered blood establishments dated March
20, 1991, entitled ``Responsibilities of Blood Establishments Related
to Errors and Accidents in the Manufacture of Blood and Blood
Components,'' CBER recommended that unlicensed registered blood
establishments and transfusion services voluntarily report to CBER
errors and accidents that may affect product quality. The memorandum
was issued, in part, because of an increase in the number of product
recalls initiated by blood establishments due to errors and accidents
in manufacturing which were not reflected in error and accident reports
to CBER.
In May of 1995, the Office of Inspector General (OIG) of the
Department of Health and Human Services issued a report on the
``Reporting Process for Blood Establishments to Notify the Food and
Drug Administration of Errors and Accidents Affecting Blood.'' The
report states that the error and accident reporting process enables the
agency to evaluate and monitor blood establishments in response to
detected errors and accidents, and regularly alert field staff and
blood establishments with trend analysis of the types of errors and
accidents reported. However, OIG placed emphasis on two existing
conditions that were impeding the success of the reporting process: (1)
Error and accident reports were not being submitted in a timely manner
by blood establishments and (2) there was no assurance that unlicensed
establishments were submitting reports. This proposed rule is intended
as a step in addressing conditions identified in the OIG report.
On July 14, 1995, FDA published a notice of availability of a
``Guideline for Quality Assurance in Blood Establishments'' (60 FR
36290) initiating a blood quality assurance program aimed at ensuring
the continued safety of the nation's blood supply and maintaining the
operational quality of blood establishments. The goals of the quality
assurance (QA) program are to significantly decrease errors, ensure the
credibility of test results, implement effective manufacturing process
and system controls, and ensure continued product safety, purity, and
potency. The QA program includes measures to prevent, detect,
investigate, assess, and correct errors. The emphasis is on preventing
errors rather than detecting them retrospectively. This guidance is
intended to assist manufacturers of blood and blood components, i.e.,
blood banks, blood centers, transfusion services, and plasmapheresis
centers, in developing QA programs that are consistent with recognized
principles of QA and the CGMP. One component of this guidance focuses
on the blood industry's self audit, including analysis and trending of
errors and accidents that may affect the safety, purity, and potency of
blood and blood components.
In the Federal Register of January 20, 1994 (59 FR 3043), FDA
announced its plan to review significant regulations under Executive
Order 12866, which requires all Federal agencies to develop a program
for periodically reviewing existing significant regulations. The
purpose of the review is to determine whether existing significant
regulations should be modified or eliminated to reduce their regulatory
burden or to make the agency's regulatory program more effective. This
proposed rule is considered part of the retrospective regulation review
and is intended to improve the effectiveness of FDA's regulatory
program.
III. Summary of the Proposed Rule
FDA is proposing to amend the regulations that require licensed
manufacturers of biological products to report errors and accidents in
manufacturing and to amend the CGMP regulations for blood and blood
components to require error and accident reporting by all manufacturers
of blood and blood components. The proposed amendments would provide
definitions for the terms ``error and accident'' and ``made available
for distribution'' in part 600 (21 CFR part 600) at Secs. 600.3 and
606.3; require a specific timeframe for reporting at Secs. 600.14 and
606.171; require reports for products that have been made available for
distribution, at Secs. 600.14 and 606.171; and extend the reporting
requirements to unlicensed registered blood establishments and
transfusion services, at Sec. 606.171.
A. Definitions (Secs. 600.3 and 606.3)
Although the terms ``error'' and ``accident'' are generally used
conjunctively, FDA has listed distinguished events affecting the
purported safety, purity, and potency of the product into two
categories.
``Made available for distribution'' is being defined because of the
numerous release and distribution patterns unique to some biological
products, and to avoid the potential for misinterpretation of the term.
1. Error and Accident
In proposed Secs. 600.3(ff) and 606.3(k), the first category of
events is defined as an incident that represents a deviation from the
CGMP, applicable standards or established specifications that may
affect the safety, purity, or potency of the biological product, or
otherwise cause the biological product to be in violation of the act or
the PHS Act. These events are within the realm of control of the
manufacturer. Examples of this category of reportable events in the
manufacturing of blood and blood components which may affect product
safety, purity, or potency include, but are not limited to: (1) Arm
preparation not performed or performed incorrectly; (2) components
prepared more than 8 hours after collection; (3) testing for ABO/Rh or
infectious diseases not performed according to the package insert; (4)
incorrect crossmatch label or tag; (5) shipment of a unit with a
repeatedly reactive viral marker test result; and (6) shipment of a
unit prior
[[Page 49644]]
to completion of all testing. Examples of reportable events for
biological products other than blood and blood components include, but
are not limited to: (1) Route of administration labeling error; (2)
shipment of a product at an inappropriate temperature; (3) mold
contamination of a vaccine; (4) missing product labels; (5) incorrect
package insert; and (6) missing lot number.
The second category of events to be reported is defined as an
unexpected or unforeseeable event that may affect the safety, purity,
or potency of the biological product, or otherwise cause the biological
product to be in violation of the Act or the PHS Act. These events
generally are beyond the control of the manufacturer. Examples of this
category of reportable events in the manufacture of blood and blood
components which may affect product safety, purity, or potency include,
but are not limited to: (1) Certain post donation information; (2) a
collection device defect that affects the product; (3) contaminated
solutions used to prepare components; (4) an autologous unit labeled
with incorrect information provided by the donor; or (5) a unit of
blood or blood components which becomes broken/damaged during shipment.
Examples of reportable events in the manufacture of biological products
other than blood and blood components which may affect product safety,
purity, or potency include, but are not limited to: (1) Sterility
compromised and beyond the control of the manufacturer; (2)
notification from a supplier of source materials concerning a quality
problem with the product shipped for use in further manufacturing; and
(3) inadvertent contamination of cell lines or replication competent
viruses.
2. Made Available for Distribution
In proposed Secs. 600.3(ii) and 606.3(l), ``made available for
distribution'' is defined as a biological product that has been
determined to meet all release criteria and to be suitable for
distribution, whether or not actual distribution has occurred. Thus,
error and accident reports would be submitted to FDA for products that
the manufacturer or blood establishment has determined are suitable for
distribution.
B. Biological Product Reporting (Sec. 600.14)
FDA has the responsibility for protecting the public health by
reviewing the safety and efficacy of biological products. FDA believes
that error and accident reports help ensure that industry identifies
instances where additional corrective action is needed, such as
additional training and revisions of standard operating procedures
(SOP's). Error and accident reports, in conjunction with inspections
and other surveillance activities, give FDA a continuing overview of
the biological product industry. While FDA provides guidance to help
industry determine how to comply with regulations, manufacturers of
biological products have the primary responsibility for ensuring the
safety, purity, and potency of their products.
Section 600.14 applies to all licensed manufacturers of biological
products. It requires manufacturers to report errors and accidents in
manufacturing promptly to the Director, Office of Compliance, CBER. FDA
agrees with the OIG's recommendations and has identified two changes
that are needed to make the error and accident reporting program more
meaningful and useful, i.e., timeliness in reporting for all biological
products and reporting by unlicensed blood establishments and
transfusion services.
1. Reporting Period
FDA is proposing to amend Sec. 600.14(a) to replace the term
``promptly'' with a reporting period of ``as soon as possible but not
to exceed 45 calendar days.''
FDA has found that licensed manufacturers of biological products
were not always submitting the error and accident reports in a
consistent and timely manner after detecting the error or accident. FDA
has found that by not previously specifying a definitive time period
for reporting errors and accidents, a liberal interpretation of the
timeframe had been taken. When reports are not submitted in a timely
manner, FDA is unable to adequately evaluate the public health
significance of an error or accident, or assess a firm's proposed
actions including activities to prevent recurrence and to address the
status of the affected products. While the agency is proposing a
maximum of 45 calendar days to report errors and accidents, FDA
encourages manufacturers to implement SOP's to submit these reports
sooner, including prior to the implementation of any corrective
actions.
2. Applicability to Unlicensed Blood Establishments
FDA is proposing the addition of Sec. Sec. 600.14(c) and 606.171 in
order to encompass all blood establishments in the reporting of errors
and accidents, not just licensed manufacturers. Registered blood
establishments and transfusion services are required to comply with the
CGMP and additional standards for blood and blood components, set forth
in parts 606 and 640, including recordkeeping requirements relating to
errors and accidents. By including error and accident reporting in part
606, the regulations would make clear that all licensed blood
manufacturers, unlicensed registered blood establishments, and
transfusion services would submit error and accident reports as a part
of their compliance with the CGMP for blood and blood components. With
full reporting, the public can be further assured that expeditious and
appropriate actions are being taken to protect all of the nation's
blood supply.
3. Reporting for Biological Products Made Available for Distribution
FDA proposes to require manufacturers to submit error and accident
reports for biological products that have been made available for
distribution. FDA believes that this reporting requirement will permit
it to conduct appropriate oversight of biological products manufactured
for distribution to the public (including blood and blood components)
and of actions taken by manufacturers to correct errors and accidents
without hindering a firm's ability to expeditiously manufacture
biological products. By requiring reports of errors and accidents after
the manufacturer has determined that a biological product is suitable
for distribution, the firm is able to investigate and correct errors
and accidents during the manufacturing process and before distribution,
and FDA is able to receive information necessary to adequately review
and monitor the quality and safety of products released for
distribution to the public, as well a firm's investigative and
corrective efforts relating to the errors and accidents. FDA is also
able to review and monitor a manufacturer's procedures for correcting
and preventing errors and accidents during manufacture by the
requirement that manufacturers investigate all such errors and
accidents (Secs. 211.192, 606.100(c), and 21 CFR 820.162), and maintain
complete records of the investigation and promptly make them available
to FDA for review during inspections (Secs. 211.198(b)(2),
606.160(b)(7)(iii), and 21 CFR 820.180).
C. Error and Accident Reporting, Blood and Blood Components
(Sec. 606.171)
FDA is proposing the addition of a new Sec. 606.171 Reporting
errors and accidents in manufacturing to subpart I, Records and Reports
of part 606. A primary objective of this proposed rule is to make the
error and accident reporting requirement applicable to all
[[Page 49645]]
blood establishments, i.e., licensed manufacturers, unlicensed
registered manufacturers, and transfusion services. Including error and
accident reporting requirements for blood and blood component
manufacturing in part 606 will assure that these reporting requirements
will become part of the CGMP and apply to any establishment that
participates in the collection, processing, compatibility testing,
storage, or distribution of blood and blood components. In order for
FDA to more effectively evaluate and monitor the blood industry, it
needs reports from the full spectrum of establishments engaged in
manufacturing and distribution of blood and blood components. Because
unlicensed registered blood establishments and transfusion services
represent a large sector of the blood processing community, FDA
believes these establishments must also be required to submit reports
of those errors or accidents that may affect the safety, purity, or
potency of distributed blood and blood components.
1. Scope
a. Establishments. FDA is proposing in the new Sec. 606.171 to
require the reporting of errors and accidents by all blood
establishments including licensed manufacturers of blood and blood
components, unlicensed registered blood establishments, and transfusion
services. All of these establishments are required to follow the CGMP
(parts 211 and 606) in their daily operation. Although certain
transfusion services are exempt from registration under Sec. 607.65(f),
all transfusion services are required under 42 CFR 493.1273(a) to
comply with the CGMP if performing compatibility testing, storage,
labeling, and recordkeeping, or any other process involving
manufacturing.
Transfusion services may receive blood or blood components from
outside sources. When transfusion services discover errors and
accidents made by an outside manufacturer in relation to such products
they should report these errors and accidents to the manufacturer. The
manufacturer, i.e., the collecting facility, would then be responsible
for notifying CBER of the errors and accidents. However, errors and
accidents in manufacturing which are made by the transfusion service,
such as incorrect identification of samples used in compatibility
testing, or incorrect tag/crossmatch label, or storing product at the
incorrect temperature should be reported to CBER directly by the
transfusion service if the product was made available for distribution.
b. Blood and blood components. FDA is proposing in new Sec. 606.171
that all blood establishments be required, as part of their CGMP
programs, to report errors and accidents for blood and blood components
made available for distribution. FDA believes this reporting mechanism
will help assure the quality and safety of the nation's blood supply.
2. Format for Reporting
FDA is not at this time proposing the use of a specific report
form. FDA has recommended to manufacturers of blood or blood components
certain essential information that should be submitted in the report.
This information should include, but not be limited to: The name of the
blood establishment, registration or CLIA (Clinical Laboratories
Improvement Act) numbers if applicable, the unit number(s), the type of
blood product(s), the nature of the error or accident, the final
disposition of the blood product, and the notification of consignee(s),
if any. The information submitted by manufacturers of biological
products other than blood or blood components should include, but not
be limited to: The name of the manufacturer, the registration/license
number of the manufacturer, the location, the type of product, the lot
number(s), the nature of the error or accident, the final disposition
of the product, and the notification of consignee(s), if any. The
report for any biological product, including blood and blood
components, should also describe contributing factors causing the error
or accident and the actions or proposed corrective actions taken by the
manufacturer of the biological product to prevent recurrence.
At this time, the agency is requesting that any establishment or
other organization submit to the docket for review any proposed format
for the reporting of errors and accidents in manufacturing to be used
by industry, and any comments on the issue. FDA is also soliciting
comments on development of a program for electronic submission of error
and accident reports.
IV. Analysis of Economic Impacts
FDA has examined the impacts of the proposed rule under Executive
Order 12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612),
and under the Unfunded Mandates Reform Act (Pub. L. 104-4). 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; and 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 that impact.
The Unfunded Mandates Reform Act requires that agencies prepare an
assessment of anticipated costs and benefits before proposing any rule
that may result in an annual expenditure by State, local and tribal
governments, in the aggregate, or by the private sector, of
$100,000,000 (adjusted annually for inflation). The agency has
determined that the proposed rule is not an economically significant
rule as described in the Executive Order, nor a significant action as
defined in the Unfunded Mandates Reform Act. Aggregate impacts of the
rule, and aggregate expenditures caused by the rule, will not approach
$100 million for either the public or the private sector.
Available information suggests that costs to the entities most
affected by this rule, including small entities, are not expected to
increase by more than approximately 0.04 percent per year, as described
in the analysis in section IV.C of this document. Therefore, the agency
certifies that this rule will not have a significant economic impact on
a substantial number of small entities.
A. Objective and Basis of the Proposed Action
As discussed previously, FDA is considering the proposed action in
response to concerns regarding the accuracy, timeliness, and
completeness of error and accident reporting associated with the
manufacturing of blood and other biological products. The proposed
reporting requirements will expedite reporting of errors and accidents
in the manufacture of such products, enhance FDA's ability to identify
potential quality assurance problems, and facilitate a rapid response
where public health may be at risk. This action is taken under the
authority of sections 351 and 361 of the PHS Act and sections 501 and
502 of the act. FDA has reviewed related Federal rules and has not
identified any rules that duplicate, overlap, or conflict with the
proposed rule.
B. Small Entities Affected
This proposal affects both entities that currently submit mandatory
error and accident reports and those entities currently subject only to
voluntary reporting. However, the magnitude of
[[Page 49646]]
the impact is expected to be greater for the latter group than for the
former.
Entities currently subject to mandatory error and accident
reporting comprise approximately 102 licensed manufacturers of
biological products (excluding blood and blood components) with 280
locations, and approximately 294 licensed manufacturers of blood and
plasma with 725 locations. Entities currently subject only to voluntary
reporting of such incidents include approximately 2,560 unlicensed
registered blood establishments and an estimated 4,500 transfusion
services inspected by the Health Care Financing Administration. FDA
believes many of these entities to be small entities as defined by the
Regulatory Flexibility Act. For example, most of the transfusion
services are located in hospitals, and nearly three-fourths of
community hospitals are either not-for-profit or have fewer than 50
beds.
C. Nature of the Impact
All of the entities described in section IV.B of this document
would be affected by the proposed rule. The main cost involved in
implementing the rule would be the time required to review current
SOP's and to ensure that the appropriate staff understand the types of
errors and accidents that must be reported and the importance of timely
reporting. The new time limit for reporting is expected to increase the
timeliness of report submissions, but because the reporting activity
itself is unchanged by this provision the costs of this increased
compliance should be limited to the preparation/revision of the SOP and
staff training activities. FDA has no precise estimate of this one-time
cost, but the agency expects that it should require an average of 2
hours per establishment to prepare the 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 provision of the proposed rule that extends mandatory error and
accident reporting to all unlicensed registered blood establishments
and transfusion services will affect nearly all such entities. At
present, these entities are requested to submit such reports
voluntarily, but FDA estimates that only about 1 percent are doing so,
and even these entities may not be submitting all the reports that
would be required under this rule. Thus, this requirement would involve
a new routine activity for the great majority of unlicensed blood
establishments and transfusion services.
FDA has no precise estimates of the cost of submitting error and
accident reports. Anecdotal evidence suggests that such reports can
take an average of 30 minutes per report to complete, and that some
blood establishments may be reporting up to 8 errors and accidents per
10,000 units of blood collected annually. It is not known whether these
anecdotal data are representative of current practice. Nor is it known
whether these figures represent unusually high (or low) levels of
quality assurance, or unusually high (or low) compliance with current
reporting requirements.
Nonetheless, these figures tentatively suggest that a small entity
that handles 10,000 units of blood annually and that is newly subject
to the requirements presented in this proposed rule might incur new
costs of 6 hours per year of staff time, 2 hours for the preparation of
the SOP, and 4 hours preparing and submitting error and accident
reports. At an estimated $37.98 per hour value of staff time, this
would lead to an annual cost of $227.88, or roughly $.028 per unit.
Based on an average cost of producing a unit of blood of $65 to $75,
this requirement would increase the average entity's per unit cost of
producing a unit of blood by approximately 0.04 percent. Entities with
above average numbers of errors and accidents would incur higher costs.
(There should not be any additional costs of investigating errors and
accidents or keeping records of them, since these activities are
already required under other sections in 21 CFR parts 200, 600, and
800).
There are no specific educational or technical skills required to
complete and submit error accident reports. These reports are generally
completed by trained and qualified employees of an establishment.
Updating SOP's and training staff regarding the new requirements of
this proposed rule would require a person knowledgeable and experienced
in medical laboratory practice.
D. Minimizing the Impact on Small Entities
A number of different possibilities for formatting and submitting
the reports are possible. FDA is soliciting comments on the following
topics and reporting alternatives: (1) Examples of simple, user-
friendly reporting formats that would minimize the time required to
submit a report but that would contain the requisite information; (2)
whether a specified, uniform format is less burdensome than permitting
entities to create their own formats or select from a range of possible
formats; and (3) whether electronic reporting is less burdensome than
paper reporting and, if so, which electronic formats are best suited to
this requirement.
V. The Paperwork Reduction Act of 1995
This proposed rule contains information collection requirements
which are subject to public comment and review by the Office of
Management and Budget (OMB) under the Paperwork Reduction Act of 1995
(44 U.S.C. 3501-3520). The title, description, and respondent
description of the information collection requirements are shown below
with an estimate of the annual reporting burden. Included in the
estimate is the time for reviewing the instructions, gathering
necessary information, and completing and reviewing the report.
With respect to the following collection of information, FDA
invites comments on: (1) Whether the proposed collection of information
is necessary for the proper performance of FDA's functions, including
whether the information will have practical utility; (2) the accuracy
of FDA's estimate of the burden of the proposed collection of
information, including the validity of the methodology and assumptions
used; (3) ways to enhance the quality, utility, and clarity of the
information to be collected; and (4) ways to minimize the burden of the
collection of information on respondents, including through the use of
automated collection techniques, when appropriate, and other forms of
information technology.
Title: Biological Product Reporting of Errors and Accidents in
Manufacturing.
Description: FDA is proposing to amend the regulations that require
licensed manufacturers of biological products to report errors and
accidents in manufacturing that may affect the safety, purity, or
potency of a product. FDA proposes to define certain terms, i.e.,
``error and accident'', and ``made available for distribution;''
replace ``promptly'' with ``as soon as possible but not to exceed 45
calendar days'' with regard to the timeframe for reporting; limit the
error and accident reporting requirements to biological products that
have been made available for distribution; and amend the CGMP
regulations to require all manufacturers of blood and blood components,
including unlicensed registered blood establishments and transfusion
services, to submit error and accident reports. FDA is proposing this
action in response to concerns regarding the accuracy, timeliness, and
completeness of error and accident reporting associated with the
manufacturing of blood and other biological products, and as an
essential tool in FDA's directive to
[[Page 49647]]
protect public health by establishing and maintaining surveillance
programs that provide timely and useful information. FDA is not at this
time proposing to require the use of a specific form for error and
accident reports, but is requesting that establishments submit to the
docket for review any proposed format for these reports. FDA is also
soliciting comments on development of a program for electronic
reporting of errors and accidents.
Description of Respondents: Manufacturers of blood and blood
components; manufacturers of other biological products.
There are approximately 102 licensed manufacturers of biological
products other than blood and blood components with 280 locations, and
294 licensed blood and plasma establishments with 725 locations. In
fiscal year 1996, these manufacturers submitted a total of 10,793 error
and accident reports. Of this total, 10,781 reports were submitted by
licensed blood and plasma establishments. Although approximately 7,060
unlicensed registered blood establishment and transfusion service
locations are currently submitting reports on a voluntary basis, FDA
received only 159 error and accident reports for fiscal year 1996 from
such entities. Based on the substantially larger number of reports
received from licensed blood and plasma establishments, FDA believes
that the number of reports currently received from unlicensed
establishments is not an accurate indicator of the number of reports
that will be submitted once the unlicensed establishments are required
to submit error and accident reports for products made available for
distribution.
The following reporting burden for proposed Sec. 600.14 was
estimated by using 1996 reporting figures for licensed manufacturers of
biological products other than blood and blood components. The
reporting burden for proposed Sec. 606.171 was estimated by using the
1996 reporting frequency average for all licensed blood and plasma
establishment locations of 15 reports per year; the number of
respondents was estimated by adding the number of unlicensed registered
blood establishment and transfusion service locations (7,060 according
to FDA's records) to the number of licensed blood and plasma
establishment locations that are already reporting. An average time of
0.5 hours (according to several respondents contacted by FDA) is used
in the preparation of each report.
Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
----------------------------------------------------------------------------------------------------------------
600.14 280 0.04 12 0.5 6.0
606.171 7,785 15 116,775 0.5 58,387.5
Total 58,393.5
----------------------------------------------------------------------------------------------------------------
There are no capital costs or operating and maintenance costs associated with this collection of information.
In compliance with section 3507(d) of the Paperwork Reduction Act
of 1995 (44 U.S.C. 3507(d)), the agency has submitted a copy of this
proposed rule to OMB for review of the information collection
provisions. Interested persons are requested to submit written comments
regarding information collection by October 23, 1997 to the Office of
Information and Regulatory Affairs, OMB (address above), ATTN: Desk
Officer for FDA.
VI. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(10) 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. Request for Comments
Interested persons may, on or before December 22, 1997, submit to
the Dockets Management Branch (address above) written comments
regarding this proposal, except that comments regarding information
collection provisions should be submitted in accordance with the
instructions in section V of this document. Two copies of any comments
on issues other than information collection are to be submitted, of
this document except that individuals may submit one copy. Comments are
to be identified with the docket number found in brackets in the
heading of this document. Received comments may be seen in the office
above between 9 a.m. and 4 p.m., Monday through Friday.
List of Subjects
21 CFR Part 600
Biologics, Reporting and recordkeeping requirements.
21 CFR Part 606
Blood, Labeling, Laboratories, and 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, it is proposed that 21 CFR parts 600
and 606 be amended as follows:
PART 600--BIOLOGICAL PRODUCTS: GENERAL
1. The authority citation for 21 CFR part 600 continues to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,
353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125
of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a,
264, 300aa-25).
2. Section 600.3 is amended by adding new paragraphs (hh) and (ii)
to read as follows:
Sec. 600.3 Definitions.
* * * * *
(hh) Error and accident means:
(1) An event that represents a deviation from current good
manufacturing practice (CGMP), applicable standards, or established
specifications that may affect the safety, purity, or potency of a
biological product, or otherwise cause the product to be in violation
of the Federal Food, Drug, and Cosmetic Act or the Public Health
Service Act, or
(2) An unexpected or unforeseeable event that may affect the
safety, purity, or potency of a biological product, or otherwise cause
the product to be in violation of the Federal Food, Drug, and Cosmetic
Act or the Public Health Service Act.
(ii) Made available for distribution means that the biological
product has been determined to meet all release
[[Page 49648]]
criteria and to be suitable for distribution.
3. Section 600.14 is amended by revising the section heading and
paragraph (a) and by adding new paragraph (c) to read as follows:
Sec. 600.14 Reporting of errors and accidents.
(a) Except as provided in paragraph (c) of this section, the
Director, Office of Compliance (HFM-650), Center for Biologics
Evaluation and Research, 1401 Rockville Pike, Rockville, MD 20852-1448,
shall be notified as soon as possible but not to exceed 45 calendar
days, of errors or accidents in the manufacture of products that may
affect the safety, purity, or potency of any biological product made
available for distribution.
* * * * *
(c) In lieu of the requirements of paragraph (a) of this section,
all manufacturers of blood and blood components shall submit reports to
FDA in accordance with Sec. 606.171 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: Secs. 201, 301, 501, 502, 505, 510, 520, 701, 704 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 351,
352, 355, 360, 360j, 371, 374); secs. 215, 351, 353, 361 of the
Public Health Service Act (42 U.S.C. 216, 262, 263a, 264).
5. Section 606.3 is amended by adding new paragraphs (k) and (l) to
read as follows:
Sec. 606.3 Definitions.
* * * * *
(k) Error and accident means:
(1) An event that represents a deviation from current good
manufacturing practice (CGMP), applicable standards, or established
specifications that may affect the safety, purity, or potency of blood
or blood components, including source plasma, or otherwise cause the
product to be in violation of the Federal Food, Drug, and Cosmetic Act
or the Public Health Service Act, or
(2) An unexpected or unforeseeable event that may affect the
safety, purity, or potency of blood or blood components, including
source plasma, or otherwise cause the product to be in violation of the
Federal Food, Drug, and Cosmetic Act or the Public Health Service Act.
(l) Made available for distribution means that the blood or blood
component, including source plasma, has been determined to meet all
release criteria and to be suitable for distribution.
6. Section 606.171 is added to subpart I to read as follows:
Sec. 606.171 Error and accident reporting, blood and blood
components.
All establishments as defined in Sec. 607.3(c) of this chapter
shall notify the Director, Office of Compliance (HFM-600), Center for
Biologics Evaluation and Research, 1401 Rockville Pike, Rockville, MD
20852-1448, as soon as possible but not to exceed 45 calendar days, of
errors or accidents in the manufacture of blood or blood components,
including source plasma, that may affect the safety, purity, or potency
of any blood or blood component made available for distribution.
Dated: June 25, 1997.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 97-25129 Filed 9-22-97; 8:45 am]
BILLING CODE 4160-01-F