24226 Federal Register / Vol. 61, No. 94 / Tuesday, May 14, 1996 / Rules and Regulations

22Mailing Address: 7500 Standish Pl., MPN–2,

Rockville, MD 20855.

Office of Programs

Office of Cosmetics and Colors

Division of Programs and Enforcement

Policy.

Division of Science and Applied

Technology.

Office of Food Labeling

Division of Programs and Enforcement

Policy.

Division of Technical Evaluation.

Division of Science and Applied

Technology.

Office of Pre-Market Approval

Division of Product Policy.

Division of Petition Control.

Division of Health Effects Evaluation.

Division of Molecular Biological

Research and Evaluation.

Division of Product Manufacture and

Use.

Office of Plant and Dairy Foods and

Beverages

Division of Programs and Enforcement

Policy.

Division of Microanalytical Evaluations.

Division of Programs and Enforcement

Policy.

Division of Virulence Assessment.

Division of Pesticides and Industrial

Chemicals.

Division of Natural Products.

Division of Food Processing and

Packaging.

Office of Seafood

Division of Special Programs.

Division of Programs and Enforcement

Policy.

Division of Science and Applied

Technology.

Office of Special Nutritionals

Division of Programs and Enforcement

Policy.

Division of Science and Applied

Technology.

Office of Special Research Skills

Division of Toxicological Research.

Division of Microbiological Studies.

Office of Systems and Support

Quality Assurance Staff.

Office of Constituent Operations

Consumer Education Staff.

Legislative Activities Staff.

Industry Activities Staff.

International Activities Staff.

Office of Field Programs

Division of Enforcement.

Division of HACCP Programs.

Division of Cooperative Programs.

Division of Field Program Planning and

Evaluation.

Office of Management Systems

Division of Information Resources

Management.

Division of Planning and Resources

Management.

Office of Scientific Analysis and

Support

Division of Mathematics.

Division of General Scientific Support.

Division of Market Studies.

Center for Veterinary Medicine22

Office of the Center Director

Office of Management

Division of Program and Information

Systems.

Division of Program Communications

and Administrative Management.

Office of Surveillance and Compliance

Division of Compliance.

Division of Animal Feeds.

Division of Surveillance.

Division of Voluntary Compliance and

Hearings Development.

Office of New Animal Drug Evaluation

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Drugs.

Division of Chemistry.

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Animals.

Division of Therapeutic Drugs for NonFood Animals.

Division of Toxicology and

Environmental Sciences.

Office of Science

Division of Residue Chemistry.

Division of Animal Research.

3. Section 5.115 is revised to read as

follows:

§ 5.115 Field Structure.

NORTHEAST REGION

Regional Field Office: 850 Third Ave.,

Brooklyn, NY 11232.

Northeast Regional Laboratory: 850

Third Ave., Brooklyn, NY 11232.

New York District Office: 850 Third

Ave., Brooklyn, NY 11232.

New England District Office: One

Montvale Ave., Stoneham, MA 02180.

Buffalo District Office: 599 Delaware

Ave., Buffalo, NY 14202.

MID-ATLANTIC REGION

Regional Field Office: 900 U.S.

Customhouse, Second and Chestnut

Sts., Philadelphia, PA 19106.

Philadelphia District Office: 900 U.S.

Customhouse, Second and Chestnut

Sts., Philadelphia, PA 19106.

Baltimore District Office: 900 Madison

Ave., Baltimore, MD 21201.

Cincinnati District Office: 1141 Central

Pkwy., Cincinnati, OH 45202–1097.

New Jersey District Office: Waterview

Corporate Center, 10 Waterview Blvd.,

3d Floor, Parsippany, NJ 07054.

SOUTHEAST REGION

Regional Field Office: 60 Eighth St. NE.,

Atlanta, GA 30309.

Southeast Regional Laboratory: 60

Eighth St. NE., Atlanta, GA 30309.

Atlanta District Office: 60 Eighth St.

NE., Atlanta, GA 30309.

Nashville District Office: 297 Plus Park

Blvd., Nashville, TN 37217.

New Orleans District Office: 4298

Elysian Fields Ave., New Orleans, LA

70122.

Florida District Office: 7200 Lake

Ellenor Dr., suite 120, Orlando, FL

32809.

San Juan District Office: 466 Fernandez

Juncos Ave., San Juan, PR 00901–3223.

MIDWEST REGION

Regional Field Office: 20 North

Michigan Ave., rm. 550, Chicago, IL

60602.

Chicago District Office: 300 South

Riverside Plaza, suite 500, South

Chicago, IL 60606.

Detroit District Office: 1560 East

Jefferson Ave., Detroit, MI 48207.

Minneapolis District Office: 240

Hennepin Ave., Minneapolis, MN

55401.

SOUTHWEST REGION

Regional Field Office: 7920 Elmbrook

Dr., suite 102, Dallas, TX 75247–4982.

Dallas District Office: 3032 Bryan St.,

Dallas, TX 75204.

Denver District Office: Bldg. 20, Denver

Federal Center, Sixth and Kipling Sts.,

P.O. Box 20587, Denver, CO 80255–

0087.

Kansas City District Office: 11510 West

80th St., Lenexa, KS 66214–3340.

St. Louis Branch: 808 North Collins

Alley, St. Louis, MO 63102.

PACIFIC REGION

Regional Field Office: Oakland Federal

Office Bldg., suite 1180–N, 1301 Clay

St., Oakland, CA 94512–5217.

San Francisco District Office: 1431

Harbor Bay Pkwy., Alameda, CA 94502–

7070.

Los Angeles District Office: 19900

MacArthur Blvd., suite 300, Irvine, CA

92715–2445.

Seattle District Office: 22201 23d Dr.

SE., Bothell, WA 98201–4421.

Dated: May 1, 1996.

William K. Hubbard,

Associate Commissioner for Policy

Coordination.

[FR Doc. 96–12091 Filed 5–13–96; 8:45 am]

BILLING CODE 4160–01–F
Federal Register / Vol. 61, No. 94 / Tuesday, May 14, 1996 / Rules and Regulations 24227

21 CFR Parts 600 and 601

[Docket No. 95N–0411]

RIN 0910–AA71

Elimination of Establishment License

Application for Specified

Biotechnology and Specified Synthetic

Biological Products

AGENCY: Food and Drug Administration,

HHS.

ACTION: Final rule.

SUMMARY: The Food and Drug

Administration (FDA) is amending the

biologics regulations to eliminate the

establishment license application (ELA)

requirement for certain biotechnology

and synthetic biological products

subject to licensing under the Public

Health Service Act (PHS Act). This final

rule also exempts these biotechnology

and synthetic biological products from

certain biologics regulations and

harmonizes the requirements applicable

to these products with those applicable

to similar drug products which are

approved under the Federal Food, Drug,

and Cosmetic Act (the act). This final

rule is part of FDA’s continuing effort to

achieve the objectives of the President’s

‘‘Reinventing Government’’ initiatives,

and it is intended to reduce unnecessary

burdens for industry without

diminishing public health protection.

EFFECTIVE DATE: May 24, 1996.

FOR FURTHER INFORMATION CONTACT:

Sharon A. Carayiannis, Center for

Biologics Evaluation and Research

(HFM–630), Food and Drug

Administration, 1401 Rockville Pike,

suite 400S, Rockville, MD 20852–1448,

301–594–3074.

SUPPLEMENTARY INFORMATION:

I. Background

In the Federal Register of January 29,

1996, FDA proposed to amend the

biologics regulations to eliminate the

ELA requirement for well-characterized

biotechnology products licensed under

the PHS Act. In that document, FDA

proposed to use the general phrase

‘‘well-characterized biotechnology

product,’’ to describe products that

would be eligible for a single license

application so that the regulatory

language would accommodate

categories of products that might later

be considered to be well-characterized

as scientific knowledge progresses. FDA

requested specific comments on

whether a definition of a wellcharacterized biotechnology product

should be included in the regulations

and, if so, what the scope of such a

definition should be.

The agency noted that technical

advances over the last 15 years have

greatly increased the ability of

manufacturers to control and analyze

the manufacture of many biotechnologyderived biological products. After over a

decade of experience with these

products, the agency has found that it

can review the safety, purity, potency,

and effectiveness of most wellcharacterized biotechnology products

without requiring submission of a

separate ELA. Accordingly, FDA

proposed procedures under which

CBER would approve most wellcharacterized biotechnology products by

requiring a single biologics license

application. FDA noted that the

proposed procedures would

significantly reduce burdens without

reducing the safety or effectiveness of

these products.

In the Federal Register of December 8,

1995 (60 FR 63048), the agency first

published an interim definition of a

well-characterized therapeutic

recombinant DNA-derived and

monoclonal antibody biotechnology

product and announced that, under

§ 610.2, the Director of CBER was no

longer requiring that manufacturers of

these products submit samples and

protocols to CBER for lot-by-lot release.

While the interim definition was

intended to be used as a basis for

determining which products would be

exempted from CBER lot-by-lot release,

FDA also used the interim definition to

prepare draft guidance on reporting

post-approval changes for biotechnology

products (as published in the Federal

Register of January 29, 1996 (61 FR 2739

at 2748), ‘‘Draft Guidance; Changes to

An Approved Application for WellCharacterized Therapeutic Recombinant

DNA-Derived and Monoclonal Antibody

Biotechnology Products’’.)

In addition, FDA held a scientific

workshop on December 11 through 13,

1995, to discuss the characterization of

therapeutic recombinant DNA-derived

and monoclonal antibody products,

including whether FDA’s interim

definition should be changed or

expanded to include other categories of

products that would be considered wellcharacterized.

After considering the public

comments received on the interim

definition, the discussion at the

workshop, and the many requests the

agency has received for further

clarification of the term ‘‘wellcharacterized,’’ FDA has determined

that it may not be possible to achieve a

sufficiently clear and specific

understanding of this term to adequately

apprise potential applicants of the

applicability of the new procedures.

Accordingly, in this final rule, FDA is

specifying, in lieu of the term ‘‘well

characterized biotechnology product,’’

the categories of products to which this

final rule will be applicable (see

comment Nos. 1 and 6).

FDA intends to evaluate the

application of lot-by-lot release for

additional products and to announce in

the Federal Register a revised

determination of which products will be

exempted from lot-by-lot release. FDA

also plans to issue guidance on the

characterization of product categories

specified in this rule. FDA anticipates

that these documents will replace the

notice published in the Federal Register

of December 8, 1995 (60 FR 63048).

This final rule is part of FDA’s

continuing effort to achieve the

objectives of the President’s

‘‘Reinventing Government’’ initiatives.

One goal of these initiatives is to

harmonize regulations administered by

FDA’s Center for Biologics Evaluation

and Research (CBER) and Center for

Drug Evaluation and Research (CDER),

to reduce unnecessary burdens for

industry without diminishing public

health protection.

II. Proposed Rule

In the January 29, 1996, proposed

rule, FDA proposed to amend § 601.2(a)

and to add a new paragraph (c) to create

a licensing scheme for wellcharacterized biotechnology products

that differs from the current licensing

scheme for biological products in four

fundamental ways. First, an applicant

seeking marketing approval for a

product that falls within the scope of

the rule would submit a single biologics

license application to CBER and would

be issued a single license. Second, for

these products, many of the

establishment and product standards set

forth in parts 600 through 680 (21 CFR

parts 600 through 680) would not be

applied. The current good

manufacturing practice (CGMP)

regulations found at parts 210 and 211

(21 CFR parts 210 and 211), in addition

to the information included in a

chemistry, manufacturing, and controls

(CMC) section of the biologics license

application, would constitute the bulk

of the applicable establishment

standards for these products. Third, in

lieu of reviewing an ELA, FDA proposed

to evaluate whether establishment

standards had been met by reviewing

information submitted in the biologics

license application and by inspecting

the facilities in which the product is

manufactured for compliance with

applicable requirements, including

CGMP’s. Fourth, FDA proposed to

amend § 600.3(t) to broaden the term
24228 Federal Register / Vol. 61, No. 94 / Tuesday, May 14, 1996 / Rules and Regulations

‘‘manufacturer’’ as it is used in parts 600

through 680 to include an applicant for

a license for a well-characterized

biotechnology product who may or may

not own the facilities engaged in

significant manufacturing steps. This

amendment would allow a single

license applicant to take responsibility

for compliance with the requirements in

parts 600 through 680 applicable to

manufacturers and would eliminate the

requirement that each contract facility

engaged in significant manufacturing

obtain its own license. Instead, each

well-characterized biotechnology

product could be covered by a single

biologics license application, which

lists all manufacturing locations,

regardless of how many separate

companies are involved in its

manufacture. In addition, FDA

requested comments on whether the

definition of ‘‘manufacturer’’in

§ 600.3(t) should also be expanded to

include license applicants for products

other than well-characterized

biotechnology products.

III. Responses to Letters of Comment

FDA allowed 30 days for comment on

the proposal of January 29, 1996.

Written comments received in response

to the proposal are on file in the Dockets

Management Branch (HFA–305), Food

and Drug Administration, 12420

Parklawn Dr., rm. 1–23, Rockville, MD

20857.

FDA received seven comments in

response to the proposed rule. The

comments, which addressed a number

of issues, were received from

manufacturers of biotechnology

products, a blood establishment, and a

biotechnology trade association.

Comments received and FDA’s

responses to the comments are

discussed below. All of the comments

supported the proposal, although many

comments contained suggestions or

requests for clarification. All of the

letters supported FDA’s efforts to

achieve the President’s ‘‘Reinventing

Government’’ initiatives and agreed that

the proposed changes will contribute to

the goal of reducing unnecessary

burdens for industry and the agency

without diminishing public health

protection.

1. Two comments requested that FDA

define well-characterized products in

the final rule to clearly identify those

entities subject to the rule and to allow

for public comment and administrative

review. However, one of these

comments also suggested that FDA

publish a companion guidance

document, updated as necessary, to

provide interpretation of this definition

based on current technology and

scientific knowledge. Two comments

requested that a definition be included

in a guideline rather than the regulation

so that it can be readily revised as the

technology advances. One comment

stated that the proposal left uncertainty

as to which products would be eligible

for the single license application.

In response to comments received,

FDA has revised its proposed

administrative approach and is

specifying, in § 601.2(a) and new

paragraph (c), the categories of products

subject to the rule. FDA has decided to

list the product categories in the

regulation in order to minimize

uncertainty about which products are

eligible for the new procedures.

2. Five comments suggested that

products in addition to those identified

in FDA’s interim definition of a wellcharacterized therapeutic recombinant

deoxyribonucleic acid (DNA) derived

and monoclonal antibody biotechnology

product could be considered wellcharacterized and requested that FDA

broaden the scope of the proposed rule

to include additional product categories.

Particular categories suggested by one or

more comments include: Proteins,

including those isolated from natural

sources; products (including vaccines

and in vitro diagnostics) made using

synthetic peptides, recombinant DNA

technology and monoclonal antibody

technology; products made using

chemical synthesis; DNA plasmid

products; highly purified and

inactivated vaccines; polysaccharides;

and any other biologic product for

which the applicant submits data from

studies that demonstrate that the

manufactured product meets prescribed

standards of safety, purity, and potency.

One comment suggested that in vitro

diagnostic products using biotechnology

components should not be treated

differently than well-characterized

biotechnology drugs. One comment

requested that FDA specify that blood,

blood components (including plasma

and stem cells), and plasma derivatives

(where the raw material is human

based) are products which should not be

included.

FDA agrees that the elimination of the

ELA requirement should apply to

product categories beyond those

originally identified in the agency’s

interim definition of a wellcharacterized therapeutic recombinant

DNA-derived and monoclonal antibody

biotechnology product. FDA is

expanding the scope of this final rule to

include additional products, based on

the technology of the manufacturing

process and the proposed use of the

products. At this time, FDA has

determined that it has sufficient

experience in reviewing investigational

and product applications to eliminate

the ELA requirements for the following

categories of products: Therapeutic

DNA plasmid products; therapeutic

synthetic peptide products of 40 or

fewer amino acids; monoclonal

antibody products for in vivo use; and

therapeutic recombinant DNA-derived

products. Methodologies are now

available to characterize these products

in a much more rigorous fashion,

allowing the products to be more clearly

evaluated by end product testing. FDA

believes that eliminating the submission

for the facility and establishment

information will not adversely affect the

public health.

FDA disagrees that vaccines and in

vitro diagnostic (IVD) products should

be included within the scope of this rule

at this time because these products raise

additional concerns in assessing safety,

purity, and potency. For vaccines, safety

is a critical concern due to the intended

use in a healthy population. For IVD

products, FDA believes that the product

and establishment standards necessary

to ensure continued safety, purity, and

potency may differ from those

applicable to products included in this

rule.

FDA agrees that blood and blood

components, including plasma, plasma

derivatives, and stem cells, are products

which should not fall within the scope

of this rule. FDA believes that license

applications for these and other

naturally derived products should

continue to include establishment

information at this time. FDA believes

that a license application that includes

detailed information on the facilities

and controls may be necessary to assess

the continued safety, purity, and

potency of these products. Because

these products involve complex issues,

such as a risk of contamination with

infectious agents, their review requires

special expertise and adequate time in

order to assess the adequacy of controls

in place at the facility. In addition, end

product testing of naturally derived

products may not be sufficient to detect

contamination with infectious agents.

FDA intends to continue to assess the

need to expand the scope of the rule to

include additional categories of

products as science and technology

advance and as the agency gains

experience in regulating biological

products under this new scheme.

3. One comment suggested that the

use of a single biologics application be

applied to all biologic products.

Another comment suggested that IVD

products be eligible for the single

license application.
Federal Register / Vol. 61, No. 94 / Tuesday, May 14, 1996 / Rules and Regulations 24229

As outlined in the President’s

November, 1995, National Performance

Review, ‘‘Reinventing the Regulation of

Drugs Made From Biotechnology,’’ FDA

will use a standardized, single

application form for all biological and

drug product approvals, regardless of

which Center regulates them. FDA will

make the harmonized form available for

public comment through a subsequent

rulemaking and will develop guidance

to assist applicants in completing the

new application form when it is

available.

4. One comment suggested that FDA

develop a guideline delineating the

responsibilities of center and field

inspection personnel to avoid

confusion. One comment suggested that

FDA application reviewers participate

in facility inspections to provide

continuity.

FDA recognizes that close cooperation

between center and field is essential to

the success of this approach. CBER and

the field offices intend to coordinate

pre- and post-licensure inspections to

provide consistency in program and

policy approaches. In addition, FDA

plans to develop guidance on facility

standards for biotechnology

manufacturing facilities to clarify

regulatory requirements and FDA

policy.

5. One comment requested that

companies have the option to submit

descriptions of systems design,

equipment validation, etc., for FDA

review and comment prior to the time

of inspection because it would be

advantageous to both industry and FDA.

FDA agrees that the submission of

facility information, such as systems

design, and early dialogue is

advantageous to both industry and FDA.

Accordingly, the agency intends to

continue to review this information,

when requested, and provide comments

early in the development process, prior

to and after the submission of the

license application. Companies should

contact the Division of Establishment

Licensing, CBER, to arrange such

reviews.

6. One comment stated that the use of

an interim definition of products that

would be eligible for single license

application under § 601.2(c) creates the

possibility that FDA might refuse to file

a biologics license application for a

product that the applicant believes is

well-characterized, even though the

application might include sufficient

data to demonstrate that the product

meets prescribed standards for safety,

purity, and potency. Another comment

suggested that the determination as to

whether a product is well-characterized

should be made during the Phase 2

clinical trials or as early in the process

as is practical.

As discussed above in the response to

comment No. 1 of this document, FDA

has decided to clearly identify, by

category, those products subject to the

rule, and thereby reduce uncertainty as

to whether a product falls within the

scope of the rule. This clear

identification of products should also

eliminate the concerns regarding a

refusal to file action and the need to

provide sufficient data to support an

applicant’s claim that its product is

‘‘well-characterized.’’ Applicants

seeking licensure of a product that falls

within a category listed in 601.2(c) will

not be required to make an initial

showing that the product is ‘‘wellcharacterized’’ to use the new

procedures. Companies may seek

guidance from FDA at any time on the

type of application that should be

submitted, and FDA encourages early

communication.

7. One comment agreed with FDA’s

proposal to exempt well-characterized

products from § 610.62, which sets out

requirements for position and

prominence of the proper name of the

product on the package label. The

comment suggested that this labeling

change should be voluntary for

currently licensed products, that

companies should be allowed to phase

in changes over a 24 month time period,

and that preapproval should not be

required.

The comment may have

misunderstood the applicability of

§ 201.10(g) (21 CFR 201.10(g)). Section

201.10(g) applies to biological products

licensed under section 351 of the PHS

Act, as well as to drugs approved under

the act. Accordingly, labels that comply

with preexisting requirements should

not require revisions to comply with the

requirements in this final rule.

8. One comment suggested that

manufacturers submitting a biologics

license application should be permitted

to cross-reference information already

supplied in an approved ELA.

FDA agrees that avoiding unnecessary

duplication of information in

applications is desirable. FDA will

permit a biologics license applicant to

cross-reference information already

submitted in an approved ELA at this

time. However, the agency may reassess

the viability of this approach in the

future. Should the information in the

approved ELA become outdated, crossreference may no longer be appropriate.

9. One comment agreed with FDA’s

proposed revision of the definition of

‘‘manufacturer’’ in § 600.3(t). Three

comments requested that FDA apply an

expanded definition of ‘‘manufacturer’’

to all biologic license applicants and not

limit application of this definition

exclusively to well-characterized

products. One of the comments favoring

a broader definition suggested the

following language for § 600.3(t):

‘‘Manufacturer’’ means any legal person

or entity engaged in the manufacture of

a product subject to license under the

act; ‘‘Manufacturer’’ also includes an

applicant for a license for a product, or

a license holder, who is responsible for

assuring that the product and

establishment standards are met.

FDA agrees with the comments

requesting the broader definition of

‘‘manufacturer’’ and is revising

§ 600.3(t) to include any license

applicant who assumes responsibility

for compliance with the applicable

product and establishment standards in

parts 600 through 680. FDA believes

that this change will facilitate contract

manufacturing arrangements for all

biological products by allowing an

applicant who does not own all the

facilities where significant

manufacturing is performed to apply for

licensure. The revised § 600.3(t) will

define ‘‘manufacturer’’ as the term is

used in parts 600 through 680. Contract

firms engaged in the manufacture,

processing, packing, or holding of a

biological drug will continue to be

subject to applicable CGMP

requirements and the amendment to

§ 600.3(t) will not affect other

definitions of ‘‘manufacturer’’ contained

in other applicable statutes and

regulations. FDA intends to revise

current guidance on contract

manufacturing arrangements for

applicants interested in pursuing such

arrangements under the new definition.

10. One comment requested that

§ 610.63, which addresses package label

and container label requirements for

products manufactured under an

arrangement involving two or more

establishments, be exempted from

applicability to well-characterized

biotechnology products because such

products would involve a single license

holder. The comment suggested that it

would be unnecessary to require that

the labeling show the names of multiple

participating manufacturers.

The agency does not agree that

§ 610.63 should be exempted from

applicability to the products covered in

this rule. Divided or shared

manufacturing arrangements could still

exist between holders of biologics

licenses for products subject to this rule

if this was an arrangement the

companies desired, and in these cases

§ 610.63 would apply.

However, FDA agrees that it is

unnecessary to identify contract
24230 Federal Register / Vol. 61, No. 94 / Tuesday, May 14, 1996 / Rules and Regulations

manufacturers on the package label and

container label of a biological product

subject to this final rule. FDA has

applied § 610.63 to require label

identification of licensed manufacturers

only. As discussed below, FDA intends

to consider the need for revisions to

§ 610.63 in separate rulemaking. FDA

also intends to revise the November 25,

1992, Policy Statement Concerning

Cooperative Manufacturing

Arrangements for Licensed Biological

Products to address contract, divided,

and shared manufacturing arrangements

under the new regulatory scheme.

11. One comment suggested that

§§ 610.60, 610.61, 610.63, 610.64, and

610.65 be eliminated for all biologic

products and be replaced by labeling

requirements described in part 201 (21

CFR part 201), subpart A.

FDA agrees that harmonizing the

labeling requirements for biologics and

drugs approved under the act, where

appropriate, is desirable. It is important

to note that biologic products are

already subject to most provisions in

subpart A of part 201. FDA is

considering revising the labeling

requirements in §§ 610.60 through

610.65 as part of the agency’s

comprehensive review and rewrite of

the general biologics regulations.

12. One comment stated that

§ 600.10(a), which describes the

requirements for an establishments to

designate a ‘‘responsible head,’’ should

not apply to well-characterized products

as currently written.

FDA agrees that § 600.10(a), as

currently written, imposes unnecessary

burdens for many modern biological

manufacturers and has made a

commitment to publish a proposed rule

to revise this regulation within 9

months of the publication of the

President’s November, 1995, National

Performance Review, ‘‘Reinventing the

Regulation of Drugs Made From

Biotechnology.’’ FDA intends to revise

the requirements to allow more

flexibility to assign control and

oversight responsibility within a

company.

13. One comment requested that

§ 600.22(g), which authorizes inspectors

to inspect and copy, as circumstances

may require, any records to be kept

under to § 600.12, be amended because

§ 600.12 will not apply to wellcharacterized biotechnology products

under this rule.

The agency believes that it is not

necessary to amend § 600.22(g) because

the CGMP requirements in parts 210

and 211 that apply to products subject

to this rule include recordkeeping

requirements and state that records are

subject to photocopying as part of an

FDA inspection (see § 211.180(b)).

14. One comment requested

clarification of § 601.3(b), which

describes the information required on

the product license form. One comment

requested that FDA eliminate the

requirement for an establishment

license number in the product license

application (PLA) for well-characterized

products because a contract

manufacturing site engaged in

multiproduct manufacture for different

manufacturers may produce several

licensed products. The comment stated

that the establishment number would

not be meaningful under such

circumstances.

FDA believes that it is unnecessary to

include an exemption for § 601.3(b)(4)

in this rule. Elsewhere in this issue of

the Federal Register, FDA is

announcing the availability of an

interim form, FDA 3439, which contains

a section in which all locations

performing manufacturing or testing of

the product are to be identified. If a

location has a license number, that

number should be included as part of

that identification, as should the

location’s registration number. If there is

no license number for the location, it

cannot be included, as is currently the

case for a new establishment filing its

first PLA and ELA.

15. One comment requested that

§ 601.22, which permits initial and

partial manufacturing of products in

short supply at other than a licensed

establishment, be amended to include a

statement clarifying the relevant

referenced regulations when § 601.22 is

applied to well-characterized products.

FDA agrees and is making conforming

amendments to § 601.22 to specify that

persons conducting the initial and

partial manufacturing of a product that

is subject to this rule shall be subject to

all regulations of subchapter F except

§§ 601.1 to 601.6, 601.9, 601.10, 601.20,

601.21; 601.30 to 601.33; 610.60 to

610.65, 600.10(b) and (c), 600.11,

600.12, 600.13, 610.11, and 610.53.

16. One comment stated that § 601.45,

which requires, for certain products,

submission of promotional materials to

the agency, should not apply to wellcharacterized biotechnology products.

The comment suggested that the

proposed rule under which promotional

labeling materials would not have to be

submitted for agency consideration

within 120 days following marketing

approval be applied to wellcharacterized products. The comment

also suggested that submission of

advertisements and promotional

labeling be regulated under

§ 314.81(b)(3)(i) (21 CFR 314.81(b)(3)(i)).

The comment may have

misunderstood the applicability of

§ 601.45. Section 601.45 applies solely

to biological products subject to subpart

E, Accelerated Approval of Biological

Products for Serious or Life Threatening

Illnesses. For biological products not

subject to subpart E, FDA has proposed

to revise requirements for submission of

advertisements and promotional

labeling to CBER to reflect procedures

found in § 314.81(b)(3)(i), in the

proposal of January 29, 1996 (61 FR

2733 at 2739).

17. One comment requested that

§ 610.9, which permits manufacturers,

under certain conditions, to modify a

particular test method or manufacturing

process, be exempted from applicability

to well-characterized biotechnology

products. The comment also suggested

that this regulation be eliminated as part

of the proposed revisions to § 601.12,

published in the Federal Register (61

FR 2739).

FDA disagrees with the comment. The

comment may have misunderstood

§ 610.9. This regulation allows

manufacturers the flexibility to modify

methods or processes specified in

regulations, if the modification can be

shown to provide equivalent assurance

of safety, purity, potency, and

effectiveness. Because this regulation

adds flexibility without compromising

the safety, purity, potency, or

effectiveness of biological products,

FDA believes that it should apply to all

biological products.

18. One comment suggested that a

broad interpretation of § 610.15, which

describes the requirements for use of

constituent materials, may require

development of sophisticated

purification methods to reduce the level

of ‘‘contaminating’’ immunoglobulins to

the one part per million level if applied

to cell culture products such as

monoclonal antibodies. The comment

suggested that § 610.15 be amended to

be applicable only to vaccine products

and products intended to be antigenic.

Section 610.15(b) applies by its terms

to cell culture-produced vaccines

intended for injection. For guidance on

the use of a serum in the medium for

production of monoclonal antibodies,

consult the Draft ‘‘Points to Consider in

the Manufacture and Testing of

Monoclonal Antibody Products for

Human Use,’’ announced in the Federal

Register of August 3, 1994 (59 FR

39571).

19. One comment suggested that

§ 600.81 (the comment references

‘‘§ 601.81,’’ but the subject is consistent

with § 600.81), which describes the

requirements for product distribution

reports, is duplicative, provides no
Federal Register / Vol. 61, No. 94 / Tuesday, May 14, 1996 / Rules and Regulations 24231

value to the manufacturer or to FDA in

ensuring the public health, and should

be eliminated. The comment requested

that distribution information for wellcharacterized biotechnology products be

regulated under § 314.81(b)(2)(ii).

FDA disagrees with this comment.

Section 600.81 differs from

§ 314.81(b)(2)(ii) in that § 600.81

requires submission of product

distribution reports every 6 months;

requires information on bulk lot

number, fill lot number and label lot

number; states that FDA may require

more detailed information, as needed;

and states that FDA may require, on

written notice, submission of reports at

times other than those stated in the

regulation. FDA believes that the

requirements in § 600.81 assist the

agency in determining adverse reaction

rates for vaccines and other biological

products, and are of use in monitoring

product safety. It should be noted that

§ 600.90 permits a licensed

manufacturer to apply to FDA for a

waiver from any of the requirements of

§ 600.81.

20. Several comments addressed

issues beyond the scope of this

rulemaking. Comments included issues

related to reporting of errors and

accidents (§ 600.14), lot release,

methods for evaluating product

characteristics, and establishing product

specifications.

Revisions to § 600.14 Reporting of

errors and other biologics regulations

are currently under consideration and

are outside the scope of this rulemaking.

However, FDA will consider all

comments received as a part of the

agency’s comprehensive rewrite of the

general biologics regulations.

IV. Summary of Changes for the Final

Rule

In response to comments received,

FDA is making the following changes in

this final rule:

In lieu of the term ‘‘well-characterized

biotechnology product,’’ FDA is specifying,

in § 601.2(a) (21 CFR 601.2(a)) and new

paragraph (c), the categories of products to

which the rule will be applicable, including

therapeutic DNA plasmid products;

therapeutic synthetic peptide products of 40

or fewer amino acids; monoclonal antibody

products for in vivo use; and therapeutic

recombinant DNA-derived products. The

definition of manufacturer has been modified

to include an applicant for a license for any

biological product where the applicant

assumes responsibility for compliance with

the applicable product and establishment

standards. The final rule also sets forth an

amendment to 21 CFR 601.22 clarifying that

section’s applicability to the categories of

products specified in new § 601.2(c).

V. Implementation Issues

Any therapeutic DNA plasmid

product, therapeutic synthetic peptide

product of 40 or fewer amino acids,

monoclonal antibody product for in

vivo use, and therapeutic recombinant

DNA-derived product for which a PLA

and an ELA are pending on the effective

date of these regulations, will be

reviewed as submitted. No new

submission will be necessary to

implement this rule change for these

products. If found acceptable for

licensure, FDA will issue a biologics

license in lieu of issuing both a product

and establishment license.

Applicants already holding an

approved ELA and PLA for a product

within the scope of this rule will not be

required to file supplements to comply

with the new requirements. The

approved PLA for the product, together

with the limited portions of the

approved ELA relevant to the new

requirements for the biologics license

application, will be deemed to

constitute an approved biologics license

application under the new regulations.

The agency recognizes that there are

a variety of contractual arrangements

that could be affected by this rule. For

example, an innovator company may

have contracted with another company

to make a product. Under the previous

regulatory scheme, a contract

manufacturer could hold both the

establishment license and the product

license. Under the new regulatory

scheme, an innovator company may

wish to hold the license. FDA

anticipates that firms desiring an

arrangement where the innovator holds

the license could surrender the original

licenses to the agency and request

reissuance of a new biological license to

the innovator under the provisions of

this final rule. FDA urges license

holders or those wishing to change their

licensing arrangements to contact the

agency for additional guidance on how

this can be accomplished.

VI. Effective Date

The final rule is effective May 24,

1996. As provided under 5 U.S.C. 553(d)

and 21 CFR 10.40(c)(4), the effective

date of a final rule may not be less than

30 days after publication, except for,

among other things, ‘‘a regulation that

grants an exemption or relieves a

restriction’’ (§ 10.40(c)(4)(i)). Because, as

described below, this rule will decrease

the regulatory burdens for specified

biotechnology and synthetic biological

products, FDA believes that an

immediate effective date is appropriate.

VII. Analysis of Impacts

A. Reduction in Burden

The harmonization of the

requirements will reduce burden on

industry because companies

manufacturing specified biotechnology

and synthetic products that are

regulated by both CBER and CDER will

be able to submit applications for

products in a consistent format.

Companies developing and

manufacturing products within the

scope of this rule will no longer have to

prepare an ELA to submit to the agency

for approval. The amount of information

that applicants will need to provide in

a biologics license application will be

less than that currently required in a

PLA and ELA. These changes will

enable companies to devote more

resources to ensuring that

manufacturing processes are properly

validated and fewer resources to

submitting documentation to the

agency. These changes will especially

benefit biotechnology companies that

lack experience preparing ELA’s and

PLA’s. According to the biotechnology

industry, preparation and submission of

an ELA may add substantially to the

cost of obtaining approval of a

biotechnology product.

The inclusion of parts 210 and 211 in

this final rule as establishment

standards will not impose any

additional burden on industry. Human

drugs, including products subject to this

rule, are already subject to the CGMP’s

in parts 210 and 211.

B. Review Under Executive Order 12866

and the Regulatory Flexibility Act

FDA has examined the impact of the

final rule under Executive Order 12866

and the Regulatory Flexibility Act (Pub.

L. 96–354). 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 final rule is consistent

with the regulatory philosophy and

principles identified in the Executive

Order. In addition, the final rule is a

significant regulatory action as defined

by the Executive Order and is subject to

review under the Executive Order

because it deals with a novel policy

issue.

In accordance with the principles of

Executive Order 12866, the overall

result of the final rule will be a

substantial reduction in burdens on
24232 Federal Register / Vol. 61, No. 94 / Tuesday, May 14, 1996 / Rules and Regulations

applicants filing for approval of a

product subject to this rule. In addition,

FDA anticipates that the final rule will

facilitate applicants’ ability to improve

their licensed products and methods of

manufacture by decreasing the burden

and cost associated with filing an

application.

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 above, the

overall result of the final rule will be a

substantial reduction of the regulatory

and reporting burdens, the agency

certifies that the final rule will 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.

C. Review Under the Paperwork

Reduction Act of 1995

This final rule contains information

collection requirements that were

submitted for review and approval to

the Director of the Office of

Management and Budget (OMB) as

required by section 3504(b) of the

Paperwork Reduction Act of 1995. As

part of this review, FDA provided

individuals and organizations an

opportunity to comment to OMB on the

information collection requirements in

the proposed rule. All comments

received agreed that FDA’s proposal to

eliminate the ELA requirements for

certain biotechnology products would

reduce the burden to industry without

diminishing the public health

protection. As a result of information

provided, FDA has revised the number

of estimated applicants yearly from 1 to

15. The estimate for completing the

application has not changed, however.

This number remains at 40. These

information collection requirements

were approved and assigned OMB

control number OMB No. 0910–0316.

The expiration date for this approval is

December 31, 1997. An agency may not

conduct or sponsor, and a person is not

required to respond to, a collection of

information unless it displays a

currently valid OMB control number.

The title, description and respondent

description of the information collection

are shown below with an estimate of the

annual reporting burden. Included in

the estimate is the time for reviewing

instructions, gathering and maintaining

the data needed, and completing and

reviewing the collection of information.

Title: Elimination of Establishment

License Application for Specified

Biotechnology and Synthetic Biological

Products.

Description: FDA is eliminating the

requirement that an ELA be submitted

and approved by FDA for specified

biotechnology and synthetic biological

products that are licensed by CBER. For

these products, in place of the ELA, a

company would be required to prepare

and submit additional information for

inclusion in a single biologics license

application, which will be the same as

the information included in the

‘‘Chemistry, manufacturing, and

controls’’ (CMC) section of a new drug

application. This regulation will

harmonize the approval and other

regulatory requirements applicable to

specified biotechnology and synthetic

biological products licensed under the

PHS Act and drugs approved under the

new drug provisions of the act.

Description of Respondents: All

applicants for a biological product

license to be approved under the Public

Health Service Act.

Estimated Annual Reporting Burden

CFR Section Number of

Respondents

Frequency of

Responses

Total Annual

Responses

Hours per

Response Total Hours

601.2(c) 15 1 15 40 600

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

Reporting or Disclosure: These

estimates are an approximation of the

average time expected to be necessary

for the collection of information. They

are based on such information as is

available to FDA.

D. Environmental Impact

The agency has determined under 21

CFR 25.24(a)(8) 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.

List of Subjects

21 CFR Part 600

Biologics, Reporting and

recordkeeping requirements.

21 CFR Part 601

Administrative practice and

procedure, Biologics, Confidential

business information.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and the Public

Health Service Act, and under authority

delegated to the Commissioner of Food

and Drugs, 21 CFR parts 600 and 601 are

amended as follows:

PART 600—BIOLOGICAL PRODUCTS:

GENERAL

1. The authority citation for 21 CFR

part 600 continues to read as follows:

Authority: Secs. 201, 501, 502, 503, 505,

510, 519, 701, 704 of the Federal Food, Drug,

and Cosmetic Act (21 U.S.C. 321, 351, 352,

353, 355, 360, 360i, 371, 374); secs. 215, 351,

352, 353, 361, 2125 of the Public Health

Service Act (42 U.S.C. 216, 262, 263, 263a,

264, 300aa–25).

2. Section 600.3 is amended by

revising paragraph (t) to read as follows:

§ 600.3 Definitions.

* * * * *

(t) Manufacturer means any legal

person or entity engaged in the

manufacture of a product subject to

license under the act; ‘‘Manufacturer’’

also includes any legal person or entity

who is an applicant for a license where

the applicant assumes responsibility for

compliance with the applicable product

and establishment standards.

* * * * *

PART 601—LICENSING

3. The authority citation for 21 CFR

part 601 continues to read as follows:

Authority: Secs. 201, 501, 502, 503, 505,

510, 513–516, 518–520, 701, 704, 721, 801 of

the Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 351, 352, 353, 355, 360, 360c–

360f, 360h–360j, 371, 374, 379e, 381); secs.

215, 301, 351, 352 of the Public Health

Service Act (42 U.S.C. 216, 241, 262, 263);

secs. 2–12 of the Fair Packaging and Labeling

Act (15 U.S.C. 1451–1461).

4. Section 601.2 is amended by

designating the text of paragraph (a) as

introductory text of (a) and by adding a

clause at the end of the introductory

text, new paragraphs (a)(1) through

(a)(4), and (c) to read as follows:

§ 601.2 Applications for establishment,

product, and biologics licenses; procedures

for filing.

(a) * * * In lieu of the procedures

described in this paragraph,

applications for the following specified
Federal Register / Vol. 61, No. 94 / Tuesday, May 14, 1996 / Rules and Regulations 24233

categories of products 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.

* * * * *

(c)(1) To obtain marketing approval

for 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 to

the Director, Center for Biologics

Evaluation and Research, a biologics

license application on a form prescribed

by the Director, Center for Biologics

Evaluation and Research. For such

products, a separate establishment

license application shall not be

required. An application for a license

for such a product shall include:

(i) Data derived from nonclinical

laboratory and clinical studies that

demonstrate that the manufactured

product meets prescribed standards 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,

(ii) If the study was not conducted in

compliance with such regulations, a

brief statement of the reason for the

noncompliance;

(iii) 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 of this chapter, and

was conducted in compliance with

requirements for informed consent set

forth in part 50 of this chapter;

(iv) A full description of

manufacturing methods;

(v) Data establishing stability of the

product through the dating period;

(vi) Sample(s) representative of the

product to be sold, bartered, or

exchanged or offered, sent, carried or

brought for sale, barter, or exchange;

(vii) Summaries of results of tests

performed on the lot(s) represented by

the submitted samples; and

(viii) Specimens of the labels,

enclosures, and containers proposed to

be used for the product.

(2) An application for license shall

not be considered as filed until all

pertinent information and data have

been received from the applicant by the

Center for Biologics Evaluation and

Research. The applicant shall also

include either a claim for categorical

exclusion under § 25.24 of this chapter

or an environmental assessment under

§ 25.31 of this chapter.

(3) Approval of the biologics license

application and issuance of the

biologics license shall constitute a

determination that the establishment

and the product meet applicable

standards established in this chapter to

ensure the continued safety, purity, and

potency of such products. Applicable

standards for the maintenance of

establishments for the manufacture of a

product subject to this paragraph (c)

shall include the good manufacturing

practice requirements set forth in parts

210 and 211 of this chapter. 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, 601.1, 601.30, 601.31, 601.32,

610.11, 610.53, and 610.62 of this

chapter.

(4) The term ‘‘product license

application,’’ as it is used in those

sections of parts 600 through 680 of this

chapter that are applicable to products

subject to this paragraph (c) shall

include a biologics license application

for 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.

(5) To the extent that the requirements

in this paragraph (c) conflict with other

requirements in this subchapter, this

paragraph (c) shall supersede such other

requirements.

5. Section 601.22 is amended by

adding a sentence after the second

sentence to read as follows:

§ 601.22 Products in short supply; initial

manufacturing at other than licensed

establishment.

* * *For persons and places authorized

under this section to conduct the initial

and partial manufacturing of a product

for shipment solely to a manufacturer of

a product subject to licensure under

§ 601.2(c), the following additional

regulations shall not be applicable:

§§ 600.10(b) and (c), 600.11, 600.12,

600.13, 610.11, and 610.53 of this

chapter * * *.

Dated: May 6, 1996.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 96–12144 Filed 5–10–96; 10:13 am]

BILLING CODE 4160–01–F

DEPARTMENT OF TRANSPORTATION

Office of the Secretary

Coast Guard

33 CFR Part 52

[OST Docket No. OST–95–878]

RIN 2105–AC31

Coast Guard Board for Correction of

Military Records; Procedural

Regulation

AGENCY: Office of the Secretary, Coast

Guard, DOT.

ACTION: Final Rule.

SUMMARY: The Department is amending

its regulation with respect to

reconsideration of final decisions of the

Board for Correction of Military Records

of the Coast Guard (BCMR). This action

is taken on the Department’s initiative

in order to streamline processing of

these cases and to clarify the

circumstances under which final

decisions can be reconsidered. The

amendment will make it possible for the

BCMR to expedite the processing of

reconsideration requests and it will

increase the resources available to meet

the requirement that all cases be

decided within 10 months of the receipt

of a completed application.

EFFECTIVE DATE: June 13, 1996.

FOR FURTHER INFORMATION CONTACT:

Robert H. Joost, Chairman, Board for

Correction of Military Records of the

Coast Guard, C–60, Office of the General

Counsel, U.S. Department of

Transportation, 400 Seventh Street, SW,

Washington, D.C. 20590–0001.

Telephone: (202) 366–9335.

SUPPLEMENTARY INFORMATION:

Comments on Proposed Rulemaking

Proposed rulemaking was published

on pages 63489–63491 of the Federal

Register of December 11, 1995 [60 FR

63489], and invited comments for 60

days ending February 9, 1996.

Comments were received from the

following sources: (1) Eugene R. Fidell,

Esq., an attorney in private practice; and

(2) Michael J. Calabro, Esq., an attorney

in private practice. The comments and

the actions taken in response to the

comments are summarized below.

Both attorneys expressed concern

with respect to the amount of time that