49642 Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules

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. Two copies of any comments

are to be submitted, 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 in 21 CFR Part 200

Drugs, Prescription drugs.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs, it is proposed that

21 CFR part 200 be amended as follows:

PART 200—GENERAL

1. The authority citation for 21 CFR

part 200 continues to read as follows:

Authority: Secs. 201, 301, 501, 502, 503,

505, 506, 507, 508, 515, 701, 704, 705 of the

Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 331, 351, 352, 353, 355, 356, 357,

358, 360e, 371, 374, 375).

2. New § 200.51 is added to subpart C

to read as follows:

§ 200.51 Sterility requirements for

inhalation solution drug products.

(a) All inhalation solutions for

nebulization shall be manufactured to

be sterile.

(b) Manufacturers shall also comply

with the recordkeeping requirements in

§ 211.113(b) of this chapter.

Dated: September 12, 1997.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 97–25130 Filed 9–22–97; 8:45 am]

BILLING CODE 4160–01–F

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.

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 (§ 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.
Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules 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 (§ 606.100(c)) and

to maintain and make available to FDA

appropriate records of such

investigations and corrections

(§§ 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 §§ 600.3 and 606.3; require a

specific timeframe for reporting at

§§ 600.14 and 606.171; require reports

for products that have been made

available for distribution, at §§ 600.14

and 606.171; and extend the reporting

requirements to unlicensed registered

blood establishments and transfusion

services, at § 606.171.

A. Definitions (§§ 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 §§ 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
49644 Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules

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 §§ 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

(§ 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

§ 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

§ § 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 (§§ 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

(§§ 211.198(b)(2), 606.160(b)(7)(iii), and

21 CFR 820.180).

C. Error and Accident Reporting, Blood

and Blood Components (§ 606.171)

FDA is proposing the addition of a

new § 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
Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules 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 § 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

§ 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 § 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
49646 Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules

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 threefourths 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 onetime 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
Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules 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 § 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

§ 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

21 CFR Section No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response Total Hours

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:

§ 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
49648 Federal Register / Vol. 62, No. 184 / Tuesday, September 23, 1997 / Proposed Rules

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:

§ 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 § 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:

§ 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:

§ 606.171 Error and accident reporting,

blood and blood components.

All establishments as defined in

§ 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

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Part 52

[ME–046–6996b; A–1–FRL–5894–7]

Approval and Promulgation of Air

Quality Implementation Plans; Maine;

(General Conformity Rule)

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule.

SUMMARY: EPA is proposing to approve

a State Implementation Plan (SIP)

revision submitted by the State of Maine

for the purpose of implementing

General Conformity (Section

176(c)(4)(C) of the Clean Air Act (CAA)

and its regulations 40 CFR part 51,

Subpart W). The Maine SIP incorporates

by reference the criteria and procedures

set forth at 40 CFR part 51, Subpart W.

This SIP revision establishes and

requires federal actions to conform to all

applicable implementation plans

developed pursuant to Section 110 and

Part D of the CAA. In the Final Rules

Section of this Federal Register, EPA is

approving the State’s SIP revision as a

direct final rule without prior proposal

because the Agency views this as a

noncontroversial revision amendment

and anticipates no adverse comments. A

detailed rationale for the approval is set

forth in the direct final rule. If no

adverse comments are received in

response to that direct final rule, no

further activity is contemplated in

relation to this proposed rule. If EPA

receives adverse comments, the direct

final rule will be withdrawn and all

public comments received will be

addressed in a subsequent final rule

based on this proposed rule. EPA will

not institute a second comment period

on this proposal. Any parties interested

in commenting on this proposal should

do so at this time.

DATES: Comments must be received on

or before October 23, 1997.

ADDRESSES: Comments may be mailed to

Susan Studlien, Deputy Director, Office

of Ecosystem Protection (mail code

CAA), U.S. Environmental Protection

Agency, Region I, JFK Federal Bldg.,

Boston, MA 02203. Copies of the State

submittal are available for public

inspection during normal business

hours, by appointment at the Office of

Ecosystem Protection, U.S.

Environmental Protection Agency,

Region I, One Congress Street, 11th

floor, Boston, MA and the Bureau of Air

Quality Control, Department of

Environmental Protection, 71 Hospital

Street, Augusta, ME 04333.

FOR FURTHER INFORMATION CONTACT:

Donald O. Cooke, (617) 565–3508, at the

EPA Region I address above.

SUPPLEMENTARY INFORMATION: For

additional information, see the direct

final rule which is located in the Rules

Section of this Federal Register.

Authority: 42 U.S.C. 7401—7671q.

Dated: September 9, 1997.

John P. DeVillars,

Regional Administrator, Region I.

[FR Doc. 97–25229 Filed 9–22–97; 8:45 am]

BILLING CODE 6560–50–P

ENVIRONMENTAL PROTECTION

AGENCY

40 CFR Part 52

[PA58–4039; AD–FRL–5897–2]

Approval and Promulgation of Air

Quality Implementation Plans;

Pennsylvania; Pennsylvania Power—

New Castle NOX RACT Proposal;

Extension of Comment Period

AGENCY: Environmental Protection

Agency (EPA).

ACTION: Proposed rule; extension of the

comment period.

SUMMARY: EPA is reopening the

comment period for a proposed rule

published on August 18, 1997 (62 FR

43959). In the August 18 document,

EPA proposed to disapprove the April

19, 1995 Pennsylvania Department of