Well-Characterized Biotechnology Products; Elimination of Establishment License Application

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 600 and 601

[Docket No. 95N-0411]

RIN 0910-AA68

Well-Characterized Biotechnology Products; Elimination of

Establishment License Application

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend

the biologics regulations to eliminate the establishment license

application (ELA) requirement for well-characterized biotechnology

products licensed under the Public Health Service Act (PHS Act). The

proposed rule would also exempt well-characterized biotechnology

products licensed under the PHS Act from certain biologics regulations

and harmonize 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 action 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.

DATES: Written comments on this proposed rule by February 28, 1996.

Submit written comments on the information collection requirements by

February 28, 1996, but not later than March 29, 1996. The agency

proposes that any final rule that may issue based on this proposal

become effective upon its date of publication in the Federal Register.

ADDRESSES: Submit written comments on this proposed rule 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 Information

and Regulatory Affairs, OMB, New Executive Office Bldg., 725 17th St.

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

FOR FURTHER INFORMATION CONTACT: Tracey H. Forfa, Center for Biologics

Evaluation and Research (HFM-630), Food and Drug Administration, 1401

Rockville Pike, suite 200N, Rockville, MD 20852-1448, 301-594-3074.

SUPPLEMENTARY INFORMATION

I. Background

In the Federal Register of December 8, 1995 (60 FR 63048), the

agency announced its interim definition of a well-characterized

therapeutic recombinant DNA-derived and monoclonal antibody

biotechnology product, as follows:

A chemical entity(ies) whose identity, purity, impurities,

potency, and quantity can be determined and controlled.

Identity:

a. Recombinant DNA Biotechnology Products

The primary structure is known (i.e., amino acid sequence), and

The secondary structure is known (e.g. disulfide linkage), and

Post-translational modifications are known (e.g.,

glycosylation), or

b. Monoclonal Antibodies

The identity can be determined by rigorous physicochemical and

immunochemical characterization without fully knowing its chemical

structure.

Purity and impurities:

The purity is quantifiable.

The impurities are quantifiable, and identified if feasible.

Potency and quantity:

The biological activity is measurable.

The quantity is measurable.

A well-characterized therapeutic recombinant DNA-derived and

monoclonal antibody product requires proper raw material controls,

process validation and controls, and sensitive and validated test

methods and specifications.

As announced in the Federal Register of October 25, 1995 (60 FR

54695), FDA held a scientific workshop on December 11, 12, and 13,

1995, to discuss the definition of a well-characterized therapeutic

recombinant DNA-derived and monoclonal antibody product and to identify

the information necessary to characterize such products. FDA intends to

consider information received at the workshop, as well as comments

received in response to this proposed rule, to determine whether the

definition previously given in this document should be expanded to

include other categories of products that would be considered to be

well-characterized, such as certain vaccines and biologic devices,

e.g., test kits for screening blood.

FDA is proposing to use the phrase ``well-characterized

biotechnology product,'' to describe the products that would be

eligible for a single license application so that the regulatory

language would accommodate such additional categories of products. FDA

has not included a definition of a well-characterized biotechnology

product in the proposed regulations because the agency intends to

clarify the definition in a guidance document that can be more readily

modified to reflect changes that may be warranted as scientific

knowledge progresses. FDA specifically invites public comment on

whether a definition of a well-characterized biotechnology product

should be included in the regulations and, if so, what the scope of

such a definition should be.

Well-characterized therapeutic recombinant DNA-derived and

monoclonal antibody products that are viruses, therapeutic sera,

toxins, antitoxins, vaccines, blood, blood components or derivatives,

allergenic products, or analogous products applicable to the

prevention, treatment, or cure of human diseases or injuries are

``biologics'' within the meaning of

[[Page 2734]]

section 351 of the PHS Act (42 U.S.C. 262). They are also ``drugs'' as

the term is defined in section 201(g) of the act (21 U.S.C. 321(g)).

Additional well-characterized biotechnology products identified in the

future may be ``devices'' as defined in section 201(h) of the act (21

U.S.C. 321(h)). Therefore, such products are subject to the provisions

of the act applicable to drugs and/or devices, including, but not

limited to, the adulteration and misbranding provisions (21 U.S.C. 351

and 352).

At the present time, these products are regulated by either FDA's

Center for Biologics Evaluation and Research (CBER) or Center for Drug

Evaluation and Research (CDER). CBER and CDER have entered into an

intercenter agreement announced in the Federal Register of November 21,

1991 (56 FR 58760), with respect to the regulation of drugs and

biological products. The intercenter agreement assigns jurisdiction to

CBER or CDER based on product class. A product class is defined as a

distinct category of agents recognizable by physical characteristics,

source materials, or pharmacologic properties. Examples of product

classes include: antibiotics, vaccines, hormones, and human blood

derivatives. Under the agreement, some well-characterized biotechnology

products, such as recombinant insulin and human growth hormone, are

assigned to CDER, while other similar recombinant products, such as

erythropoietin, colony stimulating factor, and interferon, are assigned

to CBER.

Currently, when approved under the PHS Act as biological products,

well-characterized biotechnology products are reviewed like any other

biologic; that is, both a product license application (PLA) and an ELA

are submitted to and approved by FDA before the well-characterized

biotechnology product may be shipped. When approved under the act as a

drug product, a well-characterized biotechnology product must have an

approved new drug application (NDA) in place of a PLA and ELA. Much of

the information provided in a PLA is similar to that included in an

NDA. Some of the information provided in an ELA is included in the

chemistry, manufacturing and controls section of the NDA (see

Sec. 314.50(d)(1)(21 CFR 314.50(d)(1))); however, much of the

information concerning the manufacturing facility that is included in

an ELA is not included in an NDA.

Technical advances over the last 15 years have greatly increased

the ability of manufacturers to control and analyze the manufacture of

many biotechnology-derived 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 well-

characterized biotechnology products without requiring submission of a

separate ELA. Accordingly, FDA is proposing procedures under which CBER

would approve well-characterized biotechnology products by requiring a

single biologics license application. CDER would continue to approve

NDA's for well-characterized biotechnology products. The single

biologics license application and the NDA would have an identical

format and include the same information. FDA would continue to inspect

manufacturing facilities for compliance with good manufacturing

practice requirements before approving either a biologics license

application or NDA.

FDA has determined that the review standards for well-characterized

biotechnology products across the agency are substantially identical,

notwithstanding that such standards may be specified in separate

regulations, but the manner in which information is submitted to FDA is

more burdensome when done through the ELA mechanism. Accordingly, the

agency believes that the proposed procedures will significantly reduce

burdens without reducing the safety or effectiveness of these products.

II. Legal Authority

This proposal would establish a licensing scheme for well-

characterized biotechnology products that differs from the current

licensing scheme in four fundamental ways. First, an applicant seeking

marketing approval of a well-characterized biotechnology product would

submit a single biologics license application to CBER and be issued a

single license. Second, for these products, many of the establishment

standards set forth in part 600 (21 CFR part 600) would be exempted

from applicability and the current good manufacturing practice

requirements found at parts 210 and 211 (21 CFR parts 210 and 211)

would constitute the bulk of the applicable establishment standards.

Some of the product standards set forth in part 610 (21 CFR part 610)

would also be eliminated for these products. Third, in lieu of

submitting an ELA to CBER showing compliance with establishment

standards, FDA would 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. Fourth, the term ``manufacturer'' as it is used in parts

600 through 680 (21 CFR parts 600 through 680) would be broadened to

include an applicant for a license for a well-characterized

biotechnology product who may or may not own the facilities engaged in

significant production steps. This would allow a single license

applicant to take responsibility for compliance with the requirements

in parts 600 through 680 applicable to manufacturers and eliminate the

requirement that each separate contract facility engaging in

significant manufacturing obtain a separate license.

These licensing procedures for well-characterized biotechnology-

derived biological products are authorized by section 351 of the PHS

Act. The proposed rule would establish an administrative approach to

enforce the requirements in sections 351(a) and (d) of the PHS Act

appropriate for current scientific and technological methods applied in

the manufacture of these products.

FDA's current regulations to administer and enforce the statutory

requirements embody a dual licensing scheme: Applicants must submit to

CBER an ELA and a PLA and obtain agency approval of both applications

before they may distribute a biological product. Parts 600 through 680

set out establishment and product standards that applicants must meet

before FDA issues an establishment or product license. However, a dual

licensing scheme is not compelled by the PHS Act.

Section 351(a) of the PHS Act restricts the interstate sale,

barter, and exchange of biologics to products manufactured in

establishments that have been licensed. Section 351(a) requires that a

biologic product be ``propagated or manufactured and prepared at an

establishment holding an unsuspended and unrevoked license.'' Section

351(d) authorizes the agency to prescribe regulations for the issuance,

suspension, and revocation of licenses: ``Licenses for the maintenance

of establishments for the propagation or manufacture and preparation of

[biological] products

* * * may be issued only upon a showing that the establishment and the

products for which a license is desired meet standards, designed to

insure the continued safety, purity, and potency of such products,

prescribed in regulations, and licenses for new products may be issued

only upon a showing that they meet such standards.'' The sole

limitation on the agency's discretion to issue biologic licenses is

that licenses may only be

[[Page 2735]]

issued upon a showing that both the establishment in which the product

is prepared and the product meet regulatory standards designed to

insure the continued safety, purity, and potency of such products.

The PHS Act does not prescribe requirements for the format or

content of license applications. Nor does it direct that there be two

forms of license. The clear import of section 351(a) is that the entity

responsible for the product and its manufacture should be licensed.

The agency believes that the single biologics license application

scheme that FDA is proposing for well-characterized biotechnology

products is authorized by the PHS Act because licenses would continue

to be issued only after the agency has made a determination that the

product and the establishment(s) in which it is manufactured meet

applicable regulatory standards. FDA would make its determination as to

whether the product and establishment(s) meet applicable regulatory

standards after reviewing the information submitted in the biologics

license application and after inspecting the manufacturing facilities.

FDA believes that a license holder need not be the legal owner of

each facility in which the product is manufactured as long as he or she

is responsible for assuring FDA that the product and establishment

standards are met. Accordingly, the proposed rule would permit a single

license holder to assume control of the production of a well-

characterized biotechnology product regardless of whether he or she

owns the manufacturing facilities.

FDA also believes that its administrative approach to enforcing the

PHS Act can and should change to respond to changing knowledge and

experience in reviewing the safety, purity, and potency of biological

products.

III. Summary of Proposed Rule

A. Biologics License Application.

The proposed rule would be applicable to applicants seeking

marketing approval of well-characterized biotechnology products that

are currently licensed under the provisions of the PHS Act.

In an effort to further harmonize the manner in which well-

characterized biotechnology products are regulated, the agency is

proposing in new Sec. 601.2(c) to eliminate the requirement for a

separate ELA for well-characterized biotechnology products licensed

under the PHS Act. This proposed regulation would require that an

applicant seeking marketing approval of a well-characterized

biotechnology product file a single application on a form prescribed by

CBER. The form will include a section that is the same as the

chemistry, manufacturing, and controls (CMC) section found in an NDA.

(See Sec. 314.50(d)(1)). CBER and CDER have prepared a draft form that

has been made available for comment. This draft form may be used in the

interim until a final form is available. Both CBER and CDER intend to

prepare and use the same guidance documents to aid in the preparation

of the chemistry, manufacturing, and controls section of an application

for a well-characterized biotechnology product. FDA intends that this

guidance will be made available to the public by the time of issuance

of any final rule resulting from this proposal.

The CMC section of a license application for a well-characterized

biotechnology product, like an NDA for a well-characterized

biotechnology product, would include the following elements, at a

minimum: A full description and characterization of the well-

characterized biotechnology product; the names, addresses, and

responsibilities of all manufacturers involved in the manufacture and

testing of the product; the method of manufacture, including raw

materials, solvents, and reagents; process controls and tests;

reference standards; specifications and analytical methods; a

description of the container and closure system and its compatibility

with the well-characterized biotechnology product drug substance; a

description of the storage conditions, stability study protocols, and

results; a tabulated list of all components; specifications and methods

for the drug product's ingredients; methods of manufacturing and

packaging of the well-characterized drug product including a floor plan

which designates rooms in the manufacturing facilities and operations

in each room; specifications and methods for the drug product; any

microbiology and drug product stability data; description of any

investigational formulation; environmental assessment and method

validation.

This proposal would also expand the definition in Sec. 600.3(t) of

``manufacturer'' to include a license applicant for a well-

characterized biotechnology product regardless of whether the applicant

is personally engaged in significant manufacturing steps.

These proposed changes would facilitate a company's ability to

contract out manufacture of its well-characterized biotechnology

products. The proposed rule would eliminate the requirement that each

separate contract facility engaging in significant production steps

submit an ELA and a PLA. Instead, a well-characterized biotechnology

product would be covered by a single biologics license application,

which lists all manufacturing locations, regardless of how many

separate companies are involved in its manufacture. FDA is seeking

comment on whether the definition of ``manufacturer'' in Sec. 600.3(t)

should also be expanded to include license applicants for products

other than well-characterized biotechnology products.

B. Good Manufacturing Practice Requirements.

The establishment standards for well-characterized biotechnology

products would continue to include the CGMP regulations found in parts

210 and 211 (21 CFR parts 210 and 211). FDA would review compliance

with good manufacturing practice requirements upon inspection and

applicants would be required to demonstrate such compliance in order to

obtain approval of a biologics license application.

Should well-characterized devices licensed under the PHS Act be

identified and be eligible for the new procedures, applicable CGMP

regulations would include parts 606 and 820 (21 CFR parts 606 and 820)

(for blood and blood components). FDA requests comments on whether a

specific reference to part 820 should be included in the rule.

Under section 501(a)(2)(B) of the act, the methods used in, and the

facilities or controls used for the manufacture, processing, packing,

or holding of a drug must conform to current good manufacturing

practice. Because the 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

good manufacturing practice. 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

Sec. Sec. 210.3(b)(4) and 211.1(a).) Although these CGMP regulations

are not applied to the manufacture of bulk drug components, there are

numerous instances where good manufacturing practice for bulk drug

substances and bulk drug product components would parallel the

requirements set forth in part 211. (See 43 FR 45076.) Because well-

characterized biotechnology products can be susceptible to

contamination, adequate control over

[[Page 2736]]

bulk manufacturing is important. FDA intends to use the standards of

part 211 as guidelines during inspections of manufacturers of bulk drug

substance and bulk drug product components, under the jurisdiction of

the act, to help ensure that a well-characterized biotechnology product

will have the proper raw materials controls, process validation and

controls, and sensitive and validated test methods and specifications

that are necessary to assure the safety, purity, potency, and

effectiveness of the product.

C. Applicability of Current Regulations (Parts 600-680).

In order to harmonize the regulatory standards applied by CBER and

CDER in their review of applications for well-characterized

biotechnology products, FDA is proposing to exempt well-characterized

biotechnology products licensed under the PHS Act from certain

requirements found in parts 600 through 680. The regulations that have

not been excluded in this proposed rule are those that FDA believes are

necessary to ensure the safety, purity, and potency of well-

characterized biotechnology products; are essentially the same as those

found in comparable regulations governing drug products; may not be

applicable by their terms to well-characterized biotechnology products;

or are ones that are targeted for revision. FDA requests comments on

whether well-characterized biotechnology products should be exempted

from requirements in parts 600 through 680 not identified for exclusion

in this proposal, or whether certain regulations exempted in this

proposed rule should remain applicable. FDA also requests comments on

whether well-characterized devices licensed under the PHS Act, should

such products be identified, would need to be exempted from the same or

different requirements in parts 600 through 680.

The following lists set forth those provisions that FDA proposes

would remain applicable, those that FDA proposes to exempt from

applicability to well-characterized biotechnology products, and those

that would not be applicable by their terms to well-characterized

biotechnology products.

The following sections would remain applicable to well-

characterized biotechnology products: Sec. Sec. 600.3, 600.10(a),

600.14, 600.20, 600.21, 600.22, 600.80, 600.81, 600.90, 601.2,

601.3(b), 601.4, 601.5, 601.6, 601.7, 601.8, 601.9, 601.12, 601.20,

601.21, 601.22, 601.33, 601.40, 601.41, 601.42, 601.43, 601.44, 601.45,

601.46, 601.50, 601.51, 610.1, 610.2 (Lot-by-lot release eliminated for

licensed well-characterized therapeutic recombinant DNA-derived and

monoclonal antibody products per letters to manufacturers and notice in

the Federal Register of December 8, 1995, (60 FR 63048.)), 610.9,

610.10, 610.11a, 610.12 (Equivalent methods or processes possible under

Sec. 610.9.), 610.13, 610.14, 610.15, 610.17, 610.18, 610.30, 610.40,

610.41, 610.45 (Sections 610.40 through 610.45 apply to blood and blood

components used in the manufacture of a well-characterized

biotechnology product.), 610.50, 610.60, 610.61, 610.63, 610.64,

610.65, and parts 606 (potential applicability to blood and blood

components only); 640 (potential applicability to blood and blood

products only); and 680 (would apply only to a well-characterized

biotechnology allergenic product).-

The following sections would be exempted from applicability to

well-characterized biotechnology products: Secs. 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.

The following sections by their terms would not be applicable to

well-characterized biotechnology products: Secs. 600.15, 601.3(a),

601.10, 601.25, 601.26, 610.16, 610.19, 610.20, 610.21, and parts 607,

620, 630, 650, and 660.

FDA is proposing to exempt well-characterized biotechnology

products from the requirements of Sec. 610.11, which sets out

procedures for a general safety test for biological products. FDA

believes that a general safety test requirement is not necessary to

ensure the safety, purity, and potency of a well-characterized

biotechnology product. With in-process control and process validation

and product testing, the identity of the well-characterized

biotechnology product can be determined, its purity can be controlled

and quantified, its activity and quantity can be measured, and the end-

product release specifications can be validated. The agency believes

that specific analytical tests that are available for these products

will provide a better assessment of safety than the general safety

test.

FDA is also proposing to exempt well-characterized biotechnology

products from Sec. 610.62, which sets out requirements for position and

prominence of the proper name of the product on the package label. FDA

believes that the requirements in Sec. 201.10(g) are adequate to assure

the appropriate identification of these products. -

D. Transition Issues.

Any well-characterized biotechnology product for which a PLA and an

ELA are pending on the effective date of these regulations would be

reviewed as submitted. No new submission would be necessary to

implement this rule change for these products. If found acceptable for

licensure, FDA would issue a biologics license in lieu of issuing both

a product and establishment license. Any company planning to file a PLA

or an ELA prior to April 1996 should contact the agency for guidance.

FDA specifically asks for comments on how transition issues should be

handled.

FDA anticipates that applicants already holding an approved ELA and

PLA for a well-characterized biotechnology product would not be

required to file supplements to comply with the new requirements. The

approved PLA for a well-characterized biotechnology product, together

with the limited portions of the approved ELA relevant to the new

requirements for the biologics license application, would be deemed to

constitute an approved biologics license application under the new

regulations.

IV. Proposed Effective Date

FDA proposes that a final rule resulting from this proposal become

effective upon its date of publication in the Federal Register. 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'' (Sec. 10.40(c)(4)(i)). Because, as

described below, this rule would decrease the regulatory burdens for

well-characterized biotechnology products, FDA believes that an

immediate effective date is appropriate.

V. Analysis of Impacts

A. Reduction in Burden

The proposed harmonization of the requirements would reduce burden

on industry because companies manufacturing well-characterized

biotechnology products that are regulated by both CBER and CDER would

be able to submit applications for products in a consistent format.

Companies developing and manufacturing well-characterized

biotechnology products regulated by CBER would no longer have to

prepare an ELA to submit to the agency for approval. The amount of

information that applicants would need to provide in a biologics

license application would be less than that currently required in a PLA

and ELA. These proposed changes would enable companies to devote more

resources to ensuring that

[[Page 2737]]

manufacturing processes are properly validated and fewer resources to

submitting documentation to the agency. These changes would 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 well-characterized biotechnology product.

The inclusion of parts 210 and 211 in the proposed rule as

establishment standards would not impose any additional burden on

industry. Human drugs, including well-characterized biotechnology

products, 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 proposed 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 proposed rule is consistent with the regulatory philosophy and

principles identified in the Executive Order. In addition, the proposed

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 proposed rule would be a substantial reduction in

burdens on applicants filing for approval of a well-characterized

biotechnology product. In addition, FDA anticipates that the proposed

rule would 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 previously, the overall result of

the proposed rule would be a substantial reduction of the regulatory

and 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.

C. Review Under the Paperwork Reduction Act of 1995

This proposed rule contains information collection requirements

which are subject to review by the Office of Management and Budget

(OMB) under the Paperwork Reduction Act of 1995. 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.

With respect to the following collection of information, FDA

invites comments on: (1) Whether the proposed collection of information

is necessary for the proper performance of FDA's functions, including

whether the information will have practical utility; (2) the accuracy

of FDA's estimate of the burden of the proposed collection of

information, including the validity of the methodology and assumptions

used; (3) ways to enhance the quality, utility, and clarity of the

information to be collected; and (4) ways to minimize the burden of the

collection of information on respondents, including through the use of

automated collection techniques, when appropriate, and other forms of

information technology.

Title: Well-characterized Biotechnology Products; Elimination of

Establishment License Application.

Description: FDA is proposing to eliminate the requirement that an

ELA be submitted and approved by FDA for those well-characterized

biotechnology 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 would be the same as the information included in the

``Chemistry, manufacturing, and controls'' (CMC) section of a NDA. This

proposed regulation would harmonize the approval and other regulatory

requirements for all well-characterized biotechnology product under the

PHS Act or approved as a drug 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

-----------------------------------------------------------------------------------------------------------------

Number of Frequency of Total Annual Hours per

CFR Section Respondents Responses Responses Response Total Hours

----------------------------------------------------------------------------------------------------------------

601.2(c) 1 1 1 40 40

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Reporting or Disclosure: These estimates are an approximation of

the average time expected to be necessary for a collection of

information. They are based on such information as is available to FDA.

There are no capital costs or operating and maintenance costs

associated with this information collection. The number of respondents

is dependent in part, on the definition of ``well-characterized

biotechnology products,'' now under review by the agency. At the

present time, FDA estimates the number of respondents at one a year.

The agency seeks comment on these estimates, particularly the

industry's view of the number of firms and products affected by the

collections of information requirements contained in this proposed

rule.

The agency has submitted a copy of this proposed rule to OMB for

its review of these information collections. Interested persons are

requested to send

[[Page 2738]]

comments regarding this information collection, including suggestions

for reducing this burden, 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. Submit written

comments on the information collection by February 28, 1996 but not

later than March 29, 1996.

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.

Interested persons may, on or before February 28, 1996, 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. Two copies of all comments are to be submitted, except

that individuals may submit one copy. 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 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, it is proposed that 21 CFR parts 600

and 601 be amended as follows:

PART 600--BIOLOGICAL PRODUCTS: GENERAL

3. 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).

4. Section 600.3 is amended by revising paragraph (t) to read as

follows:

Sec. 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 an applicant for a license for a well-

characterized biotechnology product.

* * * * *

PART 601--LICENSING

5. 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).

6. Section 601.2 is amended by adding a sentence at the end of

paragraph (a) and by adding a new paragraph (c) to read as follows:

Sec. 601.2 Applications for establishment and product licenses;

procedures for filing.

(a) * * * In lieu of the procedures described in this paragraph,

applications for well-characterized biotechnology products shall be

handled as set forth in paragraph (c) of this section.

* * * * *

(c) Well-characterized biotechnology products. (1) To obtain

marketing approval for a well-characterized biotechnology 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

well-characterized biotechnology products, a separate establishment

license application shall not be required. An application for a license

for a well-characterized biotechnology product shall include: 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, 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 Secs. 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; 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 samples; and specimens of the labels,

enclosures, and containers proposed to be used for the product. 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 Sec. 25.24

of this chapter or an environmental assessment under Sec. 25.31 of this

chapter.

(2) 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 well-characterized biotechnology

product 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 well-

characterized biotechnology products: Sec. Sec. 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.

[[Page 2739]]

(3) The term ``product license application,'' as it is used in

those sections of parts 600 through 680 of this chapter that are

applicable to well-characterized biotechnology products, shall include

a biologics license application for a well-characterized biotechnology

product.

(4) To the extent that the requirements in this paragraph conflict

with other requirements in this subchapter, this paragraph (c) shall

supercede such other requirements.

Dated: January 8, 1996.

William B. Schultz,

Deputy Commissioner for Policy.

[FR Doc. 96-1582 Filed 1-25-96; 10:42 am]

BILLING CODE 4160-01-F