[Federal Register Volume 62, Number 184 (Tuesday, September 23, 1997)]
[Proposed Rules]
[Pages 49642-49648]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 97-25129]


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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