40858 Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules

of the main entrance door required by

paragraph (a) of this AD. Repeat the actions

specified in paragraphs (b)(1) and (b)(2) of

this AD, thereafter, at intervals not to exceed

1,500 hours time-in-service.

(1) Clean (remove contaminants and dry

lubricant) and re-lubricate (with dry

lubricant) the main entrance door ‘‘speed’’

lock and ‘‘G’’ lock systems in accordance

with Jetstream Service Bulletin J41–52–058,

dated July 14, 1997.

(2) Following accomplishment of

paragraph (b)(1) of this AD and prior to

further flight, perform a functional test of the

main entrance door (including the ‘‘G’’ lock

system) and the ‘‘speed’’ lock system, in

accordance with the MM. If the ‘‘G’’ lock or

‘‘speed’’ lock system do not perform

satisfactorily: Prior to further flight, repair

the ‘‘G’’ lock or ‘‘speed’’ lock system in

accordance with a method approved by the

Manager, International Branch, ANM–116.

New Requirements of This AD:

(c) Within 60 days after the effective date

of this AD, replace the ‘‘G’’ lock rollers on

the main entrance door with new, improved

‘‘G’’ lock rollers in accordance with Jetstream

Alert Service Bulletin J41–A–52–059, dated

September 12, 1997, or Revision 2, dated

January 23, 1998.

(d) An alternative method of compliance or

adjustment of the compliance time that

provides an acceptable level of safety may be

used if approved by the Manager,

International Branch, ANM–116. Operators

shall submit their requests through an

appropriate FAA Principal Maintenance

Inspector, who may add comments and then

send it to the Manager, International Branch,

ANM–116.

Note 2: Information concerning the

existence of approved alternative methods of

compliance with this AD, if any, may be

obtained from the International Branch,

ANM–116.

(e) Special flight permits may be issued in

accordance with sections 21.197 and 21.199

of the Federal Aviation Regulations (14 CFR

21.197 and 21.199) to operate the airplane to

a location where the requirements of this AD

can be accomplished.

Note 3: The subject of this AD is addressed

in British airworthiness directive 001–09–97.

Issued in Renton, Washington, on July 24,

1998.

S. R. Miller,

Acting Manager, Transport Airplane

Directorate, Aircraft Certification Service.

[FR Doc. 98–20430 Filed 7–30–98; 8:45 am]

BILLING CODE 4910–13–U

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 3, 5, 10, 20, 207, 310, 312,

316, 600, 601, 607, 610, 640, and 660

[Docket No. 98N–0144]

RIN 0910–AB29

Biological Products Regulated Under

Section 351 of the Public Health

Services Act; Implementation of

Biologics License; Elimination of

Establishment License and Product

License

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

amend the biologics regulations to

eliminate references to establishment

licenses and product licenses for all

products regulated under the Public

Health Service Act (PHS Act). In lieu of

filing an establishment license

application (ELA) and product license

application (PLA) in order to market a

biological product in interstate

commerce, a manufacturer would file a

single biologics license application

(BLA) with the agency. Upon approval

of the BLA, a manufacturer would

receive a biologics license to market the

product in interstate commerce. This

action is part of FDA’s continuing effort

to achieve the objectives of the

President’s ‘‘Reinventing Government’’

initiatives and is intended to reduce

unnecessary burdens for industry

without diminishing public health

protection. This action also proposes

regulations to implement certain

sections of the Food and Drug

Administration Modernization Act of

1997 (FDAMA).

DATES: Submit written comments by

October 14, 1998. Submit written

comments on the information collection

requirements by August 31, 1998.

ADDRESSES: Submit written comments

to the Dockets Management Branch

(HFA–305), Food and Drug

Administration, 12420 Parklawn Dr.,

rm. 1–23, Rockville, MD 20857. Submit

written comments on the information

collection requirements to the Office of

Management and Budget (OMB), New

Executive Office Bldg., 725 17th St.

NW., rm. 10235, Washington, DC 20503.

FOR FURTHER INFORMATION CONTACT:

Robert A. Yetter, Center for Biologics

Evaluation and Research (HFM–10),

Food and Drug Administration, 1401

Rockville Pike, suite 200N, Rockville,

MD 20852–1448, 301–827–0373.

SUPPLEMENTARY INFORMATION:

I. Background

Currently, most manufacturers

requesting approval to market a

biological product in interstate

commerce must submit a PLA and an

ELA to FDA. FDA’s Center for Biologics

Evaluation and Research (CBER)

currently requires manufacturers to use

one of three ELA forms and 1 of 16 PLA

forms for each biological product (see

the Federal Register of July 8, 1997 (62

FR 36558)). Upon approval of the ELA

and PLA, the agency issues a product

license and an establishment license to

the manufacturer. As discussed in the

next three paragraphs, FDA has

reviewed its process of licensing

biological products and has already

taken a number of actions to reduce the

regulatory burdens imposed by the

licensing process and to make the

licensing process more consistent with

the process for the approval of new

drugs.

Manufacturers of certain biological

products are already required to submit

a BLA and obtain FDA approval of the

BLA before the product may be

introduced into interstate commerce. In

the Federal Register of May 14, 1996 (61

FR 24227), FDA issued a final rule to

amend the biologics regulations by

eliminating the ELA requirement for

specified biotechnology and synthetic

biological products licensed under

section 351 of the PHS Act (42 U.S.C.

262 et seq.). The specified

biotechnology and synthetic biological

products are: (1) Therapeutic

deoxyribonucleic acid (DNA) plasmid

products; (2) therapeutic synthetic

peptide products of 40 or fewer amino

acids; (3) monoclonal antibody products

for in vivo use; and (4) therapeutic

recombinant DNA-derived products.

This provision applies only to those

products that FDA determines pursuant

to principles articulated in the

‘‘Intercenter Agreement Between the

Center for Drug Evaluation and Research

and the Center for Biologics Evaluation

and Research’’ (effective on October 31,

1991) to be subject to licensure under

Section 351 of the PHS Act. Thus, upon

approval, manufacturers of the specified

biotechnology and synthetic biological

products receive a single biologics

license instead of a product license and

an establishment license (see § 601.2(c)

(21 CFR 601.2(c))).

In the Federal Register of July 8, 1997

(62 FR 36558), FDA announced the

availability of a revised FDA Form 356h.

FDA Form 356h was revised as a

‘‘Reinventing Government’’ initiative to
Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules 40859

harmonize application procedures with

the Center for Drug Evaluation and

Research (CDER) as outlined in the

President’s November 1995 National

Performance Review Report,

‘‘Reinventing the Regulation of Drugs

Made From Biotechnology.’’ FDA

intended that applicants for biologics

licenses for products specified in

§ 601.2(c) as well as autologous somatic

cell therapy products could begin to use

FDA Form 356h immediately and would

be required to do so beginning January

8, 1998. FDA also intended to advise

applicants for licenses for other

biological products when they can

voluntarily begin and will be required to

use FDA Form 356h. Upon approval of

a BLA submitted on FDA Form 356h,

FDA will issue a single biologics

license. FDA believes that this licensing

procedure will greatly simplify the

application process, harmonize

application procedures with those of

CDER, and reduce industry and agency

paperwork burdens. FDA intends as a

result of this proposed rule to require

that all manufacturers requesting

approval to introduce, or deliver for

introduction, a biological product into

interstate commerce use FDA Form

356h to submit a BLA in lieu of separate

establishment and product applications.

With the consolidation of the

establishment and product license

applications into a single biologics

license application, the amount of

information formerly included in the

establishment license application would

be reduced but not eliminated. Some

information formerly included in the

ELA would now be submitted as

‘‘chemistry, manufacturing, and

controls’’ (CMC) information and under

the ‘‘establishment description’’ section

of FDA Form 356h. The type and

amount of information related to the

establishment would vary according to

the specific biological product for which

licensure is being requested. To describe

what information should be included

for each type of biological product,

CBER is preparing a series of guidance

documents. Many of these guidance

documents have already been made

available, including but not limited to:

(1) ‘‘Guidance for Industry for the

Submission of Chemistry,

Manufacturing, and Controls

Information for a Therapeutic

Recombinant DNA-Derived Product or a

Monoclonal Antibody Product for In

Vivo Use’’ (61 FR 56243, October 31,

1996); (2) ‘‘Guidance for the Submission

of Chemistry, Manufacturing, and

Controls Information and Establishment

Description for Autologous Somatic Cell

Therapy Products’’ (62 FR 1460, January

10, 1997); (3) ‘‘Guidance for Industry for

the Submission of Chemistry,

Manufacturing and Controls Information

for Synthetic Peptide Substances;’’ and

(4) ‘‘Draft Guidance for Industry for the

Submission of Chemistry,

Manufacturing and Controls and

Establishment Description Information

for Human Plasma-Derived Biological

Product or Animal Plasma or SerumDerived Products’’ (63 FR 3145, January

21, 1998). All of these guidance

documents can be downloaded from the

CBER Guidelines/Guidance document

World Wide Web page at

‘‘www.fda.gov/cber/guidelines.htm’’.

These guidance documents can also be

obtained by written request to the Office

of Communication, Training, and

Manufacturers Assistance (HFM–40),

Center for Biologics Evaluation and

Research, Food and Drug

Administration, 1401 Rockville Pike,

suite 200N, Rockville, MD 20852–1448.

Send one self-addressed adhesive label

to assist the office in processing your

requests. These documents may also be

obtained by mail by calling the CBER

Voice Information System at 1–800–

835–4709 or 301–827–1800, or by fax by

calling the FAX information System at

1–888–CBER–FAX or 301–827–3844.

FDA intends in the future to announce

in the Federal Register the availability

of additional CMC guidance documents

for various biological product classes.

II. Legal Authority

FDA licenses biological products

under the authority of section 351(a) of

the PHS Act. Although the PHS Act

requires that biological products be

licensed and be safe, pure, potent, and

manufactured in facilities designed to

assure that the product continues to be

safe, pure, and potent; it does not

mandate the number or form of licenses

that FDA shall issued for each

approvable biological product. The PHS

Act also does not specify the license

application forms that manufacturers

must submit to FDA. Except for the

biological products listed under

§ 601.2(c), FDA has required

manufacturers to submit a PLA and an

ELA for each biological product.

Accordingly, upon approval, FDA issues

two licenses for each product.

On November 21, 1997, the President

signed into law the FDAMA (Public Law

105–115). Section 123 of FDAMA, in

pertinent part, amended section 351 of

the PHS Act to specify that a biologics

license shall be in effect for a biological

product prior to such product’s

introduction into interstate commerce.

FDAMA thereby statutorily codified

FDA’s administrative BLA/biologics

license ‘‘Reinventing Government’’

initiative. Section 123(a)(1) of FDAMA

further states that the Secretary of

Health and Human Services (delegated

to the Commissioner of Food and Drugs,

at 21 CFR 5.10(a)(5)) shall approve a

‘‘biologics license application’’ on the

basis of a demonstration that the

biological product that is the subject of

the application is safe, pure, and potent;

and the facility in which the biological

product is manufactured, processed,

packed, or held meets standards

designed to ensure that the biological

product continues to be safe, pure, and

potent.

The regulatory standards for

establishments manufacturing biological

products can be found in the biologics

regulations in parts 600 through 680 (21

CFR parts 600 through 680) and in the

drug and device good manufacturing

practice regulations in parts 210 and

211 (21 CFR parts 210 and 211). The

licensed manufacturer must also adhere

to product and establishment standards

established and agreed upon in the

biologics license application. These

standards from applicable regulations

and as established in licenses for

different biological products, will

continue to constitute the requirements

for the approval of biologics licenses

under section 123 of FDAMA. For

consistency and to reduce confusion,

FDA will continue to use the terms

‘‘establishment’’ and ‘‘licensed

establishment’’ in the biologics

regulations when referring to a place of

manufacturing, processing, or packing

instead of the term ‘‘facility’’ as used in

section 123 of FDAMA. FDA is

proposing to amend § 600.3(w) to make

clear that the term ‘‘establishment’’ in

the biologics regulations has the same

meaning as ‘‘facility’’ in section 123 of

FDAMA.

Section 123(a)(2) of FDAMA

eliminated section 351(d) of the PHS

Act that required licenses for the

maintenance of establishments for the

propagation or manufacture and

preparation of biological products.

Section 123(f) of FDAMA states that the

Secretary of Health and Human Services

shall take measures to minimize

differences in the review and approval

of products licensed under section 351

of the PHS Act and products approved

through new drug applications (NDA’s)

under the Federal Food, Drug, and

Cosmetic Act (the act).

Therefore, this proposal is intended to

amend regulations in chapter 21 of the

Code of Federal Regulations (CFR) in

order to implement the regulatory

changes concerning biologic license

applications and biologics licenses in

the PHS Act codified by FDAMA. This

proposal would: (1) Amend the
40860 Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules

regulations in chapter 21 CFR by

eliminating almost all references to

establishment and product applications

and licenses and substituting the terms

‘‘biologics license application’’ and

‘‘biologics license;’’ (2) codify in the

biologics regulations that FDA would

issue a ‘‘biologics license’’ upon

approval of a BLA; (3) require a

manufacturer of a biological product to

submit a BLA on FDA Form 356h to

obtain approval of the license in order

to market the product in interstate

commerce; (4) harmonize application

procedures with products approved

under a NDA; and (5) update the format

of certain regulations.

FDA believes that its administrative

approach towards reviewing regulatory

submissions under the PHS Act can and

should evolve in response to changing

technology, knowledge, and experience

in reviewing the safety, purity, and

potency of biological products.

III. Summary of Proposed Rule

A. Definition and Deletion of Terms

In order to reduce any confusion that

may result from use of the term

‘‘facility’’ in section 351 of the PHS Act

as amended by FDAMA, FDA is

proposing to amend the definition of

‘‘establishment’’ in § 601.3(w) to include

that the term has the same meaning as

‘‘facility’’ in section 351 of the PHS Act.

FDA is proposing to modify the

definition of ‘‘standards’’ in § 600.3(n)

to indicate that the term refers to

specifications and procedures

established in biologics license

applications designed to insure the

continued safety, purity, and potency of

biological products as well as to

specifications and procedures in

applicable regulations. FDA has

authority under Section 351 of the PHS

Act to establish standards in the review

and approval of BLA’s. Section 351(d) of

the PHS Act which previously stated

that standards designed to insure the

continued safety, purity, and potency of

biological products be ‘‘prescribed in

regulations’’ was removed by FDAMA.

FDA believes that allowing standards to

be established in the BLA will enable

the manufacturer and FDA to keep pace

with evolving science and technology.

Establishing standards in the BLA is

consistent with FDA’s previous effort to

streamline the license review process by

deleting certain additional standards in

the biologics regulations (see 61 FR

40153, August 1, 1996). This proposed

change to § 600.3(n) would also reduce

confusion in the biologics regulations by

establishing consistency with FDA’s

current regulation at § 601.5(b)(4)

regarding the revocation of licenses.

FDA is proposing to delete the term

‘‘licensee’’ as used in the biologics

regulations in order to reduce confusion

and to make clear the fact that it is the

licensed manufacturer who is

responsible for compliance with

product and establishment

requirements. The term ‘‘licensed

manufacturer’’ would be inserted in all

instances that currently read ‘‘licensee.’’

B. Elimination of PLA/ELA and

Implementation of BLA

In the past, in order to help ensure

that biological products were safe, pure,

and potent, FDA, and prior to FDA, the

U.S. Public Health Service believed that

it was necessary to have both the

biological product and the

establishment in which it was

manufactured licensed separately. In

light of FDA’s accumulated experience

and expertise regulating biological

products and due to technical advances

that have significantly increased the

ability of manufacturers to control and

analyze the manufacture of biological

products, FDA, and the biologics

industry to a great extent, no longer find

the separate licensing scheme for

biological products and establishments

to be necessary. After much

consideration and in a ‘‘Reinventing

Government’’ initiative to reduce

burden on industry by implementing a

single biologics licensing scheme, FDA

had already begun drafting this proposal

when FDAMA was signed into law on

November 21, 1997. Section 123 of

FDAMA in effect codifies FDA’s BLA

initiative by requiring that FDA issue a

‘‘biologics license’’ to a manufacturer

that has submitted a BLA to FDA and

has demonstrated in the agency’s view

that the product is and will be

manufactured in a manner that ensures

the product’s continued safety, purity,

and potency.

This proposal substitutes the terms

‘‘biologics license’’ or ‘‘biologics license

application’’ in lieu of references to

product and establishment applications

and product and establishment licenses

in all regulations in chapter 21 CFR. In

a few instances references to product

and establishment licenses would be

retained for historical accuracy (e.g.,

§§ 601.25 and 601.26).

Under the proposed regulations, a

manufacturer applying for approval to

market a biological product under

section 351 of the PHS Act would

submit to FDA the appropriate

establishment and product information

on the recently approved FDA Form

356h (see 62 FR 36558). Manufacturers

would no longer be required to submit

product or establishment information on

the many different PLA and ELA forms

currently in use. Upon approval of the

BLA, FDA would issue an approval

letter that in general terms states that

FDA hereby grants the licensed

manufacturer a biologics license to

manufacture the particular biological

product. FDA would not issue license

certificates separate from the approval

letter as is current agency practice. The

approval letter would serve as the

functional equivalent of a biologics

license within the meaning of section

351 of the PHS Act.

FDA is proposing in § 601.2(a) that

manufacturers would list in the BLA the

addresses of all locations of

manufacture of a biological product.

FDA believes this would simplify and

clarify the licensing processes by having

necessary establishment information in

the BLA and also by allowing FDA to

approve all locations involved in the

manufacture of the product without

having to issue an establishment license

for each location.

FDA is proposing under § 601.9(c)

that manufacturers of some biological

products would be able to list multiple

products in a BLA and FDA would be

able to issue a single biologics license to

the manufacturer for more than one

product. FDA would most likely use

this approach with products that have

been on the market for a long period of

time, and for which FDA has

considerable knowledge and expertise

regulating, such as blood and blood

components and nonstandardized

allergenic products (see sections III.E

and III.F of this document).

C. Specified Products Outlined in

Current § 601.2(c)

In order to continue harmonized

review of specified biotechnology and

specified synthetic biological products

by CDER and CBER, the products

outlined in the May 14, 1996, final rule

(61 FR 24227) would continue to be

exempt from regulations at §§ 600.10(b)

and (c), 600.11, 600.12, 600.13, 610.11,

610.53, and 610.62.

D. Radioactive Biological Products

The agency believes that the

regulations for the licensing of

radioactive biological products under

§ 601.2(b) may be confusing to the

industry and do not accurately reflect

the current policies of CBER and CDER.

FDA is therefore proposing to amend

§ 601.2(b) to clarify procedures for

submitting an application for marketing

approval for a radioactive biological

product in order to help ensure

consistency with current CBER and

CDER policies and procedures. These

proposed regulations are intended to

merely clarify when a manufacturer of
Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules 40861

a radioactive biological product should

submit a NDA to CDER or a BLA to

CBER and should not be construed as an

attempt to address or implement the

requirements of section 122 of FDAMA,

‘‘Requirements for

Radiopharmaceuticals.’’ FDA intends in

a separate rulemaking to issue proposed

regulations regarding the approval of

radiopharmaceuticals as required by

section 122 of FDAMA. The proposed

provision provides that when the

biological component of a radioactive

coupled antibody determines the site of

action, normally a BLA should be

submitted. The regulation provides

sufficient flexibility to take into account

situations that may arise in the future

where the scientific issues associated

with the radionuclide or other

chemically synthesized component are

more significant than the scientific

issues associated with the biological

component. In such cases jurisdiction

will be determined in accordance with

principles articulated in the ‘‘Intercenter

Agreement Between the Center for Drug

Evaluation and Research and the Center

for Biologics Evaluation and Research’’

effective on October 31, 1991.

E. Blood and Blood Components

Currently CBER requires

manufacturers to use as many as 10

different forms for the submission of

ELA’s and PLA’s for blood and blood

components. In addition, the agency

currently issues a product and

establishment license for each of seven

product types covered by the forms (e.g.

Whole Blood, Platelets, Plasma, Red

Blood Cells, Cryoprecipitate, Source

Plasma). Under the proposed rule, the

agency would require a manufacturer of

blood and blood components

participating in interstate commerce to

use FDA Form 356h to request approval

to market. However, a manufacturer of

blood and blood components would

only need to submit one BLA to request

approval to market one or more blood or

blood components (e.g. Whole Blood,

Platelets, Plasma, Red Blood Cells,

Cryoprecipitate, Source Plasma). FDA

believes this consolidation of forms and

submissions would result in a reduced

regulatory burden for the blood industry

because information previously

duplicated in the many blood and blood

component product and establishment

applications would be submitted only

once in the BLA.

In addition, the proposed BLA system

would simplify submission of

supplements to blood and blood

component applications. Currently,

manufacturers desiring to make a single

manufacturing change that would affect

multiple products are required to

submit a supplement to each individual

product and establishment application.

Under this proposal a manufacturer

would only need to submit one

supplement to the BLA. For example,

under the current PLA/ELA system if a

manufacturer desired to make a single

change to the irradiation procedure for

its Whole Blood, Red Blood Cells,

Platelets, and Plasma products

manufactured at 3 locations, the

manufacturer would be required to

submit 12 supplements to 4 PLA’s.

Under the proposed BLA system, the

manufacturer would only be required to

submit one supplement to the BLA

describing the change for all of the

products and locations involved. FDA

intends to continue to streamline the

blood and blood components

application process in the future as part

of FDA’s Reinvention of Blood

Regulation initiative.

In vitro diagnostic kits (IVD’s) and

blood grouping reagents involving blood

and blood products are often licensed as

individual products under section 351

of the PHS Act. Unlike other blood and

blood component products, applications

to market IVD’s and blood grouping

reagents are unique and specific for

each product. In order for FDA to

evaluate the safety, purity, potency, and

effectiveness of each IVD or blood

grouping reagent, manufacturers submit

detailed product and establishment

information to FDA in the application to

market the product. FDA would

continue to evaluate IVD’s and blood

grouping reagents on an individual basis

and would therefore require a BLA for

each product. Accordingly, upon

approval of the BLA, FDA would issue

a single biologics license for each IVD

or blood reagent grouping product.

F. Allergenic Products

A significant number of

manufacturers of allergenic products

manufacture many different types of

non-standardized allergenic extracts for

immunotherapeutic and/or diagnostic

indications. Currently, a manufacturer

of multiple non-standardized allergenic

extract products holds a single product

license for all of the non-standardized

allergenic extracts manufactured by the

firm. FDA estimates that requiring or

issuing a biologics license for each type

of non-standardized allergenic extract

from each manufacturer would be

burdensome to the allergenics industry

and FDA. Therefore, in order to simplify

application procedures and reduce

burden on industry and FDA, under the

BLA/biologics license scheme a

manufacturer of multiple nonstandardized allergenic extracts wishing

to market these products in interstate

commerce would only be required to

submit a single BLA to the agency.

However, under this proposed rule,

standardized allergenic products would

be regulated as individual biological

products. Therefore, a manufacturer that

wishes to market single or multiple

standardized allergenic products would

be required to submit a single BLA for

each standardized product because of

the detailed product and establishment

specifications necessary to manufacture

such products.

Under proposed § 601.2(e) FDA is

proposing that every manufacturer of

biological products, including allergenic

product manufacturers, holding an

unsuspended and unrevoked product

license and establishment license would

be considered to have a biologics

license. Thus, an allergenic

manufacturer holding an establishment

license and product license for multiple

non-standardized allergenic extracts

would be considered to have a single

biologics license for those products.

Likewise, a manufacturer holding an

establishment license and product

license for a single standardized

allergenic extract would be considered

to have a biologics license for that

product.

G. Current Good Manufacturing Practice

Requirements

The establishment requirements for

biological products regulated under

Section 351 of the PHS Act would

continue to include the current good

manufacturing practice (CGMP)

regulations found in parts 210, 211, 600,

606, and 820 (21 CFR part 820). FDA

would review compliance with CGMP’s

during inspections; applicants would be

required to demonstrate such

compliance in order to obtain a

biologics license.

Under section 501(a)(2)(B) of the act

(21 U.S.C. 351(a)(2)(B) et seq.) the

methods used in, and the facilities or

controls used for the manufacture,

processing, packing, or holding of a

drug must conform to CGMP. Because

bulk drug substance, drug component,

and bulk drug product meet the

definition of ‘‘drug’’ in section 201(g)(1)

of the act (21 U.S.C. 321(g)(1)), their

manufacture also must conform to

CGMP. The CGMP regulations set forth

in parts 210 and 211 are intended to

apply to the preparation of a finished

dosage form, whether or not in packaged

form. (See §§ 210.3(b)(4) and 211.1(a).)

Although these CGMP regulations are

not specifically applicable to the

manufacture of bulk drug components,

there are numerous instances where

CGMP, within the meaning of

501(a)(2)(B) of the act, for bulk drug
40862 Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules

substances and bulk drug product

components would parallel the

requirements set forth in part 211 (see

43 FR 45076, September 29, 1978).

Because biological products can be

susceptible to contamination, adequate

control over bulk manufacturing is

important. FDA intends to use the

requirements of part 211 during

inspections of manufacturers of bulk

biological drug substances and bulk

biological drug product components, to

help assure that biological products will

have the proper raw materials controls,

process validation and controls, and

sensitive and validated test methods

and specifications that are necessary to

ensure the safety, purity, potency, and

effectiveness of the product. The

establishment requirements in §§ 600.10

through 600.15 and the inspection

regulations in §§ 600.20 through 600.22

would continue to apply to all

biological products licensed under

section 351 of the PHS Act except for

those exemptions allowed under

§ 601.2(c) for specified biotechnology

and synthetic products. Therefore, for

clarity and to reduce confusion FDA

would make clear in new § 601.2(d) that

the CGMP requirements in parts 210,

211, 600, 606, and 820 are included, as

applicable, as part of the establishment

requirements for the production of a

biological product. FDA is currently

reviewing the biological product

licensing and inspection regulations in

order to update them as part of CBER’s

review of general biologics and

licensing regulations (see 59 FR 3043,

January 20, 1994; and 59 FR 28821, June

3, 1994).

H. Required Use of FDA Form 356h

Manufacturers of the four classes of

specified biotechnology products

specified in § 601.2(c) are currently

required to use FDA Form 356h when

requesting permission to market one of

these biological products in interstate

commerce. Manufacturers of autologous

somatic cell therapy products subject to

licensure under section 351 of the PHS

Act should also use FDA Form 356h.

Manufacturers of other biological

products should continue to use the

current forms until such time as final

CMC and establishment guidance

documents are made available. Ten

months after the effective date of any

final rule based on this proposal, all

manufacturers of biological products

licensed under section 351 of the PHS

Act would be required to use FDA Form

356h as the form prescribed for such

purpose under § 601.2(a). Regardless of

which form(s) has been submitted for

application to market, CBER will begin

issuing biologics licenses in lieu of

establishment and product licenses for

any biological product that is approved

on and after February 19, 1998, the

effective date of FDAMA.

IV. Administrative Implementation

Issues

A. CBER Policy on Use of the Terms

‘‘Licensed Establishment’’ and

‘‘Licensed Manufacturer’’

In order to be clear, consistent, and

reduce confusion that may result from

the proposed BLA scheme, FDA will

continue to use the terms ‘‘licensed

establishment’’ and ‘‘licensed

manufacturer’’ in the biologics

regulations. Under the proposed BLA

scheme there would be no

establishment license issued along with

an approved BLA, however, all

establishments listed in the approved

biologics license application as engaged

in the manufacture of any part of the

biological product or the whole

biological product would be considered

a licensed establishment under the

biologics regulations (including contract

manufacturers and short suppliers).

FDA believes it is important to continue

to use the term ‘‘licensed

establishment’’ in the regulations in

order to convey the importance of the

establishment in the BLA scheme as

FDA reviews, inspects and approves the

establishment as part of the biologics

license approval process.

The term ‘‘licensed manufacturer’’ as

used to pertain to biological products

regulated under section 351 of the PHS

Act would continue to mean any legal

person or entity holding an

unsuspended and unrevoked biologics

license and who is therefore ultimately

responsible for compliance with all

product and establishment requirements

under the applicable regulations and

agreed upon in the BLA. FDA believes

it is important to continue to use the

term ‘‘licensed manufacturer’’ in the

biologics regulations in order to

emphasize that the manufacturer must

have a U.S. license number issued by

FDA and must also hold a biologics

license for the biological product.

B. Applications in Preparation

FDA recognizes that it may take

applicants time to switch format from

PLA’s and ELA’s to BLA’s. Therefore,

FDA proposes to continue to accept

PLA’s and ELA’s in lieu of a BLA for 10

months after the effective date of a final

rule based on this proposal. However,

all applications submitted to the agency

after the effective date of the final rule

would be required to include all

information indicated in FDA Form

356h in order for the application to be

considered as filed by CBER. PLA’s and

ELA’s received after the effective date of

the final rule would be administratively

handled by FDA as a BLA. Any

manufacturer planning to file a PLA and

an ELA during the 10-month time

period after the effective date of these

regulations should contact FDA for

further guidance.

C. Applications Currently Under Review

FDA proposes that any biological

products for which a PLA and an ELA

are pending on the effective date of

these regulations would be reviewed as

submitted. Not withstanding the new

regulations, new submissions by the

manufacturer would not be necessary

for these products. If the PLA and ELA

are sufficient for licensure, FDA would

issue a biologics license as required by

section 351 of the PHS Act as amended

by FDAMA.

D. PLA’s and ELA’s Currently in Effect

FDA proposes under new § 601.2(e)

that a manufacturer already holding an

approved ELA and PLA for a biological

product would not be required to file

supplements to comply with the

amended regulations. The approved

PLA together with portions of the

approved ELA relevant to the new

requirements for the BLA, would be

deemed to constitute a biologics license

under section 351 of the PHS Act .

E. BLA Tracking Number and U.S.

License Number of the Manufacturer

1. BLA Tracking Number

Consistent with the proposed BLA

scheme, FDA intends to use a new

internal BLA tracking and numbering

system to track applications,

manufacturers, and approvals. Each

biological product would be assigned a

BLA tracking number at the time the

BLA is submitted by the manufacturer.

The BLA tracking number assigned by

CBER upon receipt of a BLA would

remain indefinitely associated with the

biological product. Use of the BLA

tracking number would be similar to the

use of the NDA number for drugs

approved under section 505(b) of the act

(21 U.S.C. 355(b)). After publication of

a final rule based on this proposal,

CBER intends to assign a BLA tracking

number to each currently approved

application and notify each licensed

manufacturer of their respective BLA

tracking numbers. Licensed

manufacturers will be requested to use

the BLA tracking number in all

correspondence to the agency

concerning a particular biological

product.
Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules 40863

2. U.S. License Number of the

Manufacturer

FDA issues biologics licenses (U.S.

licenses) to new manufacturers of

biological products. Upon approval of a

BLA, a manufacturer if not previously

licensed would receive a U.S. license

number that is required under section

351 of the PHS Act to appear on the

label of the biological product. The U.S.

license number would also be used to

satisfy all regulatory requirements

regarding ‘‘license numbers’’ and in all

of the same instances that the

‘‘establishment license number’’ is

currently used by industry and CBER. A

manufacturer already holding a U.S.

license number from CBER on the

effective date of any final regulations

would continue to use its current U.S.

license number as required in the

biologics regulations.

FDA would NOT issue a separate

‘‘biologics license number’’ with the

approval of each biological product. In

summary: (1) The biologics tracking

number would be assigned by FDA

when the BLA is filed, it would stay

with the biological product for its life,

and it would be used on all

correspondence regarding the product;

(2) the U.S. license number would be

assigned to each manufacturer (if not

already holding one) at the time of

licensure of a biological product and

would be used on all of the

manufacturer’s labeling for approved

biological products; and (3) the approval

letter for each biological product would

serve as the biologics license under

section 351 of the PHS Act.

F. CMC and Establishment Information

Guidance

As stated earlier in this proposed rule,

CBER has made available certain

guidance documents that outline the

recommended information to be

provided in the CMC and establishment

sections of FDA Form 356h. Biological

product classes for which CBER is

currently drafting CMC and

establishment information guidance

documents include but are not limited

to: Vaccines, allergenic products, in

vitro diagnostic products, therapeutic

plasmid DNA products, therapeutic

naturally-derived protein products,

human plasma and animal serum

derived products, and human blood and

blood component products. As these

guidance documents are completed and

made available for various biological

products, FDA will encourage

manufacturers to begin to use Form FDA

356h. FDA intends to make CMC and

establishment information guidance

documents available for all biological

product classes by the time a final rule

on this subject is published. The CMC

guidance documents are intended to

help manufacturers comply with

product and establishment requirements

in applicable regulations including but

not limited to parts 210, 211, 600, 601,

606, and 820.

G. Public Meeting

FDA intends to hold a public

workshop during the comment period of

this proposed rule to discuss the BLA/

biologics license scheme. The date,

time, and location of the meeting will be

announced in a document in a future

issue of the Federal Register.

V. Proposed Effective Date

FDA proposes that a final rule

resulting from this proposal become

effective 60 days after its date of

publication in the Federal Register.

FDA understands that considerable

resources are committed to the

preparation of applications and

therefore would continue to accept

applications in the current two

application format for 10 months after

the effective date of any final rule based

on this proposal. However, after the

effective date of the final rule all

information indicated in FDA Form

356h must be submitted in these

submissions in order for the application

to be considered by CBER as complete.

Applications submitted in the current

two application format after the

effective date of the final rule will be

administratively handled by FDA as a

BLA. After the 10-month grace period

FDA would no longer accept the two

application format (ELA and PLA) and

would only accept for filing BLA’s

submitted on FDA Form 356h.

VI. Analysis of Impacts

A. Reduction in Burden

The proposed harmonized use of FDA

form 356h for all biological products

and drugs regulated by CBER and CDER

would reduce burden on industry by

enabling manufacturers to submit

applications for biological products and

drugs in a consistent format.

Manufacturers intending to introduce

biological products into interstate

commerce would no longer have to

prepare a PLA and an ELA to submit to

the agency for approval. The amount of

information that manufacturers would

need to provide in a BLA would be less

than that currently required in a PLA

and ELA. These proposed changes

would enable manufacturers to devote

fewer resources to submitting

documentation to the agency. Much of

the information currently reviewed in

an ELA at FDA headquarters would be

reviewed at the manufacturing site

during a preapproval inspection.

According to many biological product

manufacturers, preparation, submission,

and approval of a separate PLA and ELA

for each biological product adds

substantially to the cost of licensing the

product.

The inclusion of parts 210, 211, 600,

606, and 820 in the proposed rule as

establishment requirements would only

serve to clarify existing requirements

and would not impose any additional

burden on industry. Human drugs,

including biological products regulated

under section 351 of the PHS Act, are

already subject to the CGMP’s in parts

210, 211, 600, 606, and 820.

B. Review Under Executive Order 12866

and the Regulatory Flexibility Act

FDA has examined the impact of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(5 U.S.C. 601–612). 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

impact; and equity). The agency

believes that this proposed rule is

consistent with the regulatory

philosophy and principles identified in

Executive Order 12866. In addition, the

proposed rule is a significant regulatory

action as defined in Executive Order

12866 and is subject to review because

it deals with a novel policy issue.

In accordance with the principles of

Executive Order 12866, the overall

result of the proposed rule would be a

substantial reduction in burdens on a

manufacturer filing an application to

market a biological product. In addition,

FDA anticipates that the proposed rule

would facilitate a manufacturer’s ability

to improve its licensed products and

methods of manufacture by decreasing

the burden and cost associated with

filing applications and supplements.

The Regulatory Flexibility Act

requires agencies to analyze regulatory

options that would minimize any

significant impact of a rule on small

entities. Because, as stated previously,

the overall result of the proposed rule

would be substantial reduction in

reporting burdens, the agency certifies

that the proposed rule would not have

a significant negative economic impact

on a substantial number of small

entities. Therefore, under the Regulatory

Flexibility Act, no further analysis is

required.
40864 Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules

C. The Paperwork Reduction Act of

1995

This proposed rule contains

information collection provisions that

are subject to review by the Office of

Management and Budget (OMB) under

the PRA (44 U.S.C. 3501–3520). A

description of these provisions is shown

below with an estimate of the annual

reporting burden. Included in the

estimate is the time for reviewing the

instructions, searching existing data

sources, gathering and maintaining the

data needed, and completing and

reviewing each collection of

information.

FDA invites comments on: (1)

Whether the proposed collection of

information is necessary for the proper

performance of FDA’s functions,

including whether the information will

have practical utility; (2) the accuracy of

FDA’s estimate of the burden of the

proposed collection of information,

including the validity of the

methodology and assumptions used; (3)

ways to enhance the quality, utility, and

clarity of the information to be

collected; and (4) ways to minimize the

burden of the collection of information

on respondents, including through the

use of automated collection techniques,

when appropriate, and other forms of

information technology.

Title: Biological Products Regulated

Under Section 351 of the Public Health

Service Act; Implementation of

Biologics License; Elimination of

Establishment License and Product

License.

Description: FDA is proposing to

revise the regulations regarding the

procedures for application for approval

to market a biological product regulated

under section 351 of the PHS Act.

Currently, most manufacturers must

submit an ELA and a PLA when

requesting approval to market a

biological product in interstate

commerce. Under the proposed

regulations, a manufacturer would

submit to FDA the appropriate

establishment and product information

in a single BLA in lieu of filing a

separate ELA and PLA. The BLA is

intended to replace the many different

ELA and PLA forms currently in use.

Upon approval of the BLA, a

manufacturer would receive a single

biologics license to market the product

in interstate commerce.

Description of Respondents:

Manufacturers of biological products.

The proposed rule amends the

regulations for filing an application to

market a biological product under

§ 601.2 to eliminate references to

establishment licenses and product

licenses for all products regulated under

the PHS Act. The proposed rule would

require biologics manufacturers to file a

single BLA, rather than either an ELA or

PLA, to market a biological product. The

agency estimates that the total

paperwork burden for manufacturers

filing one application that consolidates

the information currently required

under both the PLA and ELA will net a

decrease of approximately 10 percent.

The estimate reduces the number of

annual responses from a combined PLA/

BLA/ELA total of 76 to a BLA total of

60. This estimate is derived from the

total number of license applications

received by FDA in fiscal year 1997 (76)

minus the total number of ELA’s filed in

the same period (17). Based on

information provided by industry, the

time estimated to prepare an application

for FDA approval to market a product is

approximately 1,600 hours. In addition

to § 601.2, there are other regulations

included in the proposed rule that relate

to certain information to be included in

a license application including

§§ 640.21(c), 640.22(c), 640.65(a), and

660.21(a)(3) and (d). The information

collection requirements in the preceding

regulations are included in the burden

estimate below for § 601.2.

The proposed regulation also makes

several technical amendments to

conform the language throughout the

biological product regulations to the

changes proposed here for § 601.2.

Specifically, the proposed rule makes

the following technical term changes:

References to product and establishment

license, and product and establishment

applications are replaced with

‘‘biologics license’’ or ‘‘biologics license

application;’’ ‘‘licensee’’ is replaced

with ‘‘licensed manufacturer;’’ and

‘‘licensed establishments’’ is replaced

with ‘‘licensed manufacturer.’’ These

technical changes impact neither the

substantive requirements nor the

paperwork burden of these regulations,

each of which carry separate OMB

clearance numbers as follows:

§§ 207.20(c) and 207.21(a) (0910–0045);

600.80(c)(2) (0910–0308); 601.25(b)(3)

(0910–0039); 607.20(b) and 607.21

(0910–0052); 610.63 and 640.71(b)(1)

(0910–0116).

The following regulations relate to the

submission of additional information in

a supplement to a BLA. Sections

600.15(b) and 610.53(d) require

submission of a request for an

exemption or modification regarding the

temperature requirements during

shipment and from dating periods,

respectively, for certain biological

products. The preparation of an

exemption request is estimated to be 8

hours; however, no requests were

received by the agency under either

regulations in fiscal year 1997. To

account for the rare instance in which

a request for an exemption may be

made, the agency has estimated one

respondent per year in Table 1. Section

640.6 requires that an applicant submit

a request to make a certain modification

of Whole Blood. The number of any

supplement relating to Whole Blood

filed by an applicant in fiscal year 1997

totaled 74. Because the agency could not

determine the number of supplements

filed specific to § 640.6, the estimate

below is based on last year’s total

number of supplements related to

Whole Blood.

The remaining regulations,

§§ 640.21(c), 640.22(c), 640.64(c), and

640.74(a) and (b)(2), refer to information

that is collected under § 601.12, under

which the collection of information

burden is calculated. Moreover, the

proposed rule would make only

technical changes to these regulations.

For example, the term ‘‘product license’’

is changed to ‘‘biologics licence,’’ and

the term ‘‘product licensee’’ is changed

to ‘‘licensed manufacturer.’’

TABLE 1.—ESTIMATED ANNUAL REPORTING BURDEN1

21 CFR Section No. of

Respondents

Annual

Frequency per

Response

Total Annual

Responses

Hours per

Response Total Hours

601.2 60 1 60 1,600 96,000

600.15(b) 1 1 1 8 8

610.53(d) 1 1 1 8 8

640.6 74 1 74 8 592

1There are no capital costs or operating and maintenance costs associated with this collection of information.
Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules 40865

In compliance with section 3507(d) of

the PRA (44 U.S.C. 3507(d)), the agency

has submitted the information

collection provisions of this proposed

rule to OMB for review. Interested

persons are requested to send written

comments regarding information

collection by August 31, 1998, to the

Office of Information and Regulatory

Affairs, OMB, New Executive Office

Bldg., 725 17th St. NW., rm. 10235,

Washington, DC 20503, Attn: Desk

Officer for FDA.

D. Environmental Impact

The agency has determined under 21

CFR 25.30 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.

Interested persons may, on or before

October 14, 1998, submit to the Dockets

Management Branch (address above)

written comments regarding the

proposal. Two copies of any comments

are to be submitted, except that

individuals may submit one copy.

Comments are to be identified with the

docket number found in brackets in the

heading of this document. The

comments received are available for

public examination in the Dockets

Management Branch between 9 a.m. and

4 p.m., Monday through Friday. Submit

written comments on the information

collection requirements to the Office of

Information and Regulatory

Management, OMB (address above).

List of Subjects

21 CFR Part 3

Administrative practice and

procedure, Biologics, Drugs, Medical

devices.

21 CFR Part 5

Authority delegations (Government

agencies), Imports, Organization and

functions (Government agencies).

21 CFR Part 10

Administrative practice and

procedure, News media.

21 CFR Part 20

Confidential business information,

Courts, Freedom of information,

Government employees.

21 CFR Part 207

Drugs, Reporting and recordkeeping

requirements.

21 CFR Part 310

Administrative practice and

procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping

requirements.

21 CFR Part 312

Drugs, Exports, Imports,

Investigations, Labeling, Medical

research, Reporting and recordkeeping

requirements, Safety.

21 CFR Part 316

Administrative practice and

procedure, Drugs, Reporting and

recordkeeping requirements.

21 CFR Part 600

Biologics, Reporting and

recordkeeping requirements.

21 CFR Part 601

Administrative practice and

procedure, Biologics, Confidential

business information.

21 CFR Part 607

Blood.

21 CFR Parts 610 and 660

Biologics, Labeling, Reporting and

recordkeeping requirements.

21 CFR Part 640

Blood, Labeling, Reporting and

recordkeeping requirements.

Therefore, under the Federal Food,

Drug, and Cosmetic Act, the Public

Health Service Act, and authority

delegated to the Commissioner of Food

and Drugs, it is proposed that 21 CFR

parts 3, 5, 10, 20, 207, 310, 312, 316,

600, 601, 607, 610, 640, and 660 be

amended to read as follows:

PART 3—PRODUCT JURISDICTION

1. The authority citation for 21 CFR

part 3 continues to read as follows:

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

355, 357, 360, 360c–360f, 360h–360j, 360gg–

360ss, 371(a), 379e, 381, 394; 42 U.S.C. 216,

262.

2. Section 3.2 is amended by revising

paragraph (k) to read as follows:

§ 3.2 Definitions.

* * * * *

(k) Premarket review includes the

examination of data and information in

an application for premarket review

described in sections 505, 507, 510(k),

513(f), 515, or 520(g) or 520(l) of the act

or section 351 of the Public Health

Service Act of data and information

contained in any investigational new

drug (IND) application, investigational

device exemption (IDE), new drug

application (NDA), antibiotic

application, biologics license

application, device premarket

notification, device reclassification

petition, and premarket approval

application (PMA).

* * * * *

PART 5—DELEGATIONS OF

AUTHORITY AND ORGANIZATION

3. The authority citation for 21 CFR

part 5 continues to read as follows:

Authority: 5 U.S.C. 504, 552, App. 2; 7

U.S.C. 138a, 2271; 15 U.S.C. 638, 1261–1282,

3701–3711a; 15 U.S.C. 1451–1461; 21 U.S.C.

41–50, 61–63, 141–149, 321–394, 467f,

679(b), 801–886, 1031–1309; 35 U.S.C. 156;

42 U.S.C. 241, 242, 242a, 242l, 242n, 243,

262, 263, 264, 265, 300u–300u–5, 300aa–1;

1395y, 3246b, 4332, 4831(a), 10007–10008;

E.O. 11921, 41 FR 24294, 3 CFR, 1977 Comp.,

p. 124–131; E.O. 12591, 52 FR 13414, 3 CFR,

1988 Comp., p. 220–223.

4. Section 5.58 is amended by revising

paragraph (a)(3) to read as follows:

§ 5.58 Orphan products.

(a) * * *

(3) Applications for biologics licenses

for biological products; or

* * * * *

5. Section 5.67 is amended by revising

paragraphs (a), (b), and (c) to read as

follows:

§ 5.67 Issuance of notices of opportunity

for a hearing on proposals for denial of

approval of applications for licenses or

revocation of licenses and certain notices

of revocation of licenses.

* * * * *

(a) Notices of opportunity for a

hearing on proposals to deny approval

or filing of applications for biologics

licenses under § 601.4(b) of this chapter.

(b) Notices of opportunity for a

hearing on proposals to revoke biologics

licenses under § 601.5(b) of this chapter.

(c) Notices of revocation, at the

manufacturer’s request, of biologics

licenses under §§ 601.5(a) and 601.8 of

this chapter.

* * * * *

PART 10—ADMINISTRATIVE

PRACTICES AND PROCEDURES

6. The authority citation for 21 CFR

part 10 is revised to read as follows:

Authority: 5 U.S.C. 551–558, 701–706; 15

U.S.C. 1451–1461; 21 U.S.C. 141–149, 321–

397, 467f, 679, 821, 1034; 28 U.S.C. 2112; 42

U.S.C. 201, 262, 263b, 264.

7. Section 10.50 is amended by

revising paragraph (c)(19) to read as

follows:

§ 10.50 Promulgation of regulations and

orders after an opportunity for a formal

evidentiary public hearing.

* * * * *

(c) * * *
40866 Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules

(19) Section 351(a) of the Public

Health Service Act on a biologics

license for a biological product.

* * * * *

PART 20—PUBLIC INFORMATION

8. The authority citation for 21 CFR

part 20 is revised to read as follows:

Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19

U.S.C. 2531–2582; 21 U.S.C. 321–393, 1401–

1403; 42 U.S.C. 241, 242, 242a, 242l, 242n,

243, 262, 263, 263b–263n, 264, 265, 300u–

300u–5, 300aa–1.

9. Section 20.100 is amended by

revising paragraph (c)(24) to read as

follows:

§ 20.100 Applicability; cross-reference to

other regulations.

* * * * *

(c) * * *

(24) Applications for biologics

licenses for biological products, in

§ 601.51 of this chapter.

* * * * *

PART 207—REGISTRATION OF

PRODUCERS OF DRUGS AND LISTING

OF DRUGS IN COMMERCIAL

DISTRIBUTION

10. The authority citation for 21 CFR

part 207 continues to read as follows:

Authority: 21 U.S.C. 331, 351, 352, 355,

357, 360, 360b, 371, 374; 42 U.S.C. 262.

11. Section 207.20 is amended by

revising paragraph (c) to read as follows:

§ 207.20 Who must register and submit a

drug list.

* * * * *

(c) Before beginning manufacture or

processing of a drug subject to one of

the following applications, an owner or

operator of an establishment is required

to register before the agency approves it:

A new drug application, a new animal

drug application, a medicated feed

application, an antibiotic application, or

a biologics license application.

* * * * *

12. Section 207.21 is amended by

revising the second sentence of

paragraph (a) to read as follows:

§ 207.21 Times for registration and drug

listing.

(a) * * * If the owner or operator

of the establishment has not previously

entered into such an operation, the

owner or operator shall register within

5 days after submitting a new drug

application, new animal drug

application, medicated feed application,

antibiotic application, or a biologics

license application. * * *

* * * * *

PART 310—NEW DRUGS

13. The authority citation for 21 CFR

part 310 continues to read as follows:

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

353, 355, 357, 360b–360f, 360j, 361(a), 371,

374, 375, 379e; 42 U.S.C. 216, 241, 242(a),

262, 263b–263n.

14. Section 310.4 is revised to read as

follows:

§ 310.4 Biologics; products subject to

license control.

(a) Except for radioactive biological

products intended for human use as

described in § 601.2(b) of this chapter, a

new drug shall not be deemed to be

subject to section 505 of the act if it is

a drug licensed under section 351 of the

Public Health Service Act (42 U.S.C. 262

et seq.) or under the animal virus,

serum, and toxin law of March 4, 1913

(21 U.S.C. 151 et seq.).

(b) A radioactive biological product

(as defined in § 600.3(ee) of this chapter)

intended for human use, except as

identified in § 601.2(b)(1) of this

chapter, is subject to section 505 of the

act. Any license for such a radioactive

biological product which was issued

under section 351 of the Public Health

Service Act (42 U.S.C. 262 et seq.) and

which was not revoked or suspended as

of August 25, 1975, shall constitute an

approved new drug application in effect

under the same terms and conditions as

set forth in such license application and

such portions of the establishment

license relating to such product, which

include data and information required

under part 314 of this chapter for a new

drug application. Any such radioactive

biological product for which licensure

under the Public Health Service Act was

pending on August 25, 1975, shall, upon

determination that it is acceptable for

licensure, be approved as a new drug

application in lieu of issuance of a

biological product license.

15. Section 310.503 is amended by

revising the first sentence of paragraph

(b) to read as follows:

§ 310.503 Requirements regarding certain

radioactive drugs.

* * * * *

(b) It is the opinion of the Nuclear

Regulatory Commission, and the Food

and Drug Administration that this

exemption should not apply for certain

specific drugs and that these drugs

should be appropriately labeled for uses

for which safety and effectiveness can

be demonstrated by new drug

applications or through licensing under

the Public Health Service Act (42 U.S.C.

262 et seq.) in the case of biologics. *

* *

* * * * *

PART 312—INVESTIGATIONAL NEW

DRUG APPLICATION

16. The authority citation for 21 CFR

part 312 continues to read as follows:

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

353, 355, 357, 371; 42 U.S.C. 262.

17. Section 312.3 is amended in

paragraph (b) by revising the definition

for Marketing application to read as

follows:

§ 312.3 Definitions and interpretations.

* * * * *

(b) * * *

Marketing application means an

application for a new drug submitted

under section 505(b) of the act, a request

to provide for certification of an

antibiotic submitted under section 507

of the act, or a biologics license

application for a biological product

submitted under the Public Health

Service Act.

* * * * *

PART 316—ORPHAN DRUGS

18. The authority citation for 21 CFR

part 316 continues to read as follows:

Authority: 21 U.S.C. 360aa, 360bb, 360cc,

360dd, 371.

19. Section 316.3 is amended by

revising paragraph (b)(9) to read as

follows:

§ 316.3 Definitions.

* * * * *

(b) * * *

(9) Marketing application means an

application for approval of a new drug

filed under section 505(b) of the act, a

request for certification of an antibiotic

under section 507 of the act, or an

application for a biologics license

submitted under section 351 of the

Public Health Service Act (42 U.S.C.

262).

* * * * *

PART 600—BIOLOGICAL PRODUCTS:

GENERAL

20. 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.

21. Section 600.3 is amended by

revising paragraph (n) and (w) to read as

follows:

§ 600.3 Definitions.

* * * * *

(n) The word standards means

specifications and procedures

applicable to an establishment or to the

manufacture or release of products,

which are prescribed in this subchapter
Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules 40867

or established in the biologics license

application designed to insure the

continued safety, purity, and potency of

such products.

* * * * *

(w) Establishment has the same

meaning as ‘‘facility’’ in section 351 of

the Public Health Service Act and

includes all locations.

* * * * *

22. Section 600.15 is amended by

revising paragraph (b) to read as follows:

§ 600.15 Temperatures during shipment.

* * * * *

(b) Exemptions. Exemptions or

modifications shall be made only upon

written approval, in the form of a

supplement to the biologics license

application, approved by the Director,

Center for Biologics Evaluation and

Research.

23. Section 600.21 is amended by

revising the first sentence to read as

follows:

§ 600.21 Time of inspection.

The inspection of an establishment

for which a biologics license application

is pending need not be made until the

establishment is in operation and is

manufacturing the complete product for

which a biologics license is desired. *

* *

24. Section 600.80 is amended by

revising the first sentence of paragraph

(b), the first and second sentences of

paragraph (c)(2)(i), and by revising

paragraphs (g) and (j) to read as follows:

§ 600.80 Postmarketing reporting of

adverse experiences.

* * * * *

(b) Review of adverse experiences.

Any person having a biologics license

under § 601.20 of this chapter shall

promptly review all adverse experience

information pertaining to its product

obtained or otherwise received by the

licensed manufacturer from any source,

foreign or domestic, including

information derived from commercial

marketing experience, postmarketing

clinical investigations, postmarketing

epidemiological/surveillance studies,

reports in the scientific literature, and

unpublished scientific papers. * * *

* * * * *

(c) * * *

(2) Periodic adverse experience

reports. (i) The licensed manufacturer

shall report each adverse experience not

reported under paragraph (c)(1)(i) of this

section at quarterly intervals, for 3 years

from the date of issuance of the

biologics license, and then at annual

intervals. The licensed manufacturer

shall submit each quarterly report

within 30 days of the close of the

quarter (the first quarter beginning on

the date of issuance of the biologics

license) and each annual report within

60 days of the anniversary date of the

issuance of the biologics license. * * *

* * * * *

(g) Multiple reports. A licensed

manufacturer should not include in

reports under this section any adverse

experience that occurred in clinical

trials if they were previously submitted

as part of the biologics license

application. If a report refers to more

than one biological product marketed by

a licensed manufacturer, the licensed

manufacturer should submit the report

to the biologics license application for

the product listed first in the report.

* * * * *

(j) Revocation of biologics license. If a

licensed manufacturer fails to establish

and maintain records and make reports

required under this section with respect

to a licensed biological product, FDA

may revoke the biologics license for

such a product in accordance with the

procedures of § 601.5 of this chapter.

* * * * *

PART 601—LICENSING

25. The authority citation for 21 CFR

part 601 is revised to read as follows:

Authority: 15 U.S.C. 1451–1461; 21 U.S.C.

321, 351, 352, 353, 355, 360, 360c–360f,

360h–360j, 371, 374, 379e, 381; 42 U.S.C.

216, 241, 262, 263.

§ 601.1 [Removed]

26. Section 601.1 Two forms of

licenses is removed.

27. Section 601.2 is revised to read as

follows:

§ 601.2 Applications for biologics

licenses; procedures for filing.

(a) General. To obtain a biologics

license under section 351 of the Public

Health Service Act for any biological

product, the manufacturer shall submit

an application to the Director, Center for

Biologics Evaluation and Research, on

forms prescribed for such purposes, and

shall submit data derived from

nonclinical laboratory and clinical

studies which demonstrate that the

manufactured product meets prescribed

requirements of safety, purity, and

potency; with respect to each

nonclinical laboratory study, either a

statement that the study was conducted

in compliance with the requirements set

forth in part 58 of this chapter, or, if the

study was not conducted in compliance

with such regulations, a brief statement

of the reason for the noncompliance;

statements regarding each clinical

investigation involving human subjects

contained in the application, that it

either was conducted in compliance

with the requirements for institutional

review set forth in part 56 of this

chapter; or was not subject to such

requirements in accordance with

§ 56.104 or § 56.105, and was conducted

in compliance with requirements for

informed consent set forth in part 50 of

this chapter. A full description of

manufacturing methods; data

establishing stability of the product

through the dating period; sample(s)

representative of the product to be sold,

bartered, or exchanged or offered, sent,

carried or brought for sale, barter, or

exchange; summaries of results of tests

performed on the lot(s) represented by

the submitted sample(s); specimens of

the labels, enclosures, and containers

proposed to be used for the product and;

the address of each location involved in

the manufacture of the biological

product shall be listed in the biologics

license application. An application for a

biologics license shall not be considered

as filed until all pertinent information

and data have been received from the

manufacturer by the Center for Biologics

Evaluation and Research. The applicant

shall also include either a claim for

categorical exclusion under § 25.30 or

§ 25.31 of this chapter or an

environmental assessment under § 25.40

of this chapter. In lieu of the procedures

described in this paragraph,

applications for radioactive biological

products shall be handled as set forth in

paragraph (b) of this section. The

applicant, or the applicant’s attorney,

agent, or other authorized official shall

sign the application. An application for

any of the following specified categories

of biological products subject to

licensure shall be handled as set forth

in paragraph (c) of this section:

(1) Therapeutic DNA plasmid

products;

(2) Therapeutic synthetic peptide

products of 40 or fewer amino acids;

(3) Monoclonal antibody products

for in vivo use; and

(4) Therapeutic recombinant DNAderived products.

(b) Radioactive biological products.

To obtain marketing approval for a

radioactive biological product, as

defined in § 600.3(ee) of this chapter,

the manufacturer of such product shall

comply with the following:

(1) An applicant for a radioactive

coupled antibody, which means a

product that consists of an antibody

component coupled with a radionuclide

component (or an antibody component

intended solely to be coupled with a

radionuclide) in which both

components provide a pharmacological

effect but the biological component

determines the site of action, shall
40868 Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules

submit a biologics license application to

the Director, Center for Biologics

Evaluation and Research, Food and

Drug Administration, except if, as

determined by FDA, there are

significant scientific issues associated

with the radionuclide or other

chemically synthesized component, in

which case a new drug application shall

be submitted to the Center for Drug

Evaluation and Research, Food and

Drug Administration;

(2) An applicant for a radioactive

biological product other than as

described in paragraph (b)(1) of this

section, shall submit a new drug

application to the Center for Drug

Evaluation and Research, Food and

Drug Administration.

(c)(1) To obtain marketing approval

for a biological product subject to

licensure which is a therapeutic DNA

plasmid product, therapeutic synthetic

peptide product of 40 or fewer amino

acids, monoclonal antibody product for

in vivo use, or therapeutic recombinant

DNA-derived product, an applicant

shall submit a biologics license

application in accordance with

paragraph (a) of this section except that

the following sections in parts 600

through 680 of this chapter shall not be

applicable to such products:

§§ 600.10(b) and (c), 600.11, 600.12,

600.13, 610.11, 610.53, and 610.62 of

this chapter.

(2) To the extent that the requirements

in this paragraph (c) conflict with other

requirements in this subchapter, this

paragraph (c) shall supersede other

requirements.

(d) Approval of a biologics license

application or issuance of a biologics

license shall constitute a determination

that the establishment(s) and the

product meet applicable requirements to

ensure the continued safety, purity, and

potency of such products. Applicable

requirements for the maintenance of

establishments for the manufacture of a

product subject to this section shall

include but not be limited to the good

manufacturing practice requirements set

forth in parts 210, 211, 600, 606, and

820 of this chapter.

(e) Any establishment and product

license for a biological product issued

under section 351 of the Public Health

Service Act (42 U.S.C. 201 et seq.) that

has not been revoked or suspended as

of (insert effective date of final rule),

shall constitute an approved biologics

license application in effect under the

same terms and conditions set forth in

such product license and such portions

of the establishment license relating to

such product.

§ 601.3 [Removed]

28. Section 601.3 License forms is

removed.

29. Section 601.4 is amended by

revising paragraph (a) and the first

sentence of paragraph (b) to read as

follows:

§ 601.4 Issuance and denial of license.

(a) A biologics license shall be issued

upon a determination by the Director,

Center for Biologics Evaluation and

Research that the establishment(s) and

the product meet the applicable

requirements established in this

chapter. A biologics license shall be

valid until suspended or revoked.

(b) If the Commissioner, determines

that the establishment or product does

not meet the requirements established

in this chapter, the biologics license

application shall be denied and the

applicant shall be informed of the

grounds for, and of an opportunity for

a hearing on, the decision. * * *

30. Section 601.5 is revised to read as

follows:

§ 601.5 Revocation of license.

(a) A biologics license shall be

revoked upon application of the

manufacturer giving notice of intention

to discontinue the manufacture of all

products manufactured under such

license or to discontinue the

manufacture of a particular product for

which a license is held and waiving an

opportunity for a hearing on the matter.

(b)(1) The Commissioner shall notify

the licensed manufacturer of the

intention to revoke the biologics license,

setting forth the grounds for, and

offering an opportunity for a hearing on,

the proposed revocation if the

Commissioner finds any of the

following:

(i) Authorized Food and Drug

Administration employees after

reasonable efforts have been unable to

gain access to an establishment or a

location for the purpose of carrying out

the inspection required under § 600.21

of this chapter,

(ii) Manufacturing of products or of a

product has been discontinued to an

extent that a meaningful inspection or

evaluation cannot be made,

(iii) The manufacturer has failed to

report a change as required by § 601.12,

(iv) The establishment or any location

thereof, or the product for which the

license has been issued, fails to conform

to the applicable standards established

in the license and in this chapter

designed to ensure the continued safety,

purity, and potency of the manufactured

product,

(v) The establishment or the

manufacturing methods have been so

changed as to require a new showing

that the establishment or product meets

the requirements established in this

chapter in order to protect the public

health, or

(vi) The licensed product is not safe

and effective for all of its intended uses

or is misbranded with respect to any

such use.

(2) Except as provided in § 601.6 or in

cases involving willfulness, the

notification required in this paragraph

shall provide a reasonable period for the

licensed manufacturer to demonstrate or

achieve compliance with the

requirements of this chapter, before

proceedings will be instituted for the

revocation of the license. If compliance

is not demonstrated or achieved and the

licensed manufacturer does not waive

the opportunity for a hearing, the

Commissioner shall issue a notice of

opportunity for hearing on the matter

under § 12.21(b) of this chapter.

31. Section 601.6 is revised to read as

follows:

§ 601.6 Suspension of license.

(a) Whenever the Commissioner has

reasonable grounds to believe that any

of the grounds for revocation of a

license exist and that by reason thereof

there is a danger to health, the

Commissioner may notify the licensed

manufacturer that the biologics license

is suspended and require that the

licensed manufacturer do the following:

(1) Notify the selling agents and

distributors to whom such product or

products have been delivered of such

suspension, and

(2) Furnish to the Director, Center for

Biologics Evaluation and Research,

complete records of such deliveries and

notice of suspension.

(b) Upon suspension of a license, the

Commissioner shall either:

(1) Proceed under the provisions of

§ 601.5(b) to revoke the license, or

(2) If the licensed manufacturer

agrees, hold revocation in abeyance

pending resolution of the matters

involved.

32. Section 601.9 is revised to read as

follows:

§ 601.9 Licenses; reissuance.

(a) Compliance with requirements. A

biologics license, previously suspended

or revoked, may be reissued or

reinstated upon a showing of

compliance with requirements and

upon such inspection and examination

as may be considered necessary by the

Director, Center for Biologics Evaluation

and Research.

(b) Exclusion of noncomplying

location. A biologics license, excluding

a location or locations that fail to
Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules 40869

comply with the requirements in this

chapter, may be issued without further

application and concurrently with the

suspension or revocation of the license

for noncompliance at the excluded

location or locations.

(c) Exclusion of noncomplying

product(s). In the case of multiple

products included under a single

biologics license application, a biologics

license may be issued, excluding the

noncompliant product(s), without

further application and concurrently

with the suspension or revocation of the

biologics license for a noncompliant

product(s).

§ 601.10 [Removed]

33. Section 601.10 Establishment

licenses; issuance and conditions is

removed.

34. Section 601.20 is revised to read

as follows:

§ 601.20 Biologics licenses; issuance and

conditions.

(a) Examination—compliance with

requirements. A biologics license

application shall be approved only upon

examination of the product and upon a

determination that the product complies

with the standards established in

biologics license application and the

requirements prescribed in the

regulations in this chapter including but

not limited to the good manufacturing

practice requirements set forth in parts

210, 211, 600, 606, and 820 of this

chapter.

(b) Availability of product. No

biologics license shall be issued unless:

(1) The product intended for

introduction into interstate commerce is

available for examination, and

(2) Such product is available for

inspection during all phases of

manufacture.

(c) Manufacturing process—

impairment of assurances. No product

shall be licensed if any part of the

process of or relating to the manufacture

of such product, in the judgment of the

Director, Center for Biologics Evaluation

and Research, would impair the

assurances of continued safety, purity,

and potency as provided by the

regulations contained in this chapter.

(d) Inspection—compliance with

requirements. A biologics license shall

be issued or a biologics license

application approved only after

inspection of the establishment(s) listed

in the biologics license application and

upon a determination that the

establishment(s) complies with the

standards established in the biologics

license application and the

requirements prescribed in applicable

regulations.

(e) One biologics license to cover all

locations. One biologics license shall be

issued to cover all locations meeting the

establishment standards identified in

the approved biologics license

application and each location shall be

subject to inspection by FDA officials.

35. Section 601.21 is revised to read

as follows:

§ 601.21 Products under development.

A biological product undergoing

development, but not yet ready for a

biologics license, may be shipped or

otherwise delivered from one State or

possession into another State or

possession provided such shipment or

delivery is not for sale, barter, or

exchange, except as provided in section

505(i) of the Federal Food, Drug, and

Cosmetic Act, as amended, and the

regulations thereunder (21 CFR parts

312 and 812).

36. Section 601.22 is amended by

revising the section heading and the

first and second sentences to read as

follows:

§ 601.22 Products in short supply; initial

manufacturing at other than licensed

location.

A biologics license issued to a

manufacturer and covering all locations

of manufacture shall authorize persons

other than such manufacturer to

conduct at places other than such

locations the initial, and partial

manufacturing of a product for

shipment solely to such manufacturer

only to the extent that the names of such

persons and places are registered with

the Commissioner of Food and Drugs

and either of the following is found

upon application of such manufacturer,

that the product is in short supply due

either to the peculiar growth

requirements of the organism involved

or to the scarcity of the animal required

for manufacturing purposes, and such

manufacturer has established with

respect to such persons and places such

procedures, inspections, tests or other

arrangements as will assure full

compliance with the applicable

regulations of this subchapter related to

continued safety, purity, and potency.

Such persons and places shall be subject

to all regulations of this subchapter

except §§ 601.2 to 601.6, 601.9, 601.10,

601.20, 601.21 to 601.33, and §§ 610.60

to 610.65 of this chapter. * * *

37. Sections 601.25 is amended in

paragraph (b)(3) under ‘‘Biological

Products Review Information’’ by

revising section VIII and by revising the

third sentence of paragraph (f)(3) to read

as follows:

§ 601.25 Review procedures to determine

that licensed biological products are safe,

effective, and not misbranded under

prescribed, recommended, or suggested

conditions of use.

* * * * *

(b) * * *

(3) * * *

BIOLOGICAL PRODUCTS REVIEW

INFORMATION

* * * * *

VIII. If the submission is by a licensed

manufacturer, a statement signed by the

authorized official of the licensed

manufacturer shall be included, stating that

to the best of his or her knowledge and belief,

it includes all information, favorable and

unfavorable, pertinent to an evaluation of the

safety, effectiveness, and labeling of the

product, including information derived from

investigation, commercial marketing, or

published literature. If the submission is by

an interested person other than a licensed

manufacturer, a statement signed by the

person responsible for such submission shall

be included, stating that to the best of his

knowledge and belief, it fairly reflects a

balance of all the available information,

favorable and unfavorable available to him,

pertinent to an evaluation of the safety,

effectiveness, and labeling of the product.

* * * * *

(f) * * *

(3) * * * Where the Commissioner

determines that the potential benefits

outweigh the potential risks, the

proposed order shall provide that the

biologics license for any biological

product, falling within this paragraph

will not be revoked but will remain in

effect on an interim basis while the data

necessary to support its continued

marketing are being obtained for

evaluation by the Food and Drug

Administration. * * *

* * * * *

38. Section 601.26 is amended by

revising the second sentence of the

introductory text of paragraph (e), the

first, fourth and fifth sentences of

paragraph (f)(1), the second sentence of

paragraph (f)(2), and the first sentence of

paragraph (f)(3) to read as follows:

§ 601.26 Reclassification procedures to

determine that licensed biological products

are safe, effective, and not misbranded

under prescribed, recommended, or

suggested conditions of use.

* * * * *

(e) * * * Where the Commissioner

determines that there is a compelling

medical need and no suitable alternative

therapeutic, prophylactic, or diagnostic

agent for any biological product that is

available in sufficient quantities to meet

current medical needs, the final order

shall provide that the biologics license

application for that biological product

will not be revoked, but will remain in

effect on an interim basis while the data
40870 Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules

necessary to support its continued

marketing are being obtained for

evaluation by the Food and Drug

Administration. * * *

(f) Additional studies and labeling. (1)

Within 60 days following publication of

the final order, each licensed

manufacturer for a biological product

designated as requiring further study to

justify continued marketing on an

interim basis, under paragraph (e) of

this section, shall submit to the

Commissioner a written statement

intended to show that studies adequate

and appropriate to resolve the questions

raised about the product have been

undertaken. * * * The Commissioner

may extend this 60-day period if

necessary, either to review and act on

proposed protocols or upon indication

from the licensed manufacturer that the

studies will commence at a specified

reasonable time. If no such commitment

is made, or adequate and appropriate

studies are not undertaken, the biologics

license or licenses shall be revoked.

* * *

(2) * * * If the progress report is

inadequate or if the Commissioner

concludes that the studies are not being

pursued promptly and diligently, or if

interim results indicate the product is

not a medical necessity, the biologics

license or licenses shall be revoked.

(3) Promptly upon completion of the

studies undertaken on the product, the

Commissioner will review all available

data and will either retain or revoke the

biologics license or licenses involved. *

* *

* * * * *

39. Section 601.51 is amended by

revising the section heading, the first

sentence of paragraph (a), and paragraph

(b) to read as follows:

§ 601.51 Confidentiality of data and

information in applications for biologics

licenses.

(a) For purposes of this section the

biological product file includes all data

and information submitted with or

incorporated by reference in any

application for a biologics license, IND’s

incorporated into any such application,

master files, and other related

submissions. * * *

(b) The existence of a biological

product file will not be disclosed by the

Food and Drug Administration before a

biologics license application has been

approved unless it has previously been

publicly disclosed or acknowledged.

The Director of the Center for Biologics

Evaluation and Research will maintain

a list available for public disclosure of

biological products for which a license

application has been approved.

* * * * *

PART 607—ESTABLISHMENT

REGISTRATION AND PRODUCT

LISTING FOR MANUFACTURERS OF

HUMAN BLOOD AND BLOOD

PRODUCTS

40. The authority citation for 21 CFR

part 607 continues to read as follows:

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

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

41. Section 607.20 is amended by

revising paragraph (b) to read as follows:

§ 607.20 Who must register and submit a

blood product list.

* * * * *

(b) Preparatory to engaging in the

manufacture of blood products, owners

or operators of establishments who are

submitting a biologics license

application to manufacture blood

products are required to register before

the biologics license application is

approved.

* * * * *

42. Section 607.21 is amended by

revising the second sentence to read as

follows:

§ 607.21 Times for establishment

registration and blood product listing.

* * * If the owner or operator of the

establishment has not previously

entered into such operation (defined in

§ 607.3(d)) for which a license is

required, registration shall follow

within 5 days after the submission of a

biologics license application in order to

manufacture blood products. * * *

PART 610—GENERAL BIOLOGICAL

PRODUCTS STANDARDS

43. The authority citation for 21 CFR

part 610 continues to read as follows:

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

355, 360, 371; 42 U.S.C. 216, 262, 263, 263a,

264.

44. Section 610.13 is amended by

revising the introductory paragraph and

the first sentence of paragraph (a)(1) to

read as follows:

§ 610.13 Purity.

Products shall be free of extraneous

material except that which is

unavoidable in the manufacturing

process described in the approved

biologics license application. In

addition, products shall be tested as

provided in paragraphs (a) and (b) of

this section.

(a)(1) Test for residual moisture. Each

lot of dried product shall be tested for

residual moisture and shall meet and

not exceed established limits as

specified by an approved method on file

in the biologics license application. * *

*

* * * * *

45. Section 610.53 is amended by

revising paragraph (d) to read as

follows:

§ 610.53 Dating periods for licensed

biological products.

* * * * *

(d) Exemptions. Exemptions or

modifications shall be made only upon

written approval, in the form of a

supplement to the biologics license

application, issued by the Director,

Center for Biologics Evaluation and

Research.

46. Section 610.63 is revised to read

as follows:

§ 610.63 Divided manufacturing

responsibility to be shown.

If two or more licensed manufacturers

participate in the manufacture of a

biological product, the name, address,

and license number of each must appear

on the package label, and on the label

of the container if capable of bearing a

full label.

PART 640—ADDITIONAL STANDARDS

FOR HUMAN BLOOD AND BLOOD

PRODUCTS

47. The authority citation for 21 CFR

part 640 continues to read as follows:

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

355, 360, 371; 42 U.S.C. 216, 262, 263, 263a,

264.

48. Section 640.6 is amended by

revising the introductory text to read as

follows:

§ 640.6 Modifications of Whole Blood.

Upon approval by the Director,

Center for Biologics Evaluation and

Research, of a supplement to the

biologics license application for Whole

Blood a manufacturer may prepare

Whole Blood from which the

antihemophilic factor has been

removed, provided the Whole Blood

meets the applicable requirements of

this subchapter and the following

conditions are met:

* * * * *

49. Section 640.21 is amended by

revising paragraph (c) to read as follows:

§ 640.21 Suitability of donors.

* * * * *

(c) Plateletpheresis donors shall meet

criteria for suitability as described in a

biologics license application or a

supplement to the biologics license

application, and must have the written

approval of the Director, Center for

Biologics Evaluation and Research,

Food and Drug Administration.
Federal Register / Vol. 63, No. 147 / Friday, July 31, 1998 / Proposed Rules 40871

50. Section 640.22 is amended by

revising paragraph (c) to read as follows:

§ 640.22 Collection of source material.

* * * * *

(c) If plateletpheresis is used, the

procedure for collection shall be as

described in a biologics license

application or a supplement to a

biologics license application, and must

have the written approval of the

Director, Center for Biologics Evaluation

and Research, Food and Drug

Administration.

* * * * *

51. Section 640.64 is amended by

revising the second sentence of the

introductory text of paragraph (c) to

read as follows:

§ 640.64 Collection of blood for Source

Plasma.

* * * * *

(c) * * * One of the following

formulas shall be used in the indicated

volumes, except that a different formula

may be used for plasma for manufacture

into noninjectable products if prior

written approval is obtained from the

Director of the Center for Biologics

Evaluation and Research at the time of

licensing or in the form of a supplement

to the biologics license application for

Source Plasma.

* * * * *

52. Section 640.65 is amended by

revising the last sentence of paragraph

(a) to read as follows:

§ 640.65 Plasmapheresis.

(a) * * * This procedure shall be

described in detail in the biologics

license application.

* * * * *

53. Section 640.71 is amended by

revising the introductory text of

paragraphs (a) and (b) and by revising

paragraph (b)(1) to read as follows:

§ 640.71 Manufacturing responsibility.

(a) All steps in the manufacture of

Source Plasma, including donor

examination, blood collection,

plasmapheresis, laboratory testing,

labeling, storage, and issuing shall be

performed by personnel of the licensed

manufacturer of the Source Plasma,

except that the following tests may be

performed by personnel of a

manufacturer licensed for blood or

blood derivatives under section 351(a)

of the Public Health Service Act, or by

a clinical laboratory that meets the

standards of the Clinical Laboratories

Improvement Act of 1967 (CLIA) (42

U.S.C. 263a): Provided, The

establishment or the clinical laboratory

is qualified to perform the assigned

test(s).

* * * * *

(b) Such testing shall not be

considered divided manufacturing,

which requires two biologics licenses

for Source Plasma: Provided, That

(1) The results of such tests are

maintained by the licensed

manufacturer of the Source Plasma

whereby such results may be reviewed

by a licensed physician as required in

§ 640.65(b)(2) and by an authorized

representative of the Food and Drug

Administration.

* * * * *

54. Section 640.74 is amended by

revising paragraph (a) and the last

sentence of paragraph (b)(2) to read as

follows:

§ 640.74 Modification of Source Plasma.

(a) Upon approval by the Director,

Center for Biologics Evaluation and

Research, Food and Drug

Administration, of a supplement to the

biologics license application for Source

Plasma, a manufacturer may prepare

Source Plasma as a liquid product for a

licensed blood derivative manufacturer

who has indicated a need for a liquid

product.

(b) * * *

(2) * * * Such evidence may be

submitted by either the licensed

manufacturer of the Source Plasma

Liquid or the manufacturer of the final

blood derivative product who has

requested the Source Plasma Liquid.

* * * * *

PART 660—ADDITIONAL STANDARDS

FOR DIAGNOSTIC SUBSTANCES FOR

LABORATORY TESTS

55. The authority citation for 21 CFR

part 660 continues to read as follows:

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

355, 360, 371; 42 U.S.C. 216, 262, 263, 263a,

264.

56. Section 660.21 is amended by

revising paragraphs (a)(3) and (d) to read

as follows:

§ 660.21 Processing.

(a) * * *

(3) A lot may be subdivided into

clean, sterile vessels. Each subdivision

shall constitute a sublot. If lots are to be

subdivided, the manufacturer shall

include this information in the biologics

license application. The manufacturer

shall describe the test specifications to

verify that each sublot is identical to

other sublots of the lot.

* * * * *

(d) Volume of final product. Each

manufacturer shall identify the possible

final container volumes in the biologics

license application.

* * * * *

57. Section 660.30 is amended by

revising paragraph (b) to read as follows:

§ 660.30 Reagent Red Blood Cells.

* * * * *

(b) Source. Reagent Red Blood Cells

shall be prepared from human

peripheral blood meeting the criteria of

§§ 660.31 and 660.32, or from umbilical

cord cells which shall be collected and

prepared according to the

manufacturer’s biologics license

application.

58. Section 660.33 is amended by

revising the fifth sentence to read as

follows:

§ 660.33 Testing of source material.

* * * Where fewer than three donor

sources of an antibody specificity are

available, test discrepancies shall be

resolved in accordance with the

manufacturer’s biologics license

application. * * *

Dated: July 22, 1998.

Michael A. Friedman,

Acting Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 98–20427 Filed 7–30–98; 8:45 am]

BILLING CODE 4160–01–F

DEPARTMENT OF THE INTERIOR

Office of Surface Mining Reclamation

and Enforcement

30 CFR Parts 707 and 874

RIN 1029–AB89

Abandoned Mine Land (AML)

Reclamation Program; Enhancing AML

Reclamation

AGENCY: Office of Surface Mining

Reclamation and Enforcement, Interior.

ACTION: Proposed rule, reopening and

extension of comment period.

SUMMARY: The Office of Surface Mining

Reclamation and Enforcement (OSM) is

reopening and extending the comment

period for the proposed rule, Enhancing

AML Reclamation, published on June

25, 1998 (63 FR 34768). The comment

period closed on July 27, 1998, and is

being reopened and extended for 15

days.

DATES: Written comments: We will

accept written comments on the

proposed rule until 5 p.m., Eastern time,

on August 11, 1998.

ADDRESSES: If you wish to comment,

you may mail or hand deliver comments