Biological Products; Reporting of Errors and Accidents in Manufacturing

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.

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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

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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

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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

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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