Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations 66621

Decoquinate in

grams per ton

Combination in grams

per ton Indications for use Limitations Sponsor

*******

Chlortetracycline approximately 400,

varying with body

weight and feed consumption to provide

10 mg/lb of body

weight per day.

Calves, beef and nonlactating dairy cattle: prevention of coccidiosis caused

by Eimeria bovis and E. zuernii, for

treatment of bacterial enteritis caused

by Escherichia coli, and for treatment

of bacterial pneumonia caused by

Pasteurella multocida organisms susceptible to chlortetracycline.

Feed Type C feed to provide 22.7 mg

decoquinate and 1 g chlortetracycline/

100 lb body weight (0.5 mg/kg)/day

for not more than 5 days. Type C

feed may be prepared from Type B

feed containing 535.8 to 5,440 g/ton

decoquinate and 6,700 to 80,000 g/

ton chlortetracycline. When consumed, feed 22.7 mg decoquinate/

100 lb body weight/day for a total of

28 days to prevent coccidiosis. Withdraw 24 hours prior to slaughter. Do

not feed to calves to be processed for

veal. Do not feed to animals producing milk for food.

046573

*******

Dated: October 26, 2000.

Stephen F. Sundlof,

Director, Center for Veterinary Medicine.

[FR Doc. 00–28524 Filed 11–6–00; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Part 558

New Animal Drugs for Use in Animal

Feeds; Pyrantel Tartrate

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

animal drug regulations to reflect

approval of an abbreviated new animal

drug application (ANADA) filed by

Farnam Companies, Inc. The ANADA

provides for use of pyrantel tartrate in

horse feed for the prevention and

control of various species of internal

parasites.

DATES: This rule is effective November

7, 2000.

FOR FURTHER INFORMATION CONTACT:

Lonnie W. Luther, Center for Veterinary

Medicine (HFV–102), Food and Drug

Administration, 7500 Standish Pl.,

Rockville, MD 20855, 301–827–0209.

SUPPLEMENTARY INFORMATION: Farnam

Companies, Inc., 301 West Osborn,

Phoenix, AZ 85013–3928, is sponsor of

ANADA 200–282 that provides for use

of CONTINUEXTM (pyrantel tartrate)

Daily Dewormer. The ANADA provides

for use of pyrantel tartrate in horse feed

for the prevention and control of various

species of internal parasites. The

ANADA is approved as a generic copy

of Pfizer Inc.’s NADA 140–819 for

STRONGID 48. ANADA 200–282 is

approved as of September 26, 2000, and

the regulations are amended in 21 CFR

558.485 to reflect the approval. The

basis for approval is discussed in the

freedom of information summary.

In accordance with the freedom of

information provisions of 21 CFR part

20 and 514.11(e)(2)(ii), a summary of

safety and effectiveness data and

information submitted to support

approval of this application may be seen

in the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 5630 Fishers Lane, rm.

1061, Rockville, MD 20852, between 9

a.m. and 4 p.m., Monday through

Friday.

The agency has determined under 21

CFR 25.33(a)(1) 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.

This rule does not meet the definition

of ‘‘rule’’ in 5 U.S.C. 804(3)(A) because

it is a rule of ‘‘particular applicability.’’

Therefore, it is not subject to the

congressional review requirements in 5

U.S.C. 801–808.

List of Subjects in 21 CFR Part 558

Animal drugs, Animal feeds.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to the Commissioner

of Food and Drugs and redelegated to

the Center for Veterinary Medicine, 21

CFR part 558 is amended as follows:

PART 558—NEW ANIMAL DRUGS FOR

USE IN ANIMAL FEEDS

1. The authority citation for 21 CFR

part 558 continues to read as follows:

Authority: 21 U.S.C. 360b, 371.

2. Section 558.485 is amended by

adding paragraph (a)(29) to read as

follows:

§ 558.485 Pyrantel tartrate.

(a) * * *

(29) To 017135: 48 grams per pound,

paragraph (e)(2) of this section.

* * * * *

Dated: October 26, 2000.

Stephen F. Sundlof,

Director, Center for Veterinary Medicine.

[FR Doc. 00–28523 Filed 11–6–00; 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

Biological Product Deviations in

Manufacturing

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

regulation requiring licensed

66622 Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations

manufacturers of biological products to

report errors and accidents in

manufacturing that may affect the

safety, purity, or potency of a product.

FDA also is amending the current good

manufacturing practice (CGMP)

regulations for blood and blood

components to require establishments

involved in the manufacture of blood

and blood components, including

licensed manufacturers, unlicensed

registered establishments and

transfusion services, to report biological

product deviations in manufacturing.

The final rule requires licensed

manufacturers, unlicensed registered

blood establishments, and transfusion

services who had control over the

product when a deviation occurred to

report to FDA the biological product

deviation if the product has been

distributed. The final rule also

establishes a 45-day reporting period.

FDA is issuing the final rule as part of

a retrospective review under Executive

Order 12866 of significant FDA

regulations to improve the effectiveness

of FDA’s regulatory program.

DATES: This rule is effective May 7,

2000.

FOR FURTHER INFORMATION CONTACT:

Paula S. McKeever, Center for Biologics

Evaluation and Research (HFM–17),

Food and Drug Administration, 1401

Rockville Pike, suite 200N, Rockville,

MD 20852, 301–827–6210.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of September

23, 1997 (62 FR 49642), FDA published

a proposed rule to amend the

requirements for reporting errors and

accidents in manufacturing biological

products in § 600.14 (21 CFR 600.14).

The proposed rule would also have

added § 606.171 and expanded the

requirement for reporting of errors and

accidents in the manufacturing of

biological products to include

unlicensed registered blood

establishments and transfusion services.

FDA provided 90 days for comments on

the proposed rule.

FDA is extending a reporting

requirement to establishments defined

in 21 CFR 607.3(c) that manufacture

blood and blood components. Such

establishments include unlicensed

registered blood establishments and

transfusion services (hereinafter referred

to as ‘‘unlicensed blood

establishments’’). FDA believes this

action is necessary because it has

observed an increase in the number of

product recalls initiated by unlicensed

blood establishments due to biological

product deviations in manufacturing

that were not reported voluntarily to the

agency. FDA is also narrowing the scope

of the reporting requirement as

discussed in section II of this document

to those reports that are necessary to

protect the public health, while

relieving industry of some reporting

burden. FDA also believes the reporting

requirement will address concerns,

identified by the Office of Inspector

General of the Department of Health and

Human Services, that: (1) Error and

accident reports required under § 600.14

were not being submitted in a timely

manner; and (2) unlicensed blood

establishments were not obligated to

submit such reports.

II. Highlights of the Final Rule

In response to comments received on

the proposed rule, FDA has revised

several substantive provisions of the

proposed rule. FDA has replaced the

term ‘‘error and accident’’with the term

‘‘biological product deviation.’’ In

§§ 600.14(b) and 606.171(b), the final

rule more clearly describes the types of

events, now termed ‘‘biological product

deviations,’’ that must be reported to

FDA. These are events which may affect

the safety, purity, or potency of a

distributed biological product and

which represent either a deviation from

CGMP, applicable regulations,

applicable standards, or established

specifications, or are unforeseen or

unexpected.

In an effort to reduce the reporting

burden on both industry and the agency,

while protecting the public health, FDA

has changed the threshold for when a

deviation must be reported. As

proposed, a licensed manufacturer or

unlicensed blood establishment would

have reported deviations related to

products ‘‘made available for

distribution.’’ The final rule focuses on

deviations involving distributed

products only, because such deviations

may involve products administered to

patients, and therefore present the

greatest risk to public health.

FDA defines the terms ‘‘distributed’’

and ‘‘control’’ to make clear that the

reporting requirement applies only to

distributed product. The final rule

defines ‘‘distributed’’ as meaning the

biological product has left the control of

the licensed manufacturer or unlicensed

blood establishment; or the licensed

manufacturer has provided Source

Plasma or any other blood component

for use in the manufacture of a licensed

product. ‘‘Control’’ is defined as having

responsibility for maintaining a

product’s continued safety, purity, and

potency, and compliance with

applicable product and establishment

standards and CGMP requirements.

If the product never leaves the control

of the licensed manufacturer or

unlicensed blood establishment, no

biological product deviation report

(BPDR) should be filed. However, the

licensed manufacturer or unlicensed

blood establishment who discovers a

biological product deviation before the

product has left its control must

investigate the deviation. Such an

obligation exists independent of this

rule. For example, under CGMP, a

licensed manufacturer must thoroughly

investigate unexplained discrepancies

and batch failures, including the failure

of a product to meet specifications, and

must document the discovery,

investigation, and followup taken (parts

211 and 820 (21 CFR parts 211 and

820)). Manufacturers of in vitro

products licensed under section 351 of

the Public Health Service Act (PHS Act)

(42 U.S.C. 262) must investigate the

cause of nonconformities related to

product, processes, and the quality

system, and identify the action needed

to correct and prevent recurrence of

nonconforming product and other

quality problems ( § 820.100). The

CGMP regulations applicable to licensed

and unlicensed blood establishments

provide, ‘‘A thorough investigation,

including the conclusions and followup, of any unexplained discrepancy or

the failure of a lot or unit to meet any

of its specifications shall be made and

recorded’’ (§ 606.100(c) (21 CFR

606.100(c))). FDA will monitor internal

quality assurance (QA) procedures

through routine inspections.

In § 600.14(a)(2)(i), FDA has limited

the exception to the reporting

requirement for manufacturers of in

vitro diagnostic products to

manufacturers who only manufacture in

vitro diagnostic products that are not

licensed under section 351 of the PHS

Act. Manufacturers of such products

continue to have reporting obligations

under 21 CFR part 803. Establishments

that manufacture both in vitro

diagnostic products licensed under

section 351 of the PHS Act and

unlicensed medical devices will be

required to report under § 600.14 only

those events which may affect the

safety, purity, or potency of the licensed

product.

In § 600.14(a)(2)(iii), FDA is clarifying

the reporting requirement for licensed

manufacturers of biological products

when the manufacturer, as part of its

license application, is approved to

manufacture Source Plasma or any other

blood component for further

manufacture of other biological

products. When a biological product

deviation occurs during the

manufacture of the Source Plasma or

Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations 66623

any other blood component, the BPDR

must be submitted under § 606.171.

When a biological product deviation

occurs after the manufacture of that

Source Plasma or any other blood

component and during the manufacture

of another biological product, the BPDR

is submitted under § 600.14. When a

licensed manufacturer provides Source

Plasma or any other blood component

for use in the manufacture of another

licensed biological product, such Source

Plasma or any other blood component

has been distributed under § 606.3(k).

FDA also is clarifying the reporting

responsibilities of licensed

manufacturers and unlicensed blood

establishments who contract out certain

manufacturing steps. A manufacturer

who contracts with another person to

perform any manufacturing step but

who retains control over the product is

still responsible for reporting under the

rule even if the deviation occurred or

was discovered at the contract

establishment. Sections 600.14(a)(1) and

606.171(a)(1) make explicit that licensed

manufacturers and unlicensed blood

establishments must establish, maintain,

and follow a procedure for receiving

from their contractors the information

necessary to fulfill their reporting

requirements.

FDA is retaining the proposed 45-day

reporting time in the final rule but is

clarifying that the 45-day time period

runs from the date that the

manufacturer, its agent, or another

person performing a manufacturing,

holding, or distribution step under the

manufacturer’s control, first discovers

information reasonably suggesting a

reportable event has occurred. FDA is

also adding a requirement in

§§ 600.14(d) and 606.171(d) that

licensed manufacturers and unlicensed

blood establishments use Form FDA–

3486 to report biological product

deviations. This form is available in

paper form and also on the Internet.

Sections 600.14(e) and 606.171(e)

indicate where and how the BPDR form

should be submitted.

Finally, FDA has written the final rule

using plain language in accordance with

the presidential memorandum on plain

language in government writing, dated

June 1, 1998. FDA has adopted the plain

language approach to make its written

communications with the public more

accessible and understandable. As a

result, FDA is expanding § 600.14 and

606.171 in the final rule to address the

following: (1) Who must report, (2)

What must be reported, (3) When must

the report be submitted, (4) How must

the report be submitted, and (5) Where

must the report be sent?

III. Comments on the Proposed Rule

and FDA Responses

FDA received 98 comments on the

proposed rule. The comments were

submitted by manufacturers, blood

establishments, trade associations,

professional associations, Department of

Defense, and individuals. In addition,

the Office of Management and Budget

(OMB) forwarded to FDA a number of

comments it received on the proposed

rule. Thirty-two comments supported

FDA’s goal of creating a standardized

reporting system to identify biological

product deviations in manufacturing

and recognized the importance to blood

safety of requiring prompt reporting of

biological product deviations in the

manufacture of blood and blood

components. Fifteen comments objected

to the proposed rule. Several comments,

mostly those from transfusion services

and pharmaceutical entities, objected to

a mandatory reporting requirement

being applied to them. Several

expressed concerns that the reporting

burden would be overwhelming.

In general, the comments expressed

specific concerns about the scope and

content of the proposed rule and

requested clarification of certain

definitions. FDA summarizes and

responds to each of the received

comments in the following sections.

A. General Comments

(Comment 1) Twenty-one comments

questioned the public health benefit of

the proposed rule and asked FDA to

further define its public health and

safety objective. Many of the comments

suggested that the reporting system

overlapped existing QA programs and

was, therefore, unnecessary.

The objectives of the biological

product deviation reporting requirement

are to: (1) Enable FDA to respond when

public health may be at risk, (2)

expedite reporting of biological product

deviations in manufacturing, (3) provide

FDA with uniform data to track trends

that may indicate broader threats to the

public health, (4) create a uniform

reporting requirement that can be

enforced against noncomplying entities,

and (5) help ensure licensed

manufacturers and unlicensed blood

establishments are taking appropriate

actions to investigate and correct

biological product deviations.

The reporting system will enable the

agency to evaluate and monitor blood

establishments in response to detected

deviations, and regularly alert field staff

and blood establishments with trend

analysis of the types of deviations

reported. Under the existing rule, there

were two impediments to the success of

the reporting process: (1) Error and

accident reports were not being

submitted in a timely manner by

establishments, and (2) there was no

assurance that unlicensed blood

establishments were submitting reports.

The reporting system is not intended

to overlap QA programs. Instead, it

provides FDA with information that an

individual establishment’s QA program

may not detect. For example, if an event

occurs once a year in every

establishment, it may not appear

significant to any single establishment.

The reporting system will allow FDA to

recognize the significance of that event

in a timely fashion and to take

appropriate action to protect the public

health. Reporting of biological product

deviations will enable FDA to identify

areas in which further regulation or

guidance is needed to assist licensed

manufacturers and unlicensed blood

establishments in decreasing the

occurrence of these events.

(Comment 2) Fifty comments wanted

to know how FDA will use or analyze

the information and what procedure

FDA will use to respond to reports

received under the rule. Two comments

stated that the reports should not be

used as a basis for issuing a Form FDA–

483.

A BPDR alone will not be a basis for

issuing a Form FDA–483. Form FDA–

483 is a list a list of observations noted

during an FDA inspection and issued to

the firm at the conclusion of the

inspection. The firm is expected to

respond to the observations and make

the necessary corrections. First, this

information will aid FDA, licensed

manufacturers, and unlicensed blood

establishments in appropriately

targeting QA efforts to improve product

quality and reduce manufacturing

problems. In addition to reviewing

reports upon receipt at FDA, FDA will

review all reports during routine

inspections and examine all

manufacturing deviations, not merely

reportable deviations, to ensure that the

establishment has followed all

established standard operating

procedures (SOP’s) related to

investigation, followup, and reporting of

deviations. Secondly, the BPDR’s will

inform FDA about specific problems

licensed manufacturers and unlicensed

blood establishments encounter in the

manufacture of biological products.

FDA intends to provide this data to

industry, in accordance with its

responsibility to safeguard trade secrets

and confidential commercial

information. FDA already provides this

kind of data in fiscal quarter summaries,

available to the public by mail,

facsimile, and Internet. Thirdly, these

66624 Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations

reports will identify areas needing

future guidance from the agency. FDA

will issue such guidance in accordance

with its good guidance practices

(GGP’s).

A BPDR alone will not be a basis for

issuing a Form FDA–483. However, a

documented failure to follow CGMP or

other regulatory compliance problem

connected to a deviation may become an

observation on a Form FDA–483. For

example, an investigator may include an

observation under one of the following

conditions: (1) The deviation reoccurs

because of inadequate corrective action,

(2) investigation of the deviation is

inadequate, or (3) the deviation

represents an underlying systemic

problem in the operation. Significant

CGMP deficiencies related to a BPDR

may also become the subject of a Form

FDA–483 observation. Of course, an

investigator may include the failure to

file a BPDR as an observation on a Form

FDA–483.

(Comment 3) Several comments

expressed concern that FDA would not

have the resources to handle the reports

submitted under the proposed rule.

After reviewing the comments to the

proposed rule, FDA has worked actively

to reduce the burden of reporting on

licensed manufacturers, unlicensed

blood establishments, and the agency

under the final rule. FDA has refocused

the final rule to require reports only for

distributed products. FDA is also

developing a standardized format for

reporting, which will not only

streamline the process for the reporter,

but also allow FDA to process the

reports more efficiently. FDA believes

that the reporting requirement under the

final rule will not present an undue

burden on licensed manufacturers,

unlicensed blood establishments, or the

agency.

(Comment 4) Three comments asked

how FDA would enforce the proposed

rule.

In 1983, through a memorandum of

understanding (MOU), the Healthcare

Financing Administration (HCFA) and

FDA coordinated all federally

authorized inspections of unlicensed

blood establishments in order to

minimize duplication of effort and to

reduce the burden on affected facilities.

HCFA and FDA will use their usual

enforcement tools available under the

Federal Food, Drug, and Cosmetic Act

(the act) (21 U.S.C. 301 et seq.) and the

PHS Act (42 U.S.C. 201 et seq.). The

agencies will review compliance with

the reporting requirements during

inspections. If upon inspection of a

licensed manufacturer or unlicensed

blood establishment, the inspecting

agency discovers the establishment is

not complying with the biological

product deviation reporting

requirement, or the requirements for

investigation and followup, the

inspecting agency may take further

enforcement action, as warranted.

(Comment 5) One comment

questioned whether biological product

deviation reports would be subject to

the Freedom of Information Act (FOIA)

and, accordingly, available to the media

or public and whether reporting could

cause disclosure of confidential

information.

BPDR’s would be subject to disclosure

under the provisions of the FOIA and

the implementing regulations in 21 CFR

part 20. FDA will appropriately purge

all nondisclosable information prior to

the release of the reports.

(Comment 6) Seven comments

requested that FDA obtain additional

data and hold a public meeting before

implementing a final rule. One

comment suggested proceeding with a

demonstration project first.

In addition to following the normal

rulemaking process, FDA has discussed

the rule in various public forums. FDA

believes interested parties have been

given ample opportunity to express

their views on the proposed rule. A

‘‘demonstration program’’ is

unnecessary because this is not a new

program, but a revision and updating of

an existing program with which most

licensed manufacturers have

experience. However, FDA may engage

in further public discussion to provide

guidance to industry concerning what

constitutes a reportable deviation within

the parameters of the final rule.

(Comment 7) Three comments

requested that FDA develop guidance

for the proposed rule.

FDA agrees that guidance to industry

would be helpful. FDA has developed

draft guidance regarding those events it

would expect to be reported under this

rule. The draft guidance recognizes that

licensed manufacturers and unlicensed

blood establishments may shoulder a

wide range of responsibilities in

manufacturing. A manufacturer of

licensed biological products would be

in control of the product for more steps

in manufacturing than a small hospital

transfusion service. Accordingly, the

draft guidance describes specific

guidance for each type of licensed

manufacturer and unlicensed blood

establishment. The notice of availability

for the draft guidances specific for

licensed manufacturers of products

other than blood and blood components,

and licensed and unlicensed blood

establishments will issue in the Federal

Register in the near future.

(Comment 8) FDA received several

comments from industry that extending

the reporting requirement to unlicensed

entities in proposed § 606.171 imposed

an unnecessary burden on these entities.

FDA indicated in proposing this

regulation that one of its primary

objectives was to make the biological

product deviation reporting requirement

applicable to all blood establishments,

whether licensed manufacturers,

unlicensed registered blood

establishments, or transfusion services.

In the proposed rule, FDA stated that

reports from the full spectrum of

establishments engaged in

manufacturing and distribution of blood

and blood components were necessary

to effectively evaluate and monitor the

blood industry. FDA continues to

believe that a mandatory reporting

requirement is necessary for all

establishments involved in blood and

blood product manufacturing and is

establishing the biological deviation

reporting requirement as part of the

CGMP regulations, which these

establishments must follow.

B. Scope

(Comment 9) One comment

recommended FDA adopt a single

mechanism for reporting all errors and

accidents, adverse events, etc., for all

blood products, medical devices and all

drugs, and eliminate all other reporting

programs, voluntary or mandatory.

FDA recognizes that the reporting

programs for biological products,

human drugs, and medical devices have

varying requirements. What is reported,

and how it is reported, are different

under the different systems. These

differences are intentional. For example,

the adverse event reporting (AER) and

medical device reporting systems focus

on patient impact. The starting point for

reporting, therefore, is often patient

reaction to a product. In contrast,

biological product deviation reporting

focuses on the manufacturing process as

it may affect the safety, purity, and

potency of the product. FDA anticipates

that information submitted in BPDR’s

will improve product quality and may

help reduce the incidence of adverse

patient outcomes without undue burden

on licensed manufacturers and

unlicensed blood establishments.

(Comment 10) Five comments stated

that the proposed rule should apply

only to blood and blood products and

should not extend to biotechnology

products. These comments argued that

the need to revise error and accident

regulations for biotechnology products

is not clear because there does not exist

a pattern of recalls for these products.

The comments stated that the recall

Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations 66625

guidelines in part 7 (21 CFR part 7) and

the AER system (21 CFR 600.80) are

adequate to ensure the safety and

quality of biotechnology products.

The regulatory scheme for

biotechnology products has always

included recall guidelines (part 7), AER,

and error and accident reporting (

§ 600.14). These three programs, each

designed to serve different objectives,

have worked together to ensure the

safety and quality of biotechnology

products. Adverse experience reporting

focuses on patient outcomes.

Consequently, the type and specificity

of the information reported as adverse

experiences differs substantially from

that required in biological product

deviation reports. Under the recall

provisions of part 7, manufacturers

notify FDA when they voluntarily

remove products from the marketplace

that are in violation of the laws

administered by FDA. The biological

product deviation regulations are

designed to gather information about the

events that give rise to defective or

potentially defective products and

provide FDA with an essential tool to

monitor potential risks to public health

and to facilitate a response when

necessary.

Section 600.14, in its current form,

requires error and accident reporting by

all licensed biological product

manufacturers, including manufacturers

of biotechnology products. This rule

would not impose new requirements on

such manufacturers. In fact, by limiting

reporting to biological product

deviations involving distributed

products, the new rule would decrease

the preexisting burden on such

manufacturers. FDA believes the revised

reporting requirement is necessary to

ensure that all manufacturers

understand their reporting

requirements, to expedite biological

product deviation reporting, and to

enable FDA to monitor accurately the

safety of biological products.

(Comment 11) Ten comments

requested that transfusion centers not be

regulated to the same extent as blood

collection centers and the

pharmaceutical industry under the

proposed rule. Of these, five comments

proposed that the reporting guidelines

themselves be specific to each type of

establishment. Six comments called for

definitions or examples specific to

transfusion service practice and two

comments called for separate data

collection forms.

FDA believes that in order to achieve

an accurate overview of the industry, it

is most useful to impose the same

reporting requirement on all blood

establishments, including transfusion

centers. However, FDA recognizes that

different regulated entities may need

specific guidance on how the biological

deviation reporting requirement will

apply to them. FDA is issuing guidance

to support the final rule that will

include examples specific to blood and

source plasma collection centers,

pharmaceutical and biological device

manufacturers, and transfusion services.

FDA also developed a biological

product deviation reporting form. FDA

believes one form for all the entities

covered under the rule will facilitate

processing of the reports and will aid

reporters in providing the necessary

information. The agency will provide

separate instructions on completing and

submitting the biological product

deviation reporting form.

(Comment 12) Eight comments asked

how the biological product deviation

reporting requirement will affect the

new drug application (NDA) Field Alert

Report regulations under 21 CFR

314.81(b)(1) and several comments

recommended harmonizing these

regulations.

The BPDR’s will have little, if any

affect on the NDA Field Alert

regulations. The NDA Field Alert

regulations are applicable only to those

products that are approved for

marketing under the provisions of part

314 (21 CFR part 314), and not to drug

products subject to licensing under the

PHS Act. FDA has harmonized a

number of regulations for certain

biotechnology products where products

regulated as biological products subject

to licensure are similar to products

subject to regulation as new drugs. See

§ 601.2(c) (21 CFR 601.2(c)) for a list of

such biotechnology products and

§ 314.70(g), 601.2(c)(1) and (c)(2), and

601.12 (21 CFR 601.12) for examples of

harmonization.

For these biotechnology products, a

total of 13 error and accident reports

were submitted under § 600.14 in the

fiscal year (FY) 1999. Because FDA

believes this is a very small burden to

industry, FDA has determined that

reports for such biotechnology products

should continue to be submitted

consistent with the requirements for

other biological products under § 600.14

of the final rule. This will allow the

Center for Biologics Evaluation and

Research (CBER) to keep all reports in

a single data base and will facilitate the

overall assessment of its biological

product deviation reporting program. If

the level of reporting or the needs of the

agency change, FDA will reconsider

whether to harmonize its reporting

requirements for biotechnology

products.

(Comment 13) Twenty-two comments

recommended developing a tiered

system of reporting based on the

severity of the deviation in which

serious errors or accidents would be

reported and all other errors and

accidents would be handled through

internal QA programs.

FDA considers any biological product

deviation that may affect the safety,

purity, and potency of a product to be

‘‘serious.’’ However, deviations that are

discovered before distribution pose less

of a threat to the public health because

no patient would receive the product,

and because the licensed manufacturer

or unlicensed blood establishment’s QA

procedures worked to prevent the

distribution of product subject to that

biological product deviation.

Accordingly, FDA has established an

approach to reporting biological product

deviations that limits reporting to events

that involve distributed products and

that may affect the safety, purity, or

potency of the product.

(Comment 14) Eighteen comments

recommended adopting an alternative

reporting system such as the medical

event reporting system for transfusion

medicine (MERS–TM).

MERS–TM, a voluntary reporting

system, was designed as a standard

method for collection and analysis of

event reports for blood establishments

to implement as part of their QA system.

The MERS–TM is designed to capture

all manufacturing errors and accidents,

including those ‘‘near miss’’ events that

may be discovered by the blood

establishment prior to distribution of

the product. While FDA believes that

the MERS–TM system is useful in

reporting ‘‘near miss’’ events on a

voluntary basis, FDA is limiting the

requirement for reporting to biological

product deviations affecting distributed

products.

C. Definitions

(Comment 15) Forty-five comments

requested clarification of the definition

of the terms ‘‘errors and accidents’’ in

proposed §§ 600.3(hh) and 606.3(k).

Several of these comments suggested

alternative language.

FDA is clarifying the regulations by

eliminating the terms ‘‘error and

accident.’’ The classification of events

as an ‘‘error’’ or ‘‘accident’’ is

immaterial to the purposes underlying

the rule and appears to have caused

confusion. Consequently, FDA has

revised the rule to focus the reporting

requirement on events that represent a

deviation from CGMP, applicable

regulations, applicable standards or

established specifications, or represent

unexpected or unforeseeable events,

66626 Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations

which may affect the safety, purity, or

potency of a distributed product. Such

events are reportable regardless of

whether or not they are considered

‘‘errors’’ or ‘‘accidents.’’ In the final

rule, FDA has termed such events

‘‘biological product deviations’’ and

described what constitutes a biological

product deviation in §§ 600.14(b) and

606.171(b).

(Comment 16) Three comments

suggested that the reporting requirement

in proposed §§ 600.3(hh)(1) and

606.3(k)(1) should be limited to

deviations from CGMP and that

extending it to ‘‘applicable standards’’

or ‘‘established specifications’’ was

beyond the FDA’s jurisdiction.

FDA disagrees with the suggestion

that such matters are beyond FDA’s

jurisdiction. As set out in §§ 600.14(b)

and 606.171(b), licensed manufacturers

and unlicensed blood establishments

must submit a BPDR only if the

deviation ‘‘may affect the safety, purity,

or potency’’ of a product, and if other

reporting criteria are met. Events

affecting the safety, purity, and potency

of biological products fall squarely

within FDA’s jurisdiction. Moreover,

the PHS Act requires FDA to consider

‘‘standards designed to assure that the

biological product continues to be safe,

pure, and potent’’ (42 U.S.C.

262(a)(2)(B)(i)(II)).

(Comment 17) Thirty-two comments

requested clarification of the definition

of ‘‘made available for distribution’’ in

proposed §§ 600.3(ii) and 606.3(l).

Thirty-seven comments requested that

the definition be amended to limit the

scope of the proposed rule to reporting

of deviations which occur after a

product has been distributed, and six

comments asked that ‘‘made available

for distribution’’ be defined by each

facility based on their established

process controls.

FDA agrees with the comments that

suggested that the scope be limited to

those products that have been

distributed and has written the final

rule to reflect this. FDA considers all

events that may affect the safety, purity,

or potency of a biological product to be

significant, whether prior to or after

distribution. Limiting the reporting

requirement to distributed products will

reduce the burden of reporting on

licensed manufacturers, unlicensed

blood establishments, and on FDA,

while not sacrificing public safety.

Licensed manufacturers and

unlicensed blood establishments remain

obligated to document, investigate and

followup any event that may affect the

safety, purity, or potency of a biological

product under CGMP regulations,

whether the event is reportable under

this rule or not. FDA will continue to

monitor both reportable and

nonreportable events and corrective

actions through inspections.

(Comment 18) One comment stated

the term ‘‘made available for

distribution’’ in proposed §§ 600.3(ii)

and 606.3(l) is ambiguous in relation to

intermediates since at each intermediate

state the product may be released for

further processing.

FDA has clarified the final rule by

limiting reporting of biological product

deviations to distributed products, i.e.,

they have left the licensed manufacturer

or unlicensed blood establishment who

controlled the product at the time the

deviation occurred; or the licensed

manufacturer has provided Source

Plasma or any other blood component

for use in the manufacture of a licensed

product.

D. Who Must Report?

(Comment 19) One comment asked for

clarification on how FDA will apply this

regulation to cooperative manufacturing

arrangements, including shared and

contract manufacturers.

Under § 600.14, it is the licensed

manufacturer who must report

biological product deviations. That is

because, up until the time the product

is distributed, it is the license holder

who is responsible for maintaining the

continued safety, purity, and potency of

the biological product, for compliance

with applicable product and

establishment standards, and for

compliance with CGMP. If the license

holder arranges for another

manufacturer to perform a

manufacturing step, that manufacturing

step is performed under the license

holder’s control, and the license holder

must report biological product

deviations that occur during that

manufacturing step. In shared

manufacturing situations, where two or

more manufacturers operate under their

own license, each manufacturer would

report a biological product deviation

that occurred when the product was in

its control; i.e., when the first shared

manufacturer completes his

manufacturing step and sends the

product to the second shared

manufacturer for additional

manufacturing, the product is

considered distributed by the first

shared manufacturer.

Section 606.171 applies to all blood

establishments, including licensed

establishments, unlicensed registered

blood establishments, and transfusion

services. The rule requires the blood

establishment that has control over a

product when a blood product deviation

occurs to report to FDA. If a blood

establishment contracts a manufacturing

step to another facility, or enters into a

shared manufacturing agreement, the

establishment responsible for

maintaining the continued safety,

purity, and potency of the product and

for compliance with applicable product

and establishment standards, and for

compliance with CGMP, must submit a

BPDR for any deviation occurring while

the biological product is under its

control.

(Comment 20) One comment

suggested FDA require both the blood

bank or transfusion service who receives

a defective product from a licensed

manufacturer and the licensed

manufacturer to report biological

product deviations to ensure the

effectiveness of the reporting process.

In the final rule, FDA has attempted

to eliminate duplicate reporting by

regulated entities. The licensed

manufacturer or unlicensed blood

establishment who had control over the

product when the deviation occurred is

in the best position to provide the

necessary information to FDA.

Therefore, under the final rule, the

licensed manufacturer or unlicensed

blood establishment who had control

over the product when the deviation

occurred is responsible for reporting.

Consignees should report product

deficiencies to the licensed

manufacturer or unlicensed blood

establishment and assist in the

investigation of the product’s

deficiencies, if necessary.

Example 1: An unlicensed blood

establishment pools 10 units of

cryoprecipitate and affixed an incorrect,

extended expiration date. The

unlicensed blood establishment issues

the pooled cryoprecipitate to a patient.

The unlicensed blood establishment

would be required to submit a BPDR to

FDA because: (1) The product did not

meet CGMP; (2) the unlicensed blood

establishment had control of the

product when the deviation occurred;

(3) the deviation may have affected the

safety, purity, and potency of the

product for the patient; and (4) the

product was distributed.

Example 2: An unlicensed blood

establishment receives a unit of

irradiated red blood cells from a

licensed manufacturer and issues the

product to a patient requiring irradiated

red blood cells. The licensed

manufacturer of the blood product

subsequently notifies the unlicensed

blood establishment that the unit was

improperly irradiated. The licensed

manufacturer, not the unlicensed blood

establishment, is required to submit a

BPDR to FDA because: (1) The product

did not meet CGMP; (2) the deviation

Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations 66627

occurred under the control of the

licensed manufacturer; (3) the deviation

may affect the safety, purity, and

potency of the product; and (4) the

licensed manufacturer distributed the

product to the unlicensed blood

establishment.

E. What Kind of Events Are Reportable?

(Comment 21) Forty-two comments

stated that FDA provided insufficient

information about what events must be

reported in proposed §§ 600.14 and

606.171. Numerous comments also

expressed concern regarding the

examples of what events to report that

FDA provided in the preamble to the

proposed rule. Ten comments asked for

information on what not to report.

Seven comments asked FDA to provide

specific examples of events to be

reported by hospital-based transfusion

services.

In response to these comments, FDA

has changed the final rule to limit

reportable events to those involving

distributed products. As discussed in

comment seven of this document, FDA

developed guidance that will provide

specific examples of reportable events

as those events relate to the various

regulated entities. FDA considered these

comments in developing its guidance.

(Comment 22) Two comments asked

whether the proposed rule was limited

to manufacturing activities or whether it

included nonmanufacturing events such

as testing, storage, labeling, and

recordkeeping.

FDA disagrees with the interpretation

that testing, storage, labeling, and

recordkeeping are not manufacturing

activities. The term ‘‘manufacture’’ is

defined in 21 CFR 600.3(u) as ‘‘all steps

in propagation or manufacture and

preparation’’ and includes, for example,

filling, testing, labeling, packaging, and

storage.

The final rule further states in

§§ 600.14(b) and 606.171(b) that any

event, and information relevant to the

event, associated with manufacturing, to

include testing, processing, packing,

labeling, or storage, or with the holding,

or distribution, must be reported if they

meet the other criteria. If a

recordkeeping error may have affected

the safety, purity, and potency of the

product and meets the other criteria in

§§ 600.14(b) and 606.171(b), it is

reportable under the regulations.

(Comment 23) One comment asked

how a licensed manufacturer or

unlicensed blood establishment would

distinguish between an error and

accident that would be reportable from

any unexplained discrepancies or inprocess or final specification

investigations conducted under

§ 211.192 or other regulation, which

would not have to be reported.

The requirements to investigate

discrepancies under § 211.192 and to

report product deviations under

§§ 600.14 and 606.171 are not mutually

exclusive. Under § 211.192,

manufacturers are required to

investigate any unexplained

discrepancies or failure to meet inprocess or final product specifications.

The CGMP regulations applicable to

blood establishments provide, ‘‘A

thorough investigation, including the

conclusions and follow-up, of any

unexplained discrepancy or the failure

of a lot or unit to meet any of its

specifications shall be made and

recorded’’ (§ 606.100(c)). If during the

investigation the criteria described in

§§ 600.14(b) and 606.171(b) are met, a

BPDR is required.

(Comment 24) One comment asked

whether the biological product

deviation reporting requirement applied

to validation batches submitted in

support of a biologics license

application (BLA), or to materials

submitted under an investigative new

drug application (IND).

Under §§ 600.14 and 606.171,

biological product deviations related to

products under an IND would not be

reportable unless the product was

licensed for another intended use.

However, information related to the

deviation may be required to be

reported under the IND regulations in

21 CFR part 312. Biological product

deviations related to validation batches

would not be reportable unless the

products were distributed after receipt

of a biologics license.

(Comment 25) One comment asked if

the submission of a supplement for

reprocessing would preclude the

submission of a BPDR.

The submission of a supplement for

reprocessing would not preclude the

submission of a BPDR. If a product has

been distributed and a licensed

manufacturer or unlicensed blood

establishment determines that a

biological product deviation has

occurred, then the licensed

manufacturer or unlicensed blood

establishment must submit a BPDR

whether or not it subsequently

reprocesses the product. If the licensed

manufacturer or unlicensed blood

establishment discovers a biological

product deviation before it distributes

the product, and subsequently

reprocesses and distributes the affected

product, no BPDR would be required as

long as the reprocessed product was

unaffected by the original deviation.

F. What Type of Information Do

Licensed Manufacturers and Unlicensed

Blood Establishments Report?

(Comment 26) Two comments

requested that FDA delete any reference

to ‘‘disposition of the product’’ from the

information that is to be reported under

the rule because this information would

not be available within the 45-day time

requirement.

FDA believes licensed manufacturers

and unlicensed blood establishments

will usually know the disposition of the

product within the 45-day reporting

period. Licensed manufacturers and

unlicensed blood establishments should

know if the product was shipped to

another facility, destroyed, quarantined,

designated for reprocessing, disposed of

in some other manner, or, in many

cases, administered to a patient.

(Comment 27) Seventeen comments

recommended that if the product has

been subject to recall, then the recall

should be the instrument for reporting

the disposition of the product.

FDA disagrees. FDA believes

information on the disposition of the

product and retrieval efforts are

important in analyzing the impact of

reported deviations on the public and

should be submitted in BPDR’s. The

information required for the BPDR is not

as extensive as the recall information

voluntarily provided to the district. The

information regarding final disposition

does not need to be complete by the

time the BPDR is submitted. By

obtaining as much information as

possible on the disposition of a product

at the time the report is submitted, FDA

will be able to perform appropriate

followup action. The draft guidance

document will further describe the

required information to be reported in

the BPDR.

(Comment 28) One comment asked if

FDA would require licensed

manufacturers and unlicensed blood

establishments to consider previous and

subsequent lots in investigating any lot

that instigated a BPDR.

The regulations in this final rule do

not affect the manner in which a

biological product deviation is

investigated. The obligation to

investigate a biological product

deviation is part of the CGMP

regulations for biological drug products

and biological devices, including blood

and blood components. The CGMP

requirements for blood establishments,

whether licensed or unlicensed, require

blood establishments to thoroughly

investigate discrepancies (§ 606.100(c))

and to maintain and make available to

FDA appropriate records of such

investigation, conclusions, and

66628 Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations

followup (§§ 606.100(c) and

606.160(b)(7)(iii) (21 CFR

606.160(b)(7)(iii))). Licensed

manufacturers subject to drug CGMP

(§§ 211.192 and 211.198) and medical

device manufacturers (see § 820.100) are

similarly obligated to investigate,

correct, and record findings related to

biological product deviations. Under

these existing regulations FDA expects

the licensed manufacturer or unlicensed

blood establishment to determine what

impact the deviation may have had on

other product lots and take appropriate

corrective action. These regulations do

not mandate the manner of investigation

by a licensed manufacturer or

unlicensed blood establishment but

require that the investigation be

complete.

G. When to Report

(Comment 29) Twenty-three

comments stated that 45-calendar days

to report a biological product deviation

as proposed in §§ 600.14(a) and 606.171

is not enough time since licensed

manufacturers and unlicensed blood

establishments must analyze and correct

the deviation prior to reporting. One

comment suggested that fewer than 45

days to report would be better.

In adopting a 45-day time

requirement, FDA looked at the history

of reporting under the prior regulations

and determined that 45 days was a

reasonable period given the importance

of timely reporting. The agency

reviewed the reports submitted during

FY 1997 through 1999 and an average of

73 percent of the reports was received

within 45 days.

Licensed manufacturers and

unlicensed blood establishments should

not wait to report biological product

deviations until after completing their

corrective actions. Rather, licensed

manufacturers and unlicensed blood

establishments should submit BPDR’s as

soon as possible but no later than 45

days after the date that the licensed

manufacturer or unlicensed blood

establishment, its agent, or another

person performing a manufacturing,

holding, or distribution step under the

manufacturer’s or establishment’s

control, first discovers information

reasonably suggesting a reportable event

has occurred. The reports should

include information on the intended

followup to be taken if followup is not

completed prior to submission of the

report. To facilitate timely reporting by

licensed manufacturers and unlicensed

blood establishments, FDA is providing

guidance on how to report as well as a

standardized form for reporting.

(Comment 30) Fourteen comments

requested clarification as to when the

45-day reporting time limit begins.

Several of these comments offered

various possible starting dates.

In response to these comments, FDA

has clarified the 45-day time

requirement in the final rule. The 45

days commence on ‘‘the date (the

licensed manufacturer or unlicensed

blood establishment, its agent, or

another person who performs a

manufacturing, holding, or distribution

step under the control of the licensed

manufacturer or unlicensed

establishment) acquire(s) information

reasonably suggesting that a reportable

event has occurred.’’ For example, if a

manufacturer contracted with a third

party to receive and process its

customer complaints, that third party

would be the manufacturer’s agent for

purposes of this rule, and the 45 days

would begin to run upon the agent’s

receipt of information reasonably

suggesting a reportable event has

occurred.

(Comment 31) Four comments

recommended adopting a hierarchy for

when to report based on the potential

risk of the deviation. For example, one

comment suggested errors with

substantial risk be reported within 45

days, errors with moderate risk be

reported when the internal investigation

is complete and errors with minimal

risk be reported in an annual report.

FDA has adopted a simpler approach

based on the potential public health risk

of the event. Biological product

deviations involving distributed

products must be reported within 45

days. Biological product deviations that

are discovered before the product leaves

the control of the licensed manufacturer

or unlicensed blood establishments are

nonreportable, but reviewable during

routine inspections, because such

events present significantly less public

health risk.

H. How to Report

(Comment 32) Forty-seven comments

requested a standardized format for

reporting biological product deviations

and several of these submitted a

proposed form. Fourteen comments

requested one form for hospital-based

transfusion centers and a separate form

for blood collection centers and

pharmaceutical manufacturers.

Seventeen comments requested FDA to

develop means for electronic reporting.

One comment suggested FDA supply

forms to blood suppliers.

FDA recognizes the need for a

standardized method for reporting

biological product deviations. FDA has

developed a form for licensed

manufacturers and unlicensed blood

establishments to use to report under

the final rule and is issuing guidance

including instructions for completing

the biological product deviation

reporting form. FDA also has developed

an electronic format for reporting. The

agency has taken into consideration the

comments and sample forms submitted

in devising the biological product

deviation reporting form. The agency

also is requesting comments to the

docket from the public on the report

form and the instructions for preparing

the report in accordance with the

Paperwork Reduction Act of 1995. The

agency is making the form available in

various ways, including the FDA

website at http://www.fda.gov/cber and

the CBER FAX information system at 1–

888–CBER–FAX.

IV. Analysis of Impacts

FDA has examined the impacts of the

final rule under Executive Order 12866

and the Regulatory Flexibility Act (5

U.S.C. 601–612) (as amended by subtitle

D of the Small Business Regulatory

Fairness Act of 1996 (Public Law 104–

121)), and the Unfunded Mandates

Reform Act of 1995 (Public Law

104094). Executive Order 12866 directs

agencies to assess all costs and benefits

of available regulatory alternatives and,

when regulation is necessary, to select

regulatory approaches that maximize

net benefits (including potential

economic, environmental, public health

and safety, and other advantages;

distributive impacts; and equity). The

Regulatory Flexibility Act requires

agencies to analyze whether a rule may

have a significant impact on a

substantial number of small entities

and, if it does, to analyze regulatory

options that would minimize the

impact. Section 202(a) of the Unfunded

Mandates Reform Act requires that

agencies prepare a written statement of

anticipated costs and benefits before

proposing any rule that may result in an

expenditure by State, local, and tribal

governments, in the aggregate, or by the

private sector, of $100 million (adjusted

annually for inflation) in any one year.

The agency has determined that the

final rule is a significant action as

defined in section 3, paragraph (f)(4) of

Executive Order 12866. We have also

determined that this rule will not result

in aggregate expenditures for State,

local, and tribal governments, or the

private sector of $100 million in any one

year. Based on FDA’s analysis using

available data, the agency does not

anticipate that the rule will result in a

significant impact on a substantial

number of small entities.

Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations 66629

1This estimated wage rate is based on the rate of

$37.98 used in the proposed rule published in 1997,

inflation-adjusted to 1999.

A. Estimated Economic Impact

The rule will have an impact on

licensed manufacturers and unlicensed

blood establishments as described in

table 1 of this document. All of these

types of establishments will experience

both a one-time cost impact to make

changes to their recordkeeping systems

and reporting procedures, as well as an

annual cost impact associated with the

ongoing reporting of product deviations

that are encountered. Table 1 below

summarizes these two components of

cost impact. The rule is estimated to

have an aggregate one-time cost impact

of $8,131,648 and an annual cost impact

of $340,319. These estimates are

detailed in the discussion that follows.

TABLE 1.—SUMMARY OF ESTIMATED COST IMPACT OF THE RULE

Industry Affected Total OneTime Cost

Total Annual

Cost

Licensed Manufacturers (Other than Blood and Blood Components)

111 Manufacturers of biologics $348,096 ($1,803)1

Subtotal for manufacturers of biologics $348,096 ($1,803)1

Blood Establishments

Licensed blood establishments $727,552 ($286,395)1

2,800 Registered blood establishment $4,390,400 $95,397

3,400 Transfusion services $2,665,600 $533,120

Subtotal for blood establishments $7,783,552 $342,122

Total Cost Impact $8,131,648 $340,319

1Use of parenthesis indicates savings.

Based on the agency’s registration

data base, there are an estimated 111

licensed biologics manufacturers, 232

licensed blood establishments, and

2,800 unlicensed registered blood

establishments. Based on data from the

HCFA, there are estimated to be 3,400

transfusion services currently in

operation. Such manufacturers and

establishments currently conduct some

QA activities. The impact of the final

rule reflects the change in these ongoing

activities that would be required by the

rule.

B. One-Time Costs for Affected

Establishments

Licensed biologics manufacturers

must comply with part 211 or part 820;

and licensed and unlicensed blood

establishments must comply with parts

211 and 606 (21 CFR part 606), which

encompasses a variety of QA activities

embodied in CGMP’s, to include

investigating problems, performing

followup, and recordkeeping.

The proposed rule stated that FDA

had no precise estimates of the one-time

cost for preparation and/or revision of

the SOP, staff training, and time spent

making the report. The agency expected

that such activities would require an

average of 2 hours to create an SOP for

submitting error and accident reports,

and approximately 1 hour to review and

update existing SOP’s at the

establishments that have been reporting.

The majority of the comments from

industry stated that the estimates were

underestimated. However, only a couple

of comments, based on their experience,

suggested a range of timeframes from 20

hours to a few days to develop and

implement a new SOP. FDA has

reassessed the time for staff review of

the requirements of the rule,

establishing or making adjustments to

current systems and procedures, and for

staff training. These estimates are

discussed below.

Licensed biologics manufacturers

currently have recordkeeping systems

and QA systems in place. These

establishments are estimated to incur a

one-time cost for staff review of the

requirements of the rule, and

accompanying modifications to current

systems and procedures, and for staff

training in the use of modified

procedures. FDA estimates that these

activities may require a total of 80 hours

of staff time. Using an estimated hourly

wage rate of $39.20,1 the total one-time

cost for these manufacturers is

estimated to be $348,096 ($39.20 × 80 ×

111).

For blood establishments, the changes

made in response to the rule are

expected to vary according to whether

the establishment is currently licensed.

The 232 licensed blood establishments

are currently required to report the

product deviations under § 606.14.

These facilities are likely to have

systems in place for keeping record of

product deviations, and will not be

expected to have to establish a new

reporting system. However, the licensed

blood establishments are also likely to

handle the majority of product deviation

reports, because these facilities account

for an estimated 90 percent of the total

volume of U.S. blood collections. The

licensed blood establishments will need

to allocate staff time for a one-time

review of the rule and some

modifications to their current

recordkeeping system and reporting

procedures. In addition, these facilities

will allocate a few hours of training time

to review the reporting changes with

staff who will be involved in the

reporting of product deviations to FDA.

FDA estimates that these activities may

require a total of 80 hours of staff time.

Using an estimated hourly wage rate of

$39.20, the total one-time cost for these

manufacturers is estimated to be

$727,552 ($39.20 x 80 x 232).

The 2,800 registered blood

establishments that are not licensed are

estimated to account for about 10

percent of total U.S. blood collections,

and currently perform product deviation

reporting on a voluntary but less

consistent basis. It is anticipated that

the registered blood establishments will

allocate staff time to establish a

recordkeeping system for reportable

product deviations involving products.

In addition, the registered blood

establishments will allocate staff time to

modify current SOP’s to comply with

the biological product deviation

reporting required by the rule, and to

review the SOP changes with the staff

who will be involved in reporting these

deviations to FDA. FDA estimates that

these activities will require an average

of 40 hours of staff time per facility.

Using an estimated hourly wage rate of

$39.20, the total one-time cost for these

establishments is estimated to be

$4,390,400 ($39.20 x 40 x 2,800).

66630 Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations

Transfusion services currently

perform a variety of QA activities, but

report product deviations to FDA on a

voluntary and very limited basis.

Transfusion services currently must

comply with 42 CFR 493.1273(a). This

regulation requires transfusion services

to comply with parts 606 and 640 (21

CFR part 640) provisions, which

includes keeping records of errors and

accidents, transfusion reaction reports

and complaints, with a record of

investigation and followup. These

establishments are expected to allocate

staff time to review the requirements of

the rule, modify current SOP’s to

comply with the biological product

deviation reporting requirements, and

train appropriate staff in using the

modified procedures. This one-time

effort is estimated to involve

approximately 20 hours of staff time per

facility, yielding an estimated cost of

$2,665,600 ($39.20 x 20 x 3,400) for

transfusion services. Based on the

estimates for licensed and unlicensed

blood establishments, the total one-time

cost for blood and blood component

manufacturers is $7,783,552 ($727,552 +

$4,390,400 + $2,665,600).

C. Annual Costs for Affected

Establishments

In addition to the cost of establishing

modified systems and procedures,

unlicensed blood establishments will

experience some annual costs associated

with ongoing reporting of product

deviations that fit the criteria specified

in the rule. Those costs are estimated

below.

Licensed manufacturers and

unlicensed blood establishments will be

required to report to FDA product

deviations when: (1) The event is

associated with the manufacturing, to

include testing, processing, packing,

labeling, and storage, or with the

holding or distribution of a licensed

biological product, or a licensed or

unlicensed blood or blood component;

(2) the deviation occurs in the licensed

manufacturer or unlicensed blood

establishment’s facility or in another

facility while the product remains in the

control of the licensed manufacturer or

unlicensed blood establishment; (3) the

deviation may affect the safety, purity,

or potency of that product, and either

represents a deviation from CGMP,

applicable regulations, applicable

standards, or established specifications;

or represents an unexpected or

unforeseeable event; and (4) the

deviation involves a distributed

product.

When a manufacturer becomes aware

of a reportable product deviation, the

manufacturer investigates the deviation,

records the deviation, and performs

followup. FDA estimates that the

establishment will allocate an

additional 2 hours of staff time to

prepare and submit a report to FDA. In

the comments on the proposed rule,

FDA received one comment that

suggested the agency’s estimate of 30

minutes to file a report was reasonable

for the filing task itself, but would not

cover the time needed to prepare the

report. Other comments stated that their

establishments average 4, 6, or 8 hours

to prepare a report, but some comments

also explained that these hours included

investigations, followup, and SOP

revision. FDA agrees that 30 minutes

would not reflect the anticipated time

for preparing, in addition to filing, the

report. The reporting to FDA required in

this rule does not introduce additional

requirements for recordkeeping,

investigation, and followup of

manufacturing problems and deviations

beyond what is required under CGMP

requirements. Therefore, the estimated

time for complying with this final rule

does not include recordkeeping,

investigation, and followup of a

biological product deviation.

Licensed manufacturers already

report a broad range of product

deviations to FDA. This range includes

all deviations in products made

available for distribution, and has not

previously been limited to those

products actually distributed. Under the

existing regulation, a total of 93

biologics manufacturing deviations were

reported to FDA in 1999. Since the new

rule limits the criteria for reporting,

FDA estimates that reporting will be 25

percent reduced, yielding an estimated

total of 70 reports (93 x (1090.25)) rather

than the current 93 reports. Based on

the estimate of 2 hours to complete and

file a report, FDA estimates a total

savings of $1,803 ((93–70) × 2 × $39.20).

Under the current rule, a total of

14,611 blood and blood component

errors and accidents were reported by

licensed blood establishments to FDA in

FY 1999. These facilities are also

estimated to account for approximately

90 percent of all blood and plasma

collections, totaling approximately 26

million units, or 23,400,000 (0.90 x

26,000,000) units processed by licensed

blood establishments. The current rate

of reporting per unit of blood collected

and processed is thus 6.24 ((14,611/

23,400,000) x 10,000) per 10,000 units.

Under the final rule, FDA estimates that

reporting for these facilities will be

reduced by 25 percent, reducing the

total reports to 10,958 ((1090.25) x

14,611) or a rate of 4.68 (10,958/

23,400,000 x 10,000) per 10,000 units of

collection. This translates to a projected

savings of $286,395 ((14,611–10,958) × 2

× $39.20)).

Assuming a deviation reporting rate of

4.68 per 10,000 units for those

unlicensed registered blood

establishments that account for

approximately 10 percent of the total

blood collections of 26 million units,

the agency estimates that unlicensed

registered blood establishments will

incur new annual costs of $95,397 (0.10

x 26,000,000 x (4.68/10,000) x 2 x

$39.20) to make an estimated 1,217

reports. This translates to an increased

annual cost of approximately $34.07

($95,397/2,800) per unlicensed

registered blood establishment.

Transfusion services will be newly

required to report product deviations

that meet the criteria specified in the

rule. The annual cost to transfusion

services for this reporting requirement is

based on the voluntary annual reporting

rate of transfusion services for FY 99,

i.e., two reports per transfusion service.

This reporting rate is supported by the

estimate of BPDR’s per hospital per year

by bedsize calculated in table 2 of this

document. The reporting by the

transfusion service is estimated to

involve approximately 2 hours of staff

time at the transfusion facility. As noted

earlier, this rule does not require new

investigations of such reports. Records

of investigations and followup to

address problems with the

manufacturing process are already

required as part of the CGMP for blood

and blood components. FDA therefore

estimates the total cost of annual

reporting by transfusion services to be

$533,120 (3,400 x 2 x 2 x $39.20). This

translates to an increased annual cost of

approximately $156.80 per transfusion

service.

In summary, the annual cost impact of

the rule is estimated to be $342,122

(($95,397 + $533,120)—$286,395) for

licensed and unlicensed blood

establishments, and a net savings of

$1,803 for licensed manufacturers of

biological products other than blood

and blood components.

D. Impact on Small Entities

The agency does not anticipate that

the final rule will have a significant

impact on a substantial number of small

business establishments. However,

because of the limits of available data,

the agency is uncertain about the

number of small entities affected and

the actual extent of current product

deviations at these facilities that would

trigger reporting and determine the cost

impact. Since the agency received no

comments supported by data regarding

the estimated impact on small entities

in the proposed rule, the following

Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations 66631

analysis is based on the limited data

available.

The licensed manufacturers and

unlicensed blood establishments

affected by the final rule are included

under the major Standard Industrial

Code (SIC) group 80 for providers of

health services. According to section

601 of the Regulatory Flexibility Act of

1980, the term ‘‘small entity’’

encompasses the terms ‘‘small

business,’’ ‘‘small organization,’’ and

‘‘small governmental jurisdiction.’’

According to the Small Business

Administration (SBA), a small business

within the blood industry is an

enterprise with less than $5 million in

annual receipts. A small organization is

a not-for-profit enterprise which is

independently owned and operated and

is not dominant in its field. A ‘‘small

governmental jurisdiction’’ generally

means governments of cities, counties,

towns, townships, villages, school

districts, or special districts, with a

population of less than 50,000. Because

the rule would reduce reporting

requirements for currently licensed

facilities, FDA has focused the following

small business analysis on those blood

collection facilities and transfusion

services that will be newly required to

report these product deviations, and are

therefore expected to incur new costs.

E. Impact on Small Blood and Blood

Component Manufacturers

The FDA registry of blood

establishments does not provide an

indication of the size of the registered

entities. Although uncertain, it is likely

that some smaller facilities may

experience significant costs as a result

of compliance with the final rule.

According to the 1996 directory of the

American Association of Blood Banks

(AABB), only 34 regional and

community blood centers have annual

revenues of less than $5 million and

each collect no more than 30,000

donations per year. With an estimated

rate of 4.68 product deviation reports

per 10,000 units collected [see annual

cost estimates in section IV.C of this

document], this would imply an

estimated 14 product deviation reports

(4.68 x 3) per smaller blood center per

year, and associated cost of $1,098

($39.20 x 2 x 14 reports). The one-time

cost for these facilities is expected to be

similar to the unlicensed registered

blood establishments estimate involving

40 hours of staff time, thus $1,568

($39.20 x 40) per facility.

F. Impact on Small Transfusion Service

Facilities

Hospital transfusion services are

expected to be the primary entity

affected by the requirements, but the

extent of the small business impact is

uncertain. Although the details of

manufacturing activities at transfusion

services are not available, FDA

examined other data to develop a

preliminary assessment of small

business impact. The size of U.S.

hospitals varies substantially. The 1998

American Hospital Association (AHA)

survey data indicate a total of 5,134 U.S.

registered community hospitals grouped

into 8-bedsize categories. The average

annual revenues for facilities in these

bedsize categories range from

approximately $5.5 million to $513

million. However, since many hospitals

are not-for-profit or are operated by

State and local governments, the SBA

annual receipt criteria for small

businesses would not apply to these

facilities. Of the 5,134 U.S. community

hospitals included in the AHA report

1,330 are under the control of State and

local government, 3,045 are nonprofit

institutions and the remaining 759 are

reported to be investor-owned.

The number of hospitals that would

meet at least one of the various SBA

definitions for small entities is

uncertain. According to the AHA

statistics for 1998, the smallest reported

hospital size category includes 262

hospitals with 6 to 24 beds, and total

gross revenues of $1.43 billion, yielding

average revenues of $5.46 million. FDA

assumes that the 11 facilities reported to

be investor-owned within this bedsize

category could qualify as small entities.

Although it is possible that all nonprofit

hospitals may qualify as small entities,

it appears that a number of facilities

might be excluded from that definition

because they are reported to be hospitals

in a system. According to the AHA

survey definition, ‘‘hospitals in a

system’’ refer to those ‘‘hospitals

belonging to a corporate body that owns

and/or manages health provider

facilities or health-related subsidiaries;

the system may also own non-healthrelated facilities.’’ The AHA currently

has record of 1,592 hospitals that are

nonfederal and nonprofit (including

State and local government controlled)

that are hospitals in a system. If these

facilities were excluded, FDA estimates

that 2,783 [1,330 State & local + 3,045

nonprofit—1,592 in-a-system]

nonfederal, nonprofit hospitals may

qualify as small entities. Thus, a total of

2,794 [2,783 + 11] hospitals might

qualify as small entities.

The following analysis of potential

impact by size of hospital suggests that,

regardless of hospital size, the cost

impact of product deviation reporting

will be limited if the number of

deviation reports per facility is

proportionate to the utilization of blood

transfusions implied by relative number

of inpatient surgeries performed by

hospitals in different size categories.

Table 2 of this document estimates the

percentage of all inpatient hospital

surgeries, based on the number of

inpatient surgeries reported to AHA as

performed by hospitals in different

bedsize categories. This percentage is

used to estimate a share of the total

reports that would be made by hospitals

in each category. The estimated number

of product deviation reports per hospital

within a bedsize category is based on

the total projected number of reports

and the percentage of inpatient surgeries

reported for hospitals within each size

category.

TABLE 2.—ESTIMATES OF BPDR’S PER HOSPITAL PER YEAR BY BEDSIZE CATEGORY

Bedsize Category Nonfederal

Hospitals

Estimated Percent Inpatient

Surgeries

Estimated

Share of 1,217

Product Deviation Reports

Estimated

Reports per

Hospital1

6 to 24 262 0.21 2.6 0

25 to 49 906 2.02 24.6 0

150 to 99 1,128 6.03 73.3 0

100 to 199 1,338 19.38 235.9 0

200 to 299 692 20.99 255.4 0

300 to 399 361 16.24 197.6 1

400 to 499 196 12.17 148.1 1

500 + 251 22.97 279.5 1

1Rounded to the nearest whole number.

66632 Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations

The cost impact of product deviation

reporting is based on the table 2

estimates of reports per hospital and the

earlier estimate of one-time cost of $784

(20 hours x $39.20) per hospital to

modify systems and SOP’s for

recordkeeping and reporting. Based on

the low expected volume of reports per

hospital, the agency found that the

estimated annual reporting cost, as a

percentage of average annual facility

revenues, approached zero for hospitals

in every bedsize category. This suggests

that the relative cost impact may be

quite limited, across hospitals of

different sizes, if the number of BPDR’s

required per hospital is proportionate to

the number of inpatient surgeries

performed by hospitals in different size

categories.

G. Expected Benefits of the Rule

As described in the preamble, the

benefits of the rule relate to the safety

of biological products and protection of

the public health. The final rule focuses

on the subset of risk events in which the

product is actually distributed and the

cause of the problem is related to steps

in the manufacturing process, that may

affect the safety, purity, and potency of

the product. FDA needs to receive

timely reports of such events in order to

quickly address problems, and provide

updated industry guidance to assure

continued product safety and good

manufacturing practice. The

requirements provide FDA with the

ability to detect broader risks that

extend beyond the reach of a single

manufacturer or hospital’s QA systems

and staff resources.

In addition to these public health

benefits, the final rule benefits licensed

manufacturers in terms of a reduced

level of reporting and streamlining the

reporting process by providing a

standardized report form that may be

submitted electronically. Reporting

requirements are now focused more

narrowly on product deviations that

represent more immediate risks.

V. The Paperwork Reduction Act of

1995

This final rule contains information

collection requirements that are subject

to review by OMB under the Paperwork

Reduction Act of 1995 (the PRA) (44

U.S.C. 3501–3520). The title,

description, and respondent description

of the information collection provisions

are shown below with an estimate of the

annual reporting and recordkeeping

burden. Included in the estimate is the

time for reviewing instructions,

searching existing data sources,

gathering and maintaining the data

needed, and completing and reviewing

each collection of information.

Title: Biological Products: Reporting

of Biological Product Deviations in

Manufacturing.

Description: FDA is amending the

current regulations that require licensed

manufacturers of biological products to

report to FDA errors and accidents in

manufacturing; and adding regulations

requiring unlicensed blood

establishments to report certain

biological product deviations in the

manufacture of blood and blood

components. Under this final rule, a

licensed manufacturer or unlicensed

blood establishment must submit a

report to FDA based on the following

criteria: (1) The event is associated with

the manufacturing, to include testing,

processing, packing, labeling, and

storage, or with the holding or

distribution, of a licensed biological

product, or a licensed or unlicensed

blood or blood component; (2) the

deviation occurs in the licensed

manufacturer or unlicensed blood

establishment’s facility or in another

facility while the product remains in the

control of the licensed manufacturer or

unlicensed blood establishment; (3) the

deviation may affect the safety, purity,

or potency of that product and either

represents deviation from CGMP,

applicable regulations, applicable

standards, or established specifications;

or represents an unexpected or

unforeseeable event; and (4) the

deviation involves a distributed

product. The agency is requiring a 45-

calendar day reporting timeframe and is

making available to industry a

standardized format for reporting

biological deviations in manufacturing

that may be submitted either by hard

copy or electronically.

Authority is given to the agency to

issue regulations for the efficient

enforcement of the act under section

701 of the act (21 U.S.C. 371) and to

inspect all establishments responsible

for manufacturing biological products

(section 704 of the act (21 U.S.C. 374)

and 42 U.S.C. 262). FDA regards

biological product deviation reporting to

be an essential tool in its directive to

protect public health by establishing

and maintaining surveillance programs

that provide timely and useful

information.

Description of Respondents: Licensed

manufacturers of biological products,

unlicensed registered blood

establishments, and transfusion

services.

As required by section 3506(c)(2)(B)

of the PRA, FDA provided an

opportunity for public comment on the

information collection requirements of

the proposed rule (62 FR 49642). Nine

letters of comment on the information

collection requirements were submitted

to OMB. Most of the comments

submitted to OMB were the same as

those submitted directly to FDA in

response to the proposed rule. FDA’s

responses to these comments are found

in section III of this document.

Responses to additional comments in

the letters received by OMB that were

not addressed in section III of this

document are addressed in the

following paragraphs.

(Comment 33) One comment to OMB

and 24 comments submitted to the

docket state that the estimated time of

0.5 hours to complete a deviation report

is underestimated. Several of these

comments further state that their

establishments currently average about

4 to 6, or 6 to 8 hours for preparing a

deviation report under § 600.14. One

comment states that ‘‘[A] single

investigation in our institution may take

four hours per incident as we

thoroughly investigate, report, change

SOP’s or processes if indicated, and

follow-up to ensure that changes were

implemented and work as intended.’’

FDA agrees that the burden is

underestimated and is adjusting the

‘‘hours per response’’ estimate in table

3 from 0.5 hours to 2 hours based on:

(1) Information from industry

representatives about typical reporting

procedures, (2) the issuance of guidance

that will assist industry in identifying

reportable events, and (3) the

availability of a standardized report

form. The standardized report form, and

the ability to submit a report

electronically, should streamline the

process and improve the quality of time.

Activities such as investigating,

changing SOP’s or processes, and

followup are currently required under

parts 211, 606, and 820 and, therefore,

are not included in the burden

calculation for the separate requirement

of submitting to FDA a deviation report.

(Comment 34) Two comments state

that in determining the estimated time

for completing and submitting a

deviation report, FDA may not have met

its statutory obligations under the PRA

because it used anecdotal evidence, that

is not representative of current

practices.

When FDA seeks information from

industry to estimate burden for a

proposed rule, the agency ordinarily

contacts fewer than 10 representatives.

If FDA requested information from 10 or

more industry representatives, the

agency would be required to prepare a

separate burden analysis and seek OMB

approval before it could ask for such

information. Although less than 10

Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations 66633

persons usually do not represent the

majority of the industry, the comment

period for the proposed rule provides

the opportunity for all interested

persons to comment on the estimated

burden. For this final rule, FDA

considered all of the comments received

regarding the estimated burden numbers

and, in response, adjusted the estimates.

(Comment 35) Another comment

states that the added hourly burden of

generating these reports may

compromise the ability of hospitals to

provide optimal technical support for

blood transfusion activities.

The requirement for reporting has not

changed for licensed manufacturers.

Licensed manufacturers are currently

required to report errors and accidents

under § 600.14, and the agency

recommended reporting of errors and

accidents by unlicensed blood

establishments in a memorandum to

registered blood establishments dated

March 20, 1991. Unlicensed registered

blood establishments and transfusion

services are required under 42 CFR

493.1273(a) to comply with CGMP

regulations set forth at parts 606 and

640, and specifically with § 606.100(c)

for the investigation and followup of

any unexplained discrepancy or the

failure of a lot or unit to meet any of its

specifications, and with

§ 606.160(b)(7)(iii) for recordkeeping

requirements for errors and accidents.

The only additional requirement under

this final rule is that the unlicensed

registered blood establishment or

transfusion service submit a report

based on this recordkeeping of

deviations. FDA estimates that

preparing and submitting one report

would involve only 2 hours, and that

only two reports would be submitted

per year by an unlicensed registered

blood establishment or transfusion

service. The estimated total burden per

year is only 4 hours per establishment.

Therefore, FDA concludes that the final

rule should not affect a hospital’s ability

to provide optimal technical support for

blood transfusion activities.

(Comment 36) One comment notes

that the paper-based reporting system

that is now being used by FDA does not

provide a format from which reported

information can be entered into a usable

data base without a great deal of

difficulty and expense.

FDA agrees with the comment and

has prepared a standardized form for

reporting deviations in manufacturing a

biological product (BPDR, Form FDA–

3486) that may be downloaded from

CBER’s website or received by facsimile.

After completion, the form is sent to the

identified address in § 600.14(e). In an

effort to expedite and simplify

reporting, FDA also is providing to

industry the opportunity to complete

and submit a Form FDA–3486

electronically. The establishment may

insert the requested information into the

appropriate fields online and submit the

report through the Internet.

(Comment 37) One comment notes

that FDA estimates that there are no

capital costs or operation and

maintenance costs associated with the

proposed rule. The comment noted that

these terms are undefined.

The agency considers capital costs or

operation and maintenance costs to be

costs other than those needed for usual

and customary business practice. FDA

believes there are no capital costs or

operation and maintenance costs

associated with the maintenance of files

and records because respondents should

have the facilities and the infrastructure

for recordkeeping and retention as part

of their usual and customary practice.

The final rule provides for the use of a

standardized reporting form, which will

be available for convenience on CBER’s

website. For those establishments that

do not have access to the Internet, the

form may also be accessed and

submitted by facsimile or mail.

Therefore, the purchase of computer

equipment and Internet access would

not be necessary in order to comply

with this rule.

A. Estimated Annual Reporting Burden

The 54,208 total hours estimated in

table 3 of this document are based on

information from FDA’s data bases and

CBER’s annual summary on error and

accident reporting for FY 1999. In

calculating the reporting burden for the

revised § 600.14 in this final rule, FDA

found that approximately 111 licensed

manufacturers of biological products

other than blood and blood components

submitted 93 error and accident reports

in FY 1999 under the current § 600.14.

In calculating the reporting burden for

§ 606.171 under this final rule, FDA

found that approximately 232 licensed

manufacturers of blood and blood

components, including Source Plasma,

submitted 14,611 error and accident

reports.

In calculating the burden for

unlicensed registered blood

establishments and transfusion services

under the new § 606.171, FDA found

that 48 establishments of the estimated

2,800 unlicensed registered blood

establishments voluntarily submitted 94

error and accident reports; and 15 of the

estimated 3,400 transfusion services

voluntarily submitted 28 error and

accident reports. Based on this

voluntary reporting rate, each of the

6,200 unlicensed blood establishment is

expected to submit no more than 2

reports annually, totaling 12,400 reports

annually.

Licensed manufacturers of blood and

blood components collect 90 percent of

the nation’s blood supply. Accordingly,

the estimated total number of reports

submitted annually by each licensed

blood establishment is greater than the

total number of reports submitted by

each unlicensed blood establishment.

In the proposed rule, the agency

estimated that industry would expend

58,393.5 hours to submit approximately

116,787 total annual responses. In the

final rule, FDA estimates that it will

take 54,208 hours to submit 27,104 total

annual responses. The decrease in total

reports submitted annually is due to the

more narrow scope in the final rule,

which requires BPDR’s only for

distributed products.

B. Estimated One-Time Burden for

Implementation of Rule

FDA has estimated a total of 207,440

hours as a one-time burden for

performing the following activities: Staff

review of the requirements of the rule,

establishing or making adjustments to

current systems and SOP’s, and staff

training. As previously discussed in

section IV.B of this document, the

estimated one-time burden to perform

these activities would be 80 hours for

each licensed manufacturer of biological

products and licensed manufacturer of

blood and blood components, 40 hours

for each unlicensed registered blood

establishment, and 20 hours for each

transfusion service.

TABLE 3.—ESTIMATED ANNUAL REPORTING BURDEN1

21 CFR Section

No. of

Respondents

Annual

Frequency

per

Response

Total

Annual

Responses

Hours per

Response Total Hours

600.142 111 0.8 93 2 186

66634 Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations

TABLE 3.—ESTIMATED ANNUAL REPORTING BURDEN1—Continued

21 CFR Section

No. of

Respondents

Annual

Frequency

per

Response

Total

Annual

Responses

Hours per

Response Total Hours

606.1713 232 62.9 14,611 2 29,222

606.1714 6,200 2 12,400 2 24,800

Total 6,543 27,104 54,208

One-Time Burden5

Licensed manufacturers2 111 1 111 80 8,880

Licensed manufacturers3 232 1 232 80 18,560

Unlicensed registered blood establishments 2,800 1 2,800 40 112,000

Transfusion services 3,400 1 3,400 20 68,000

Total 207,440

1There are no capital costs or operating and maintenance costs associated with this collection of information.

2Licensed manufacturers of biological products other than blood and blood components

31ALicensed manufacturers of blood and blood components, including Source Plasma

4Unlicensed registered blood establishments and transfusion services

5One-time burden activities: Staff review of the requirements of the rule, establishing or making adjustments to current systems and SOP’s,

and staff training

The information collection

requirements of the final rule have been

submitted to OMB for review. Prior to

the effective date of the final rule, FDA

will publish a document in the Federal

Register announcing OMB’s decision to

approve, modify, or disapprove the

information collection requirements in

the final rule. An agency may not

conduct or sponsor, and a person is not

required to respond to, a collection of

information unless it displays a

currently valid OMB control number.

VI. Environmental Impact

The agency has determined under 21

CFR 25.30(j) that this action is of a type

that does not individually or

cumulatively have a significant effect on

the human environment. Therefore,

neither an environmental assessment

nor an environmental impact statement

is required.

VII. Federalism

FDA has analyzed this final rule in

accordance with the principles set forth

in Executive Order 13132. FDA has

determined that the rule does not

contain policies that have substantial

direct effects on the States, on the

relationship between the National

Government and the States, or on the

distribution of power and

responsibilities among the various

levels of government. Accordingly, the

agency has concluded that the rule does

not contain policies that have

federalism implications as defined in

the order and, consequently, a

federalism summary impact statement is

not required.

List of Subjects

21 CFR Part 600

Biologics, Reporting and

recordkeeping requirements.

21 CFR Part 606

Blood, Labeling, Laboratories,

Reporting and recordkeeping

requirements.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and the Public

Health Service Act, and under authority

delegated to the Commissioner of Food

and Drugs, 21 CFR parts 600 and 606 are

amended as follows:

PART 600—BIOLOGICAL PRODUCTS:

GENERAL

1. The authority citation for 21 CFR

part 600 continues to read as follows:

Authority: 21 U.S.C. 321, 351, 352, 353,

355, 360, 360i, 371, 374; 42 U.S.C. 216, 262,

263, 263a, 264, 300aa–25.

2. Amend § 600.3 by adding

paragraphs (hh) and (ii) to read as

follows:

§ 600.3 Definitions.

* * * * *

(hh) Distributed means the biological

product has left the control of the

licensed manufacturer.

(ii) Control means having

responsibility for maintaining the

continued safety, purity, and potency of

the product and for compliance with

applicable product and establishment

standards, and for compliance with

current good manufacturing practices.

3. Revise § 600.14 to read as follows:

§ 600.14 Reporting of biological product

deviations by licensed manufacturers.

(a) Who must report under this

section? (1) You, the manufacturer who

holds the biological product license and

who had control over the product when

the deviation occurred, must report

under this section. If you arrange for

another person to perform a

manufacturing, holding, or distribution

step, while the product is in your

control, that step is performed under

your control. You must establish,

maintain, and follow a procedure for

receiving information from that person

on all deviations, complaints, and

adverse events concerning the affected

product.

(2) Exceptions:

(i) Persons who manufacture only in

vitro diagnostic products that are not

subject to licensing under section 351 of

the Public Health Service Act do not

report biological product deviations for

those products under this section but

must report in accordance with part 803

of this chapter;

(ii) Persons who manufacture blood

and blood components, including

licensed manufacturers, unlicensed

registered blood establishments, and

transfusion services, do not report

biological product deviations for those

products under this section but must

report under § 606.171 of this chapter;

(iii) Persons who manufacture Source

Plasma or any other blood component

and use that Source Plasma or any other

blood component in the further

manufacture of another licensed

biological product must report:

(A) Under § 606.171 of this chapter, if

a biological product deviation occurs

during the manufacture of that Source

Plasma or any other blood component;

or

(B) Under this section, if a biological

product deviation occurs after the

manufacture of that Source Plasma or

Federal Register / Vol. 65, No. 216 / Tuesday, November 7, 2000 / Rules and Regulations 66635

any other blood component, and during

manufacture of the licensed biological

product.

(b) What do I report under this

section? You must report any event, and

information relevant to the event,

associated with the manufacturing, to

include testing, processing, packing,

labeling, or storage, or with the holding

or distribution, of a licensed biological

product, if that event meets all the

following criteria:

(1) Either:

(i) Represents a deviation from

current good manufacturing practice,

applicable regulations, applicable

standards, or established specifications

that may affect the safety, purity, or

potency of that product; or

(ii) Represents an unexpected or

unforeseeable event that may affect the

safety, purity, or potency of that

product; and

(2) Occurs in your facility or another

facility under contract with you; and

(3) Involves a distributed biological

product.

(c) When do I report under this

section? You should report a biological

product deviation as soon as possible

but you must report at a date not to

exceed 45-calendar days from the date

you, your agent, or another person who

performs a manufacturing, holding, or

distribution step under your control,

acquire information reasonably

suggesting that a reportable event has

occurred.

(d) How do I report under this

section? You must report on Form FDA–

3486.

(e) Where do I report under this

section? You must send the completed

Form FDA–3486 to the Director, Office

of Compliance and Biologics Quality

(HFM–600), Center for Biologics

Evaluation and Research, 1401

Rockville Pike, suite 200N, Rockville,

MD 20852–1448, by either a paper or an

electronic filing:

(1) If you make a paper filing, you

should identify on the envelope that a

BPDR (biological product deviation

report) is enclosed; or

(2) If you make an electronic filing,

you may submit the completed Form

FDA–3486 electronically through

CBER’s website at www.fda.gov/cber.

(f) How does this regulation affect

other FDA regulations? This part

supplements and does not supersede

other provisions of the regulations in

this chapter. All biological product

deviations, whether or not they are

required to be reported under this

section, should be investigated in

accordance with the applicable

provisions of parts 211 and 820 of this

chapter.

PART 606—CURRENT GOOD

MANUFACTURING PRACTICE FOR

BLOOD AND BLOOD COMPONENTS

4. The authority citation for 21 CFR

part 606 continues to read as follows:

Authority: 21 U.S.C. 321, 331, 351, 352,

355, 360, 360j, 371, 374; 42 U.S.C. 216, 262,

263a, 264.

5. Amend § 606.3 by adding

paragraphs (k) and (l) to read as follows:

§ 606.3 Definitions.

* * * * *

(k) Distributed means:

(1) The blood or blood components

have left the control of the licensed

manufacturer, unlicensed registered

blood establishment, or transfusion

service; or

(2) The licensed manufacturer has

provided Source Plasma or any other

blood component for use in the

manufacture of a licensed biological

product.

(l) Control means having

responsibility for maintaining the

continued safety, purity, and potency of

the product and for compliance with

applicable product and establishment

standards, and for compliance with

current good manufacturing practices.

6. Amend § 606.160 by revising

paragraph (b)(7)(iii) to read as follows:

§ 606.160 Records.

* * * * *

(b) * * *

(7) * * *

(iii) Biological product deviations.

* * * * *

7. Add § 606.171 to subpart I to read

as follows:

§ 606.171 Reporting of product deviations

by licensed manufacturers, unlicensed

registered blood establishments, and

transfusion services.

(a) Who must report under this

section? You, a licensed manufacturer of

blood and blood components, including

Source Plasma; an unlicensed registered

blood establishment; or a transfusion

service who had control over the

product when the deviation occurred,

must report under this section. If you

arrange for another person to perform a

manufacturing, holding, or distribution

step, while the product is in your

control, that step is performed under

your control. You must establish,

maintain, and follow a procedure for

receiving information from that person

on all deviations, complaints, and

adverse events concerning the affected

product.

(b) What do I report under this

section? You must report any event, and

information relevant to the event,

associated with the manufacturing, to

include testing, processing, packing,

labeling, or storage, or with the holding

or distribution, of both licensed and

unlicensed blood or blood components,

including Source Plasma, if that event

meets all the following criteria:

(1) Either:

(i) Represents a deviation from

current good manufacturing practice,

applicable regulations, applicable

standards, or established specifications

that may affect the safety, purity, or

potency of that product; or

(ii) Represents an unexpected or

unforeseeable event that may affect the

safety, purity, or potency of that

product; and

(2) Occurs in your facility or another

facility under contract with you; and

(3) Involves distributed blood or

blood components.

(c) When do I report under this

section? You should report a biological

product deviation as soon as possible

but you must report at a date not to

exceed 45-calendar days from the date

you, your agent, or another person who

performs a manufacturing, holding, or

distribution step under your control,

acquire information reasonably

suggesting that a reportable event has

occurred.

(d) How do I report under this

section? You must report on Form FDA–

3486.

(e) Where do I report under this

section? You must send the completed

Form FDA–3486 to the Director, Office

of Compliance and Biologics Quality

(HFM–600), 1401 Rockville Pike, suite

200N, Rockville MD, 20852–1448 by

either a paper or electronic filing:

(1) If you make a paper filing, you

should identify on the envelope that a

BPDR (biological product deviation

report) is enclosed; or

(2) If you make an electronic filing,

you may submit the completed Form

FDA–3486 electronically through

CBER’s website at www.fda.gov/cber.

(f) How does this regulation affect

other FDA regulations? This part

supplements and does not supersede

other provisions of the regulations in

this chapter. All biological product

deviations, whether or not they are

required to be reported under this

section, should be investigated in

accordance with the applicable

provisions of parts 211, 606, and 820 of

this chapter.

Dated: June 8, 2000.

Margaret M. Dotzel

Associate Commissioner for Policy

[FR Doc. 00–28133 Filed 11–3–00; 8:45 am]

BILLING CODE 4160–00–F