Biological Products Regulated Under Section 351 of the Public Health Services Act; Implementation of Biologics License; Elimination of Establishment License and Product License

DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 3, 5, 10, 20, 207, 310, 312, 316, 600, 601, 607, 610,

640, and 660

[Docket No. 98N-0144]

RIN 0910-AB29

Biological Products Regulated Under Section 351 of the Public

Health Services Act; Implementation of Biologics License; Elimination

of Establishment License and Product License

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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

the biologics regulations to eliminate references to establishment

licenses and product licenses for all products regulated under the

Public Health Service Act (PHS Act). In lieu of filing an establishment

license application (ELA) and product license application (PLA) in

order to market a biological product in interstate commerce, a

manufacturer would file a single biologics license application (BLA)

with the agency. Upon approval of the BLA, a manufacturer would receive

a biologics license to market the product in interstate commerce. This

action is part of FDA's continuing effort to achieve the objectives of

the President's ``Reinventing Government'' initiatives and is intended

to reduce unnecessary burdens for industry without diminishing public

health protection. This action also proposes regulations to implement

certain sections of the Food and Drug Administration Modernization Act

of 1997 (FDAMA).

DATES: Submit written comments by October 14, 1998. Submit written

comments on the information collection requirements by August 31, 1998.

ADDRESSES: Submit written comments to the Dockets Management Branch

(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23,

Rockville, MD 20857. Submit written comments on the information

collection requirements to the Office of Management and Budget (OMB),

New Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC

20503.

FOR FURTHER INFORMATION CONTACT: Robert A. Yetter, Center for Biologics

Evaluation and Research (HFM-10), Food and Drug Administration, 1401

Rockville Pike, suite 200N, Rockville, MD 20852-1448, 301-827-0373.

SUPPLEMENTARY INFORMATION:

I. Background

Currently, most manufacturers requesting approval to market a

biological product in interstate commerce must submit a PLA and an ELA

to FDA. FDA's Center for Biologics Evaluation and Research (CBER)

currently requires manufacturers to use one of three ELA forms and 1 of

16 PLA forms for each biological product (see the Federal Register of

July 8, 1997 (62 FR 36558)). Upon approval of the ELA and PLA, the

agency issues a product license and an establishment license to the

manufacturer. As discussed in the next three paragraphs, FDA has

reviewed its process of licensing biological products and has already

taken a number of actions to reduce the regulatory burdens imposed by

the licensing process and to make the licensing process more consistent

with the process for the approval of new drugs.

Manufacturers of certain biological products are already required

to submit a BLA and obtain FDA approval of the BLA before the product

may be introduced into interstate commerce. In the Federal Register of

May 14, 1996 (61 FR 24227), FDA issued a final rule to amend the

biologics regulations by eliminating the ELA requirement for specified

biotechnology and synthetic biological products licensed under section

351 of the PHS Act (42 U.S.C. 262 et seq.). The specified biotechnology

and synthetic biological products are: (1) Therapeutic deoxyribonucleic

acid (DNA) plasmid products; (2) therapeutic synthetic peptide products

of 40 or fewer amino acids; (3) monoclonal antibody products for in

vivo use; and (4) therapeutic recombinant DNA-derived products. This

provision applies only to those products that FDA determines pursuant

to principles articulated in the ``Intercenter Agreement Between the

Center for Drug Evaluation and Research and the Center for Biologics

Evaluation and Research'' (effective on October 31, 1991) to be subject

to licensure under Section 351 of the PHS Act. Thus, upon approval,

manufacturers of the specified biotechnology and synthetic biological

products receive a single biologics license instead of a product

license and an establishment license (see Sec. 601.2(c) (21 CFR

601.2(c))).

In the Federal Register of July 8, 1997 (62 FR 36558), FDA

announced the availability of a revised FDA Form 356h. FDA Form 356h

was revised as a ``Reinventing Government'' initiative to

[[Page 40859]]

harmonize application procedures with the Center for Drug Evaluation

and Research (CDER) as outlined in the President's November 1995

National Performance Review Report, ``Reinventing the Regulation of

Drugs Made From Biotechnology.'' FDA intended that applicants for

biologics licenses for products specified in Sec. 601.2(c) as well as

autologous somatic cell therapy products could begin to use FDA Form

356h immediately and would be required to do so beginning January 8,

1998. FDA also intended to advise applicants for licenses for other

biological products when they can voluntarily begin and will be

required to use FDA Form 356h. Upon approval of a BLA submitted on FDA

Form 356h, FDA will issue a single biologics license. FDA believes that

this licensing procedure will greatly simplify the application process,

harmonize application procedures with those of CDER, and reduce

industry and agency paperwork burdens. FDA intends as a result of this

proposed rule to require that all manufacturers requesting approval to

introduce, or deliver for introduction, a biological product into

interstate commerce use FDA Form 356h to submit a BLA in lieu of

separate establishment and product applications.

With the consolidation of the establishment and product license

applications into a single biologics license application, the amount of

information formerly included in the establishment license application

would be reduced but not eliminated. Some information formerly included

in the ELA would now be submitted as ``chemistry, manufacturing, and

controls'' (CMC) information and under the ``establishment

description'' section of FDA Form 356h. The type and amount of

information related to the establishment would vary according to the

specific biological product for which licensure is being requested. To

describe what information should be included for each type of

biological product, CBER is preparing a series of guidance documents.

Many of these guidance documents have already been made available,

including but not limited to: (1) ``Guidance for Industry for the

Submission of Chemistry, Manufacturing, and Controls Information for a

Therapeutic Recombinant DNA-Derived Product or a Monoclonal Antibody

Product for In Vivo Use'' (61 FR 56243, October 31, 1996); (2)

``Guidance for the Submission of Chemistry, Manufacturing, and Controls

Information and Establishment Description for Autologous Somatic Cell

Therapy Products'' (62 FR 1460, January 10, 1997); (3) ``Guidance for

Industry for the Submission of Chemistry, Manufacturing and Controls

Information for Synthetic Peptide Substances;'' and (4) ``Draft

Guidance for Industry for the Submission of Chemistry, Manufacturing

and Controls and Establishment Description Information for Human

Plasma-Derived Biological Product or Animal Plasma or Serum-Derived

Products'' (63 FR 3145, January 21, 1998). All of these guidance

documents can be downloaded from the CBER Guidelines/Guidance document

World Wide Web page at ``www.fda.gov/cber/guidelines.htm''. These

guidance documents can also be obtained by written request to the

Office of Communication, Training, and Manufacturers Assistance (HFM-

40), Center for Biologics Evaluation and Research, Food and Drug

Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-

1448. Send one self-addressed adhesive label to assist the office in

processing your requests. These documents may also be obtained by mail

by calling the CBER Voice Information System at 1-800-835-4709 or 301-

827-1800, or by fax by calling the FAX information System at 1-888-

CBER-FAX or 301-827-3844. FDA intends in the future to announce in the

Federal Register the availability of additional CMC guidance documents

for various biological product classes.

II. Legal Authority

FDA licenses biological products under the authority of section

351(a) of the PHS Act. Although the PHS Act requires that biological

products be licensed and be safe, pure, potent, and manufactured in

facilities designed to assure that the product continues to be safe,

pure, and potent; it does not mandate the number or form of licenses

that FDA shall issued for each approvable biological product. The PHS

Act also does not specify the license application forms that

manufacturers must submit to FDA. Except for the biological products

listed under Sec. 601.2(c), FDA has required manufacturers to submit a

PLA and an ELA for each biological product. Accordingly, upon approval,

FDA issues two licenses for each product.

On November 21, 1997, the President signed into law the FDAMA

(Public Law 105-115). Section 123 of FDAMA, in pertinent part, amended

section 351 of the PHS Act to specify that a biologics license shall be

in effect for a biological product prior to such product's introduction

into interstate commerce. FDAMA thereby statutorily codified FDA's

administrative BLA/biologics license ``Reinventing Government''

initiative. Section 123(a)(1) of FDAMA further states that the

Secretary of Health and Human Services (delegated to the Commissioner

of Food and Drugs, at 21 CFR 5.10(a)(5)) shall approve a ``biologics

license application'' on the basis of a demonstration that the

biological product that is the subject of the application is safe,

pure, and potent; and the facility in which the biological product is

manufactured, processed, packed, or held meets standards designed to

ensure that the biological product continues to be safe, pure, and

potent.

The regulatory standards for establishments manufacturing

biological products can be found in the biologics regulations in parts

600 through 680 (21 CFR parts 600 through 680) and in the drug and

device good manufacturing practice regulations in parts 210 and 211 (21

CFR parts 210 and 211). The licensed manufacturer must also adhere to

product and establishment standards established and agreed upon in the

biologics license application. These standards from applicable

regulations and as established in licenses for different biological

products, will continue to constitute the requirements for the approval

of biologics licenses under section 123 of FDAMA. For consistency and

to reduce confusion, FDA will continue to use the terms

``establishment'' and ``licensed establishment'' in the biologics

regulations when referring to a place of manufacturing, processing, or

packing instead of the term ``facility'' as used in section 123 of

FDAMA. FDA is proposing to amend Sec. 600.3(w) to make clear that the

term ``establishment'' in the biologics regulations has the same

meaning as ``facility'' in section 123 of FDAMA.

Section 123(a)(2) of FDAMA eliminated section 351(d) of the PHS Act

that required licenses for the maintenance of establishments for the

propagation or manufacture and preparation of biological products.

Section 123(f) of FDAMA states that the Secretary of Health and Human

Services shall take measures to minimize differences in the review and

approval of products licensed under section 351 of the PHS Act and

products approved through new drug applications (NDA's) under the

Federal Food, Drug, and Cosmetic Act (the act).

Therefore, this proposal is intended to amend regulations in

chapter 21 of the Code of Federal Regulations (CFR) in order to

implement the regulatory changes concerning biologic license

applications and biologics licenses in the PHS Act codified by FDAMA.

This proposal would: (1) Amend the

[[Page 40860]]

regulations in chapter 21 CFR by eliminating almost all references to

establishment and product applications and licenses and substituting

the terms ``biologics license application'' and ``biologics license;''

(2) codify in the biologics regulations that FDA would issue a

``biologics license'' upon approval of a BLA; (3) require a

manufacturer of a biological product to submit a BLA on FDA Form 356h

to obtain approval of the license in order to market the product in

interstate commerce; (4) harmonize application procedures with products

approved under a NDA; and (5) update the format of certain regulations.

FDA believes that its administrative approach towards reviewing

regulatory submissions under the PHS Act can and should evolve in

response to changing technology, knowledge, and experience in reviewing

the safety, purity, and potency of biological products.

III. Summary of Proposed Rule

A. Definition and Deletion of Terms

In order to reduce any confusion that may result from use of the

term ``facility'' in section 351 of the PHS Act as amended by FDAMA,

FDA is proposing to amend the definition of ``establishment'' in

Sec. 601.3(w) to include that the term has the same meaning as

``facility'' in section 351 of the PHS Act.

FDA is proposing to modify the definition of ``standards'' in

Sec. 600.3(n) to indicate that the term refers to specifications and

procedures established in biologics license applications designed to

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

as well as to specifications and procedures in applicable regulations.

FDA has authority under Section 351 of the PHS Act to establish

standards in the review and approval of BLA's. Section 351(d) of the

PHS Act which previously stated that standards designed to insure the

continued safety, purity, and potency of biological products be

``prescribed in regulations'' was removed by FDAMA. FDA believes that

allowing standards to be established in the BLA will enable the

manufacturer and FDA to keep pace with evolving science and technology.

Establishing standards in the BLA is consistent with FDA's previous

effort to streamline the license review process by deleting certain

additional standards in the biologics regulations (see 61 FR 40153,

August 1, 1996). This proposed change to Sec. 600.3(n) would also

reduce confusion in the biologics regulations by establishing

consistency with FDA's current regulation at Sec. 601.5(b)(4) regarding

the revocation of licenses.

FDA is proposing to delete the term ``licensee'' as used in the

biologics regulations in order to reduce confusion and to make clear

the fact that it is the licensed manufacturer who is responsible for

compliance with product and establishment requirements. The term

``licensed manufacturer'' would be inserted in all instances that

currently read ``licensee.''

B. Elimination of PLA/ELA and Implementation of BLA

In the past, in order to help ensure that biological products were

safe, pure, and potent, FDA, and prior to FDA, the U.S. Public Health

Service believed that it was necessary to have both the biological

product and the establishment in which it was manufactured licensed

separately. In light of FDA's accumulated experience and expertise

regulating biological products and due to technical advances that have

significantly increased the ability of manufacturers to control and

analyze the manufacture of biological products, FDA, and the biologics

industry to a great extent, no longer find the separate licensing

scheme for biological products and establishments to be necessary.

After much consideration and in a ``Reinventing Government'' initiative

to reduce burden on industry by implementing a single biologics

licensing scheme, FDA had already begun drafting this proposal when

FDAMA was signed into law on November 21, 1997. Section 123 of FDAMA in

effect codifies FDA's BLA initiative by requiring that FDA issue a

``biologics license'' to a manufacturer that has submitted a BLA to FDA

and has demonstrated in the agency's view that the product is and will

be manufactured in a manner that ensures the product's continued

safety, purity, and potency.

This proposal substitutes the terms ``biologics license'' or

``biologics license application'' in lieu of references to product and

establishment applications and product and establishment licenses in

all regulations in chapter 21 CFR. In a few instances references to

product and establishment licenses would be retained for historical

accuracy (e.g., Secs. 601.25 and 601.26).

Under the proposed regulations, a manufacturer applying for

approval to market a biological product under section 351 of the PHS

Act would submit to FDA the appropriate establishment and product

information on the recently approved FDA Form 356h (see 62 FR 36558).

Manufacturers would no longer be required to submit product or

establishment information on the many different PLA and ELA forms

currently in use. Upon approval of the BLA, FDA would issue an approval

letter that in general terms states that FDA hereby grants the licensed

manufacturer a biologics license to manufacture the particular

biological product. FDA would not issue license certificates separate

from the approval letter as is current agency practice. The approval

letter would serve as the functional equivalent of a biologics license

within the meaning of section 351 of the PHS Act.

FDA is proposing in Sec. 601.2(a) that manufacturers would list in

the BLA the addresses of all locations of manufacture of a biological

product. FDA believes this would simplify and clarify the licensing

processes by having necessary establishment information in the BLA and

also by allowing FDA to approve all locations involved in the

manufacture of the product without having to issue an establishment

license for each location.

FDA is proposing under Sec. 601.9(c) that manufacturers of some

biological products would be able to list multiple products in a BLA

and FDA would be able to issue a single biologics license to the

manufacturer for more than one product. FDA would most likely use this

approach with products that have been on the market for a long period

of time, and for which FDA has considerable knowledge and expertise

regulating, such as blood and blood components and nonstandardized

allergenic products (see sections III.E and III.F of this document).

C. Specified Products Outlined in Current Sec. 601.2(c)

In order to continue harmonized review of specified biotechnology

and specified synthetic biological products by CDER and CBER, the

products outlined in the May 14, 1996, final rule (61 FR 24227) would

continue to be exempt from regulations at Secs. 600.10(b) and (c),

600.11, 600.12, 600.13, 610.11, 610.53, and 610.62.

D. Radioactive Biological Products

The agency believes that the regulations for the licensing of

radioactive biological products under Sec. 601.2(b) may be confusing to

the industry and do not accurately reflect the current policies of CBER

and CDER. FDA is therefore proposing to amend Sec. 601.2(b) to clarify

procedures for submitting an application for marketing approval for a

radioactive biological product in order to help ensure consistency with

current CBER and CDER policies and procedures. These proposed

regulations are intended to merely clarify when a manufacturer of

[[Page 40861]]

a radioactive biological product should submit a NDA to CDER or a BLA

to CBER and should not be construed as an attempt to address or

implement the requirements of section 122 of FDAMA, ``Requirements for

Radiopharmaceuticals.'' FDA intends in a separate rulemaking to issue

proposed regulations regarding the approval of radiopharmaceuticals as

required by section 122 of FDAMA. The proposed provision provides that

when the biological component of a radioactive coupled antibody

determines the site of action, normally a BLA should be submitted. The

regulation provides sufficient flexibility to take into account

situations that may arise in the future where the scientific issues

associated with the radionuclide or other chemically synthesized

component are more significant than the scientific issues associated

with the biological component. In such cases jurisdiction will be

determined in accordance with principles articulated in the

``Intercenter Agreement Between the Center for Drug Evaluation and

Research and the Center for Biologics Evaluation and Research''

effective on October 31, 1991.

E. Blood and Blood Components

Currently CBER requires manufacturers to use as many as 10

different forms for the submission of ELA's and PLA's for blood and

blood components. In addition, the agency currently issues a product

and establishment license for each of seven product types covered by

the forms (e.g. Whole Blood, Platelets, Plasma, Red Blood Cells,

Cryoprecipitate, Source Plasma). Under the proposed rule, the agency

would require a manufacturer of blood and blood components

participating in interstate commerce to use FDA Form 356h to request

approval to market. However, a manufacturer of blood and blood

components would only need to submit one BLA to request approval to

market one or more blood or blood components (e.g. Whole Blood,

Platelets, Plasma, Red Blood Cells, Cryoprecipitate, Source Plasma).

FDA believes this consolidation of forms and submissions would result

in a reduced regulatory burden for the blood industry because

information previously duplicated in the many blood and blood component

product and establishment applications would be submitted only once in

the BLA.

In addition, the proposed BLA system would simplify submission of

supplements to blood and blood component applications. Currently,

manufacturers desiring to make a single manufacturing change that would

affect multiple products are required to submit a supplement to each

individual product and establishment application. Under this proposal a

manufacturer would only need to submit one supplement to the BLA. For

example, under the current PLA/ELA system if a manufacturer desired to

make a single change to the irradiation procedure for its Whole Blood,

Red Blood Cells, Platelets, and Plasma products manufactured at 3

locations, the manufacturer would be required to submit 12 supplements

to 4 PLA's. Under the proposed BLA system, the manufacturer would only

be required to submit one supplement to the BLA describing the change

for all of the products and locations involved. FDA intends to continue

to streamline the blood and blood components application process in the

future as part of FDA's Reinvention of Blood Regulation initiative.

In vitro diagnostic kits (IVD's) and blood grouping reagents

involving blood and blood products are often licensed as individual

products under section 351 of the PHS Act. Unlike other blood and blood

component products, applications to market IVD's and blood grouping

reagents are unique and specific for each product. In order for FDA to

evaluate the safety, purity, potency, and effectiveness of each IVD or

blood grouping reagent, manufacturers submit detailed product and

establishment information to FDA in the application to market the

product. FDA would continue to evaluate IVD's and blood grouping

reagents on an individual basis and would therefore require a BLA for

each product. Accordingly, upon approval of the BLA, FDA would issue a

single biologics license for each IVD or blood reagent grouping

product.

F. Allergenic Products

A significant number of manufacturers of allergenic products

manufacture many different types of non-standardized allergenic

extracts for immunotherapeutic and/or diagnostic indications.

Currently, a manufacturer of multiple non-standardized allergenic

extract products holds a single product license for all of the non-

standardized allergenic extracts manufactured by the firm. FDA

estimates that requiring or issuing a biologics license for each type

of non-standardized allergenic extract from each manufacturer would be

burdensome to the allergenics industry and FDA. Therefore, in order to

simplify application procedures and reduce burden on industry and FDA,

under the BLA/biologics license scheme a manufacturer of multiple non-

standardized allergenic extracts wishing to market these products in

interstate commerce would only be required to submit a single BLA to

the agency.

However, under this proposed rule, standardized allergenic products

would be regulated as individual biological products. Therefore, a

manufacturer that wishes to market single or multiple standardized

allergenic products would be required to submit a single BLA for each

standardized product because of the detailed product and establishment

specifications necessary to manufacture such products.

Under proposed Sec. 601.2(e) FDA is proposing that every

manufacturer of biological products, including allergenic product

manufacturers, holding an unsuspended and unrevoked product license and

establishment license would be considered to have a biologics license.

Thus, an allergenic manufacturer holding an establishment license and

product license for multiple non-standardized allergenic extracts would

be considered to have a single biologics license for those products.

Likewise, a manufacturer holding an establishment license and product

license for a single standardized allergenic extract would be

considered to have a biologics license for that product.

G. Current Good Manufacturing Practice Requirements

The establishment requirements for biological products regulated

under Section 351 of the PHS Act would continue to include the current

good manufacturing practice (CGMP) regulations found in parts 210, 211,

600, 606, and 820 (21 CFR part 820). FDA would review compliance with

CGMP's during inspections; applicants would be required to demonstrate

such compliance in order to obtain a biologics license.

Under section 501(a)(2)(B) of the act (21 U.S.C. 351(a)(2)(B) et

seq.) the methods used in, and the facilities or controls used for the

manufacture, processing, packing, or holding of a drug must conform to

CGMP. Because bulk drug substance, drug component, and bulk drug

product meet the definition of ``drug'' in section 201(g)(1) of the act

(21 U.S.C. 321(g)(1)), their manufacture also must conform to CGMP. The

CGMP regulations set forth in parts 210 and 211 are intended to apply

to the preparation of a finished dosage form, whether or not in

packaged form. (See Secs. 210.3(b)(4) and 211.1(a).) Although these

CGMP regulations are not specifically applicable to the manufacture of

bulk drug components, there are numerous instances where CGMP, within

the meaning of 501(a)(2)(B) of the act, for bulk drug

[[Page 40862]]

substances and bulk drug product components would parallel the

requirements set forth in part 211 (see 43 FR 45076, September 29,

1978). Because biological products can be susceptible to contamination,

adequate control over bulk manufacturing is important. FDA intends to

use the requirements of part 211 during inspections of manufacturers of

bulk biological drug substances and bulk biological drug product

components, to help assure that biological products will have the

proper raw materials controls, process validation and controls, and

sensitive and validated test methods and specifications that are

necessary to ensure the safety, purity, potency, and effectiveness of

the product. The establishment requirements in Secs. 600.10 through

600.15 and the inspection regulations in Secs. 600.20 through 600.22

would continue to apply to all biological products licensed under

section 351 of the PHS Act except for those exemptions allowed under

Sec. 601.2(c) for specified biotechnology and synthetic products.

Therefore, for clarity and to reduce confusion FDA would make clear in

new Sec. 601.2(d) that the CGMP requirements in parts 210, 211, 600,

606, and 820 are included, as applicable, as part of the establishment

requirements for the production of a biological product. FDA is

currently reviewing the biological product licensing and inspection

regulations in order to update them as part of CBER's review of general

biologics and licensing regulations (see 59 FR 3043, January 20, 1994;

and 59 FR 28821, June 3, 1994).

H. Required Use of FDA Form 356h

Manufacturers of the four classes of specified biotechnology

products specified in Sec. 601.2(c) are currently required to use FDA

Form 356h when requesting permission to market one of these biological

products in interstate commerce. Manufacturers of autologous somatic

cell therapy products subject to licensure under section 351 of the PHS

Act should also use FDA Form 356h. Manufacturers of other biological

products should continue to use the current forms until such time as

final CMC and establishment guidance documents are made available. Ten

months after the effective date of any final rule based on this

proposal, all manufacturers of biological products licensed under

section 351 of the PHS Act would be required to use FDA Form 356h as

the form prescribed for such purpose under Sec. 601.2(a). Regardless of

which form(s) has been submitted for application to market, CBER will

begin issuing biologics licenses in lieu of establishment and product

licenses for any biological product that is approved on and after

February 19, 1998, the effective date of FDAMA.

IV. Administrative Implementation Issues

A. CBER Policy on Use of the Terms ``Licensed Establishment'' and

``Licensed Manufacturer''

In order to be clear, consistent, and reduce confusion that may

result from the proposed BLA scheme, FDA will continue to use the terms

``licensed establishment'' and ``licensed manufacturer'' in the

biologics regulations. Under the proposed BLA scheme there would be no

establishment license issued along with an approved BLA, however, all

establishments listed in the approved biologics license application as

engaged in the manufacture of any part of the biological product or the

whole biological product would be considered a licensed establishment

under the biologics regulations (including contract manufacturers and

short suppliers). FDA believes it is important to continue to use the

term ``licensed establishment'' in the regulations in order to convey

the importance of the establishment in the BLA scheme as FDA reviews,

inspects and approves the establishment as part of the biologics

license approval process.

The term ``licensed manufacturer'' as used to pertain to biological

products regulated under section 351 of the PHS Act would continue to

mean any legal person or entity holding an unsuspended and unrevoked

biologics license and who is therefore ultimately responsible for

compliance with all product and establishment requirements under the

applicable regulations and agreed upon in the BLA. FDA believes it is

important to continue to use the term ``licensed manufacturer'' in the

biologics regulations in order to emphasize that the manufacturer must

have a U.S. license number issued by FDA and must also hold a biologics

license for the biological product.

B. Applications in Preparation

FDA recognizes that it may take applicants time to switch format

from PLA's and ELA's to BLA's. Therefore, FDA proposes to continue to

accept PLA's and ELA's in lieu of a BLA for 10 months after the

effective date of a final rule based on this proposal. However, all

applications submitted to the agency after the effective date of the

final rule would be required to include all information indicated in

FDA Form 356h in order for the application to be considered as filed by

CBER. PLA's and ELA's received after the effective date of the final

rule would be administratively handled by FDA as a BLA. Any

manufacturer planning to file a PLA and an ELA during the 10-month time

period after the effective date of these regulations should contact FDA

for further guidance.

C. Applications Currently Under Review

FDA proposes that any biological products for which a PLA and an

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

reviewed as submitted. Not withstanding the new regulations, new

submissions by the manufacturer would not be necessary for these

products. If the PLA and ELA are sufficient for licensure, FDA would

issue a biologics license as required by section 351 of the PHS Act as

amended by FDAMA.

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

FDA proposes under new Sec. 601.2(e) that a manufacturer already

holding an approved ELA and PLA for a biological product would not be

required to file supplements to comply with the amended regulations.

The approved PLA together with portions of the approved ELA relevant to

the new requirements for the BLA, would be deemed to constitute a

biologics license under section 351 of the PHS Act .

E. BLA Tracking Number and U.S. License Number of the Manufacturer

1. BLA Tracking Number

Consistent with the proposed BLA scheme, FDA intends to use a new

internal BLA tracking and numbering system to track applications,

manufacturers, and approvals. Each biological product would be assigned

a BLA tracking number at the time the BLA is submitted by the

manufacturer. The BLA tracking number assigned by CBER upon receipt of

a BLA would remain indefinitely associated with the biological product.

Use of the BLA tracking number would be similar to the use of the NDA

number for drugs approved under section 505(b) of the act (21 U.S.C.

355(b)). After publication of a final rule based on this proposal, CBER

intends to assign a BLA tracking number to each currently approved

application and notify each licensed manufacturer of their respective

BLA tracking numbers. Licensed manufacturers will be requested to use

the BLA tracking number in all correspondence to the agency concerning

a particular biological product.

[[Page 40863]]

2. U.S. License Number of the Manufacturer

FDA issues biologics licenses (U.S. licenses) to new manufacturers

of biological products. Upon approval of a BLA, a manufacturer if not

previously licensed would receive a U.S. license number that is

required under section 351 of the PHS Act to appear on the label of the

biological product. The U.S. license number would also be used to

satisfy all regulatory requirements regarding ``license numbers'' and

in all of the same instances that the ``establishment license number''

is currently used by industry and CBER. A manufacturer already holding

a U.S. license number from CBER on the effective date of any final

regulations would continue to use its current U.S. license number as

required in the biologics regulations.

FDA would NOT issue a separate ``biologics license number'' with

the approval of each biological product. In summary: (1) The biologics

tracking number would be assigned by FDA when the BLA is filed, it

would stay with the biological product for its life, and it would be

used on all correspondence regarding the product; (2) the U.S. license

number would be assigned to each manufacturer (if not already holding

one) at the time of licensure of a biological product and would be used

on all of the manufacturer's labeling for approved biological products;

and (3) the approval letter for each biological product would serve as

the biologics license under section 351 of the PHS Act.

F. CMC and Establishment Information Guidance

As stated earlier in this proposed rule, CBER has made available

certain guidance documents that outline the recommended information to

be provided in the CMC and establishment sections of FDA Form 356h.

Biological product classes for which CBER is currently drafting CMC and

establishment information guidance documents include but are not

limited to: Vaccines, allergenic products, in vitro diagnostic

products, therapeutic plasmid DNA products, therapeutic naturally-

derived protein products, human plasma and animal serum derived

products, and human blood and blood component products. As these

guidance documents are completed and made available for various

biological products, FDA will encourage manufacturers to begin to use

Form FDA 356h. FDA intends to make CMC and establishment information

guidance documents available for all biological product classes by the

time a final rule on this subject is published. The CMC guidance

documents are intended to help manufacturers comply with product and

establishment requirements in applicable regulations including but not

limited to parts 210, 211, 600, 601, 606, and 820.

G. Public Meeting

FDA intends to hold a public workshop during the comment period of

this proposed rule to discuss the BLA/biologics license scheme. The

date, time, and location of the meeting will be announced in a document

in a future issue of the Federal Register.

V. Proposed Effective Date

FDA proposes that a final rule resulting from this proposal become

effective 60 days after its date of publication in the Federal

Register. FDA understands that considerable resources are committed to

the preparation of applications and therefore would continue to accept

applications in the current two application format for 10 months after

the effective date of any final rule based on this proposal. However,

after the effective date of the final rule all information indicated in

FDA Form 356h must be submitted in these submissions in order for the

application to be considered by CBER as complete. Applications

submitted in the current two application format after the effective

date of the final rule will be administratively handled by FDA as a

BLA. After the 10-month grace period FDA would no longer accept the two

application format (ELA and PLA) and would only accept for filing BLA's

submitted on FDA Form 356h.

VI. Analysis of Impacts

A. Reduction in Burden

The proposed harmonized use of FDA form 356h for all biological

products and drugs regulated by CBER and CDER would reduce burden on

industry by enabling manufacturers to submit applications for

biological products and drugs in a consistent format.

Manufacturers intending to introduce biological products into

interstate commerce would no longer have to prepare a PLA and an ELA to

submit to the agency for approval. The amount of information that

manufacturers would need to provide in a BLA would be less than that

currently required in a PLA and ELA. These proposed changes would

enable manufacturers to devote fewer resources to submitting

documentation to the agency. Much of the information currently reviewed

in an ELA at FDA headquarters would be reviewed at the manufacturing

site during a preapproval inspection. According to many biological

product manufacturers, preparation, submission, and approval of a

separate PLA and ELA for each biological product adds substantially to

the cost of licensing the product.

The inclusion of parts 210, 211, 600, 606, and 820 in the proposed

rule as establishment requirements would only serve to clarify existing

requirements and would not impose any additional burden on industry.

Human drugs, including biological products regulated under section 351

of the PHS Act, are already subject to the CGMP's in parts 210, 211,

600, 606, and 820.

B. Review Under Executive Order 12866 and the Regulatory Flexibility

Act

FDA has examined the impact of the proposed rule under Executive

Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612).

Executive Order 12866 directs agencies to assess all costs and benefits

of available regulatory alternatives and, when regulation is necessary,

to select regulatory approaches that maximize net benefits (including

potential economic, environmental, public health and safety, and other

advantages; distributive impact; and equity). The agency believes that

this proposed rule is consistent with the regulatory philosophy and

principles identified in Executive Order 12866. In addition, the

proposed rule is a significant regulatory action as defined in

Executive Order 12866 and is subject to review because it deals with a

novel policy issue.

In accordance with the principles of Executive Order 12866, the

overall result of the proposed rule would be a substantial reduction in

burdens on a manufacturer filing an application to market a biological

product. In addition, FDA anticipates that the proposed rule would

facilitate a manufacturer's ability to improve its licensed products

and methods of manufacture by decreasing the burden and cost associated

with filing applications and supplements.

The Regulatory Flexibility Act requires agencies to analyze

regulatory options that would minimize any significant impact of a rule

on small entities. Because, as stated previously, the overall result of

the proposed rule would be substantial reduction in reporting burdens,

the agency certifies that the proposed rule would not have a

significant negative economic impact on a substantial number of small

entities. Therefore, under the Regulatory Flexibility Act, no further

analysis is required.

[[Page 40864]]

C. The Paperwork Reduction Act of 1995

This proposed rule contains information collection provisions that

are subject to review by the Office of Management and Budget (OMB)

under the PRA (44 U.S.C. 3501-3520). A description of these provisions

is shown below with an estimate of the annual reporting burden.

Included in the estimate is the time for reviewing the instructions,

searching existing data sources, gathering and maintaining the data

needed, and completing and reviewing each collection of information.

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

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

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

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

information, including the validity of the methodology and assumptions

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

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

collection of information on respondents, including through the use of

automated collection techniques, when appropriate, and other forms of

information technology.

Title: Biological Products Regulated Under Section 351 of the

Public Health Service Act; Implementation of Biologics License;

Elimination of Establishment License and Product License.

Description: FDA is proposing to revise the regulations regarding

the procedures for application for approval to market a biological

product regulated under section 351 of the PHS Act. Currently, most

manufacturers must submit an ELA and a PLA when requesting approval to

market a biological product in interstate commerce. Under the proposed

regulations, a manufacturer would submit to FDA the appropriate

establishment and product information in a single BLA in lieu of filing

a separate ELA and PLA. The BLA is intended to replace the many

different ELA and PLA forms currently in use. Upon approval of the BLA,

a manufacturer would receive a single biologics license to market the

product in interstate commerce.

Description of Respondents: Manufacturers of biological products.

The proposed rule amends the regulations for filing an application

to market a biological product under Sec. 601.2 to eliminate references

to establishment licenses and product licenses for all products

regulated under the PHS Act. The proposed rule would require biologics

manufacturers to file a single BLA, rather than either an ELA or PLA,

to market a biological product. The agency estimates that the total

paperwork burden for manufacturers filing one application that

consolidates the information currently required under both the PLA and

ELA will net a decrease of approximately 10 percent. The estimate

reduces the number of annual responses from a combined PLA/BLA/ELA

total of 76 to a BLA total of 60. This estimate is derived from the

total number of license applications received by FDA in fiscal year

1997 (76) minus the total number of ELA's filed in the same period

(17). Based on information provided by industry, the time estimated to

prepare an application for FDA approval to market a product is

approximately 1,600 hours. In addition to Sec. 601.2, there are other

regulations included in the proposed rule that relate to certain

information to be included in a license application including

Secs. 640.21(c), 640.22(c), 640.65(a), and 660.21(a)(3) and (d). The

information collection requirements in the preceding regulations are

included in the burden estimate below for Sec. 601.2.

The proposed regulation also makes several technical amendments to

conform the language throughout the biological product regulations to

the changes proposed here for Sec. 601.2. Specifically, the proposed

rule makes the following technical term changes: References to product

and establishment license, and product and establishment applications

are replaced with ``biologics license'' or ``biologics license

application;'' ``licensee'' is replaced with ``licensed manufacturer;''

and ``licensed establishments'' is replaced with ``licensed

manufacturer.'' These technical changes impact neither the substantive

requirements nor the paperwork burden of these regulations, each of

which carry separate OMB clearance numbers as follows: Secs. 207.20(c)

and 207.21(a) (0910-0045); 600.80(c)(2) (0910-0308); 601.25(b)(3)

(0910-0039); 607.20(b) and 607.21 (0910-0052); 610.63 and 640.71(b)(1)

(0910-0116).

The following regulations relate to the submission of additional

information in a supplement to a BLA. Sections 600.15(b) and 610.53(d)

require submission of a request for an exemption or modification

regarding the temperature requirements during shipment and from dating

periods, respectively, for certain biological products. The preparation

of an exemption request is estimated to be 8 hours; however, no

requests were received by the agency under either regulations in fiscal

year 1997. To account for the rare instance in which a request for an

exemption may be made, the agency has estimated one respondent per year

in Table 1. Section 640.6 requires that an applicant submit a request

to make a certain modification of Whole Blood. The number of any

supplement relating to Whole Blood filed by an applicant in fiscal year

1997 totaled 74. Because the agency could not determine the number of

supplements filed specific to Sec. 640.6, the estimate below is based

on last year's total number of supplements related to Whole Blood.

The remaining regulations, Secs. 640.21(c), 640.22(c), 640.64(c),

and 640.74(a) and (b)(2), refer to information that is collected under

Sec. 601.12, under which the collection of information burden is

calculated. Moreover, the proposed rule would make only technical

changes to these regulations. For example, the term ``product license''

is changed to ``biologics licence,'' and the term ``product licensee''

is changed to ``licensed manufacturer.''

Table 1.--Estimated Annual Reporting Burden1

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

Annual

21 CFR Section No. of Frequency per Total Annual Hours per Total Hours

Respondents Response Responses Response

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

601.2 60 1 60 1,600 96,000

600.15(b) 1 1 1 8 8

610.53(d) 1 1 1 8 8

640.6 74 1 74 8 592

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

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

information.

[[Page 40865]]

In compliance with section 3507(d) of the PRA (44 U.S.C. 3507(d)),

the agency has submitted the information collection provisions of this

proposed rule to OMB for review. Interested persons are requested to

send written comments regarding information collection by August 31,

1998, to the Office of Information and Regulatory Affairs, OMB, New

Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC

20503, Attn: Desk Officer for FDA.

D. Environmental Impact

The agency has determined under 21 CFR 25.30 that this action is of

a type that does not individually or cumulatively have a significant

effect on the human environment. Therefore, neither an environmental

assessment nor an environmental impact statement is required.

Interested persons may, on or before October 14, 1998, submit to

the Dockets Management Branch (address above) written comments

regarding the proposal. Two copies of any comments are to be submitted,

except that individuals may submit one copy. Comments are to be

identified with the docket number found in brackets in the heading of

this document. The comments received are available for public

examination in the Dockets Management Branch between 9 a.m. and 4 p.m.,

Monday through Friday. Submit written comments on the information

collection requirements to the Office of Information and Regulatory

Management, OMB (address above).

List of Subjects

21 CFR Part 3

Administrative practice and procedure, Biologics, Drugs, Medical

devices.

21 CFR Part 5

Authority delegations (Government agencies), Imports, Organization

and functions (Government agencies).

21 CFR Part 10

Administrative practice and procedure, News media.

21 CFR Part 20

Confidential business information, Courts, Freedom of information,

Government employees.

21 CFR Part 207

Drugs, Reporting and recordkeeping requirements.

21 CFR Part 310

Administrative practice and procedure, Drugs, Labeling, Medical

devices, Reporting and recordkeeping requirements.

21 CFR Part 312

Drugs, Exports, Imports, Investigations, Labeling, Medical

research, Reporting and recordkeeping requirements, Safety.

21 CFR Part 316

Administrative practice and procedure, Drugs, Reporting and

recordkeeping requirements.

21 CFR Part 600

Biologics, Reporting and recordkeeping requirements.

21 CFR Part 601

Administrative practice and procedure, Biologics, Confidential

business information.

21 CFR Part 607

Blood.

21 CFR Parts 610 and 660

Biologics, Labeling, Reporting and recordkeeping requirements.

21 CFR Part 640

Blood, Labeling, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the

Public Health Service Act, and authority delegated to the Commissioner

of Food and Drugs, it is proposed that 21 CFR parts 3, 5, 10, 20, 207,

310, 312, 316, 600, 601, 607, 610, 640, and 660 be amended to read as

follows:

PART 3--PRODUCT JURISDICTION

1. The authority citation for 21 CFR part 3 continues to read as

follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 357, 360, 360c-

360f, 360h-360j, 360gg-360ss, 371(a), 379e, 381, 394; 42 U.S.C. 216,

262.

2. Section 3.2 is amended by revising paragraph (k) to read as

follows:

Sec. 3.2 Definitions.

* * * * *

(k) Premarket review includes the examination of data and

information in an application for premarket review described in

sections 505, 507, 510(k), 513(f), 515, or 520(g) or 520(l) of the act

or section 351 of the Public Health Service Act of data and information

contained in any investigational new drug (IND) application,

investigational device exemption (IDE), new drug application (NDA),

antibiotic application, biologics license application, device premarket

notification, device reclassification petition, and premarket approval

application (PMA).

* * * * *

PART 5--DELEGATIONS OF AUTHORITY AND ORGANIZATION

3. The authority citation for 21 CFR part 5 continues to read as

follows:

Authority: 5 U.S.C. 504, 552, App. 2; 7 U.S.C. 138a, 2271; 15

U.S.C. 638, 1261-1282, 3701-3711a; 15 U.S.C. 1451-1461; 21 U.S.C.

41-50, 61-63, 141-149, 321-394, 467f, 679(b), 801-886, 1031-1309; 35

U.S.C. 156; 42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263,

264, 265, 300u-300u-5, 300aa-1; 1395y, 3246b, 4332, 4831(a), 10007-

10008; E.O. 11921, 41 FR 24294, 3 CFR, 1977 Comp., p. 124-131; E.O.

12591, 52 FR 13414, 3 CFR, 1988 Comp., p. 220-223.

4. Section 5.58 is amended by revising paragraph (a)(3) to read as

follows:

Sec. 5.58 Orphan products.

(a) * * *

(3) Applications for biologics licenses for biological products; or

* * * * *

5. Section 5.67 is amended by revising paragraphs (a), (b), and (c)

to read as follows:

Sec. 5.67 Issuance of notices of opportunity for a hearing on

proposals for denial of approval of applications for licenses or

revocation of licenses and certain notices of revocation of licenses.

* * * * *

(a) Notices of opportunity for a hearing on proposals to deny

approval or filing of applications for biologics licenses under

Sec. 601.4(b) of this chapter.

(b) Notices of opportunity for a hearing on proposals to revoke

biologics licenses under Sec. 601.5(b) of this chapter.

(c) Notices of revocation, at the manufacturer's request, of

biologics licenses under Secs. 601.5(a) and 601.8 of this chapter.

* * * * *

PART 10--ADMINISTRATIVE PRACTICES AND PROCEDURES

6. The authority citation for 21 CFR part 10 is revised to read as

follows:

Authority: 5 U.S.C. 551-558, 701-706; 15 U.S.C. 1451-1461; 21

U.S.C. 141-149, 321-397, 467f, 679, 821, 1034; 28 U.S.C. 2112; 42

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

7. Section 10.50 is amended by revising paragraph (c)(19) to read

as follows:

Sec. 10.50 Promulgation of regulations and orders after an opportunity

for a formal evidentiary public hearing.

* * * * *

(c) * * *

[[Page 40866]]

(19) Section 351(a) of the Public Health Service Act on a biologics

license for a biological product.

* * * * *

PART 20--PUBLIC INFORMATION

8. The authority citation for 21 CFR part 20 is revised to read as

follows:

Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582; 21

U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n,

243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.

9. Section 20.100 is amended by revising paragraph (c)(24) to read

as follows:

Sec. 20.100 Applicability; cross-reference to other regulations.

* * * * *

(c) * * *

(24) Applications for biologics licenses for biological products,

in Sec. 601.51 of this chapter.

* * * * *

PART 207--REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS

IN COMMERCIAL DISTRIBUTION

10. The authority citation for 21 CFR part 207 continues to read as

follows:

Authority: 21 U.S.C. 331, 351, 352, 355, 357, 360, 360b, 371,

374; 42 U.S.C. 262.

11. Section 207.20 is amended by revising paragraph (c) to read as

follows:

Sec. 207.20 Who must register and submit a drug list.

* * * * *

(c) Before beginning manufacture or processing of a drug subject

to one of the following applications, an owner or operator of an

establishment is required to register before the agency approves it: A

new drug application, a new animal drug application, a medicated feed

application, an antibiotic application, or a biologics license

application.

* * * * *

12. Section 207.21 is amended by revising the second sentence of

paragraph (a) to read as follows:

Sec. 207.21 Times for registration and drug listing.

(a) * * * If the owner or operator of the establishment has not

previously entered into such an operation, the owner or operator shall

register within 5 days after submitting a new drug application, new

animal drug application, medicated feed application, antibiotic

application, or a biologics license application. * * *

* * * * *

PART 310--NEW DRUGS

13. The authority citation for 21 CFR part 310 continues to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 360b-

360f, 360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a),

262, 263b-263n.

14. Section 310.4 is revised to read as follows:

Sec. 310.4 Biologics; products subject to license control.

(a) Except for radioactive biological products intended for human

use as described in Sec. 601.2(b) of this chapter, a new drug shall not

be deemed to be subject to section 505 of the act if it is a drug

licensed under section 351 of the Public Health Service Act (42 U.S.C.

262 et seq.) or under the animal virus, serum, and toxin law of March

4, 1913 (21 U.S.C. 151 et seq.).

(b) A radioactive biological product (as defined in Sec. 600.3(ee)

of this chapter) intended for human use, except as identified in

Sec. 601.2(b)(1) of this chapter, is subject to section 505 of the act.

Any license for such a radioactive biological product which was issued

under section 351 of the Public Health Service Act (42 U.S.C. 262 et

seq.) and which was not revoked or suspended as of August 25, 1975,

shall constitute an approved new drug application in effect under the

same terms and conditions as set forth in such license application and

such portions of the establishment license relating to such product,

which include data and information required under part 314 of this

chapter for a new drug application. Any such radioactive biological

product for which licensure under the Public Health Service Act was

pending on August 25, 1975, shall, upon determination that it is

acceptable for licensure, be approved as a new drug application in lieu

of issuance of a biological product license.

15. Section 310.503 is amended by revising the first sentence of

paragraph (b) to read as follows:

Sec. 310.503 Requirements regarding certain radioactive drugs.

* * * * *

(b) It is the opinion of the Nuclear Regulatory Commission, and

the Food and Drug Administration that this exemption should not apply

for certain specific drugs and that these drugs should be appropriately

labeled for uses for which safety and effectiveness can be demonstrated

by new drug applications or through licensing under the Public Health

Service Act (42 U.S.C. 262 et seq.) in the case of biologics. * * *

* * * * *

PART 312--INVESTIGATIONAL NEW DRUG APPLICATION

16. The authority citation for 21 CFR part 312 continues to read as

follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 357, 371; 42

U.S.C. 262.

17. Section 312.3 is amended in paragraph (b) by revising the

definition for Marketing application to read as follows:

Sec. 312.3 Definitions and interpretations.

* * * * *

(b) * * *

Marketing application means an application for a new drug

submitted under section 505(b) of the act, a request to provide for

certification of an antibiotic submitted under section 507 of the act,

or a biologics license application for a biological product submitted

under the Public Health Service Act.

* * * * *

PART 316--ORPHAN DRUGS

18. The authority citation for 21 CFR part 316 continues to read as

follows:

Authority: 21 U.S.C. 360aa, 360bb, 360cc, 360dd, 371.

19. Section 316.3 is amended by revising paragraph (b)(9) to read

as follows:

Sec. 316.3 Definitions.

* * * * *

(b) * * *

(9) Marketing application means an application for approval of a

new drug filed under section 505(b) of the act, a request for

certification of an antibiotic under section 507 of the act, or an

application for a biologics license submitted under section 351 of the

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

* * * * *

PART 600--BIOLOGICAL PRODUCTS: GENERAL

20. The authority citation for 21 CFR part 600 continues to read as

follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371,

374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.

21. Section 600.3 is amended by revising paragraph (n) and (w) to

read as follows:

Sec. 600.3 Definitions.

* * * * *

(n) The word standards means specifications and procedures

applicable to an establishment or to the manufacture or release of

products, which are prescribed in this subchapter

[[Page 40867]]

or established in the biologics license application designed to insure

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

* * * * *

(w) Establishment has the same meaning as ``facility'' in section

351 of the Public Health Service Act and includes all locations.

* * * * *

22. Section 600.15 is amended by revising paragraph (b) to read as

follows:

Sec. 600.15 Temperatures during shipment.

* * * * *

(b) Exemptions. Exemptions or modifications shall be made only

upon written approval, in the form of a supplement to the biologics

license application, approved by the Director, Center for Biologics

Evaluation and Research.

23. Section 600.21 is amended by revising the first sentence to

read as follows:

Sec. 600.21 Time of inspection.

The inspection of an establishment for which a biologics license

application is pending need not be made until the establishment is in

operation and is manufacturing the complete product for which a

biologics license is desired. * * *

24. Section 600.80 is amended by revising the first sentence of

paragraph (b), the first and second sentences of paragraph (c)(2)(i),

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

Sec. 600.80 Postmarketing reporting of adverse experiences.

* * * * *

(b) Review of adverse experiences. Any person having a biologics

license under Sec. 601.20 of this chapter shall promptly review all

adverse experience information pertaining to its product obtained or

otherwise received by the licensed manufacturer from any source,

foreign or domestic, including information derived from commercial

marketing experience, postmarketing clinical investigations,

postmarketing epidemiological/surveillance studies, reports in the

scientific literature, and unpublished scientific papers. * * *

* * * * *

(c) * * *

(2) Periodic adverse experience reports. (i) The licensed

manufacturer shall report each adverse experience not reported under

paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years

from the date of issuance of the biologics license, and then at annual

intervals. The licensed manufacturer shall submit each quarterly report

within 30 days of the close of the quarter (the first quarter beginning

on the date of issuance of the biologics license) and each annual

report within 60 days of the anniversary date of the issuance of the

biologics license. * * *

* * * * *

(g) Multiple reports. A licensed manufacturer should not include in

reports under this section any adverse experience that occurred in

clinical trials if they were previously submitted as part of the

biologics license application. If a report refers to more than one

biological product marketed by a licensed manufacturer, the licensed

manufacturer should submit the report to the biologics license

application for the product listed first in the report.

* * * * *

(j) Revocation of biologics license. If a licensed manufacturer

fails to establish and maintain records and make reports required under

this section with respect to a licensed biological product, FDA may

revoke the biologics license for such a product in accordance with the

procedures of Sec. 601.5 of this chapter.

* * * * *

PART 601--LICENSING

25. The authority citation for 21 CFR part 601 is revised to read

as follows:

Authority: 15 U.S.C. 1451-1461; 21 U.S.C. 321, 351, 352, 353,

355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216,

241, 262, 263.

Sec. 601.1 [Removed]

26. Section 601.1 Two forms of licenses is removed.

27. Section 601.2 is revised to read as follows:

Sec. 601.2 Applications for biologics licenses; procedures for filing.

(a) General. To obtain a biologics license under section 351 of the

Public Health Service Act for any biological product, the manufacturer

shall submit an application to the Director, Center for Biologics

Evaluation and Research, on forms prescribed for such purposes, and

shall submit data derived from nonclinical laboratory and clinical

studies which demonstrate that the manufactured product meets

prescribed requirements of safety, purity, and potency; with respect to

each nonclinical laboratory study, either a statement that the study

was conducted in compliance with the requirements set forth in part 58

of this chapter, or, if the study was not conducted in compliance with

such regulations, a brief statement of the reason for the

noncompliance; statements regarding each clinical investigation

involving human subjects contained in the application, that it either

was conducted in compliance with the requirements for institutional

review set forth in part 56 of this chapter; or was not subject to such

requirements in accordance with Sec. 56.104 or Sec. 56.105, and was

conducted in compliance with requirements for informed consent set

forth in part 50 of this chapter. A full description of manufacturing

methods; data establishing stability of the product through the dating

period; sample(s) representative of the product to be sold, bartered,

or exchanged or offered, sent, carried or brought for sale, barter, or

exchange; summaries of results of tests performed on the lot(s)

represented by the submitted sample(s); specimens of the labels,

enclosures, and containers proposed to be used for the product and; the

address of each location involved in the manufacture of the biological

product shall be listed in the biologics license application. An

application for a biologics license shall not be considered as filed

until all pertinent information and data have been received from the

manufacturer by the Center for Biologics Evaluation and Research. The

applicant shall also include either a claim for categorical exclusion

under Sec. 25.30 or Sec. 25.31 of this chapter or an environmental

assessment under Sec. 25.40 of this chapter. In lieu of the procedures

described in this paragraph, applications for radioactive biological

products shall be handled as set forth in paragraph (b) of this

section. The applicant, or the applicant's attorney, agent, or other

authorized official shall sign the application. An application for any

of the following specified categories of biological products subject to

licensure shall be handled as set forth in paragraph (c) of this

section:

(1) Therapeutic DNA plasmid products;

(2) Therapeutic synthetic peptide products of 40 or fewer amino

acids;

(3) Monoclonal antibody products for in vivo use; and

(4) Therapeutic recombinant DNA-derived products.

(b) Radioactive biological products. To obtain marketing approval

for a radioactive biological product, as defined in Sec. 600.3(ee) of

this chapter, the manufacturer of such product shall comply with the

following:

(1) An applicant for a radioactive coupled antibody, which means a

product that consists of an antibody component coupled with a

radionuclide component (or an antibody component intended solely to be

coupled with a radionuclide) in which both components provide a

pharmacological effect but the biological component determines the site

of action, shall

[[Page 40868]]

submit a biologics license application to the Director, Center for

Biologics Evaluation and Research, Food and Drug Administration, except

if, as determined by FDA, there are significant scientific issues

associated with the radionuclide or other chemically synthesized

component, in which case a new drug application shall be submitted to

the Center for Drug Evaluation and Research, Food and Drug

Administration;

(2) An applicant for a radioactive biological product other than as

described in paragraph (b)(1) of this section, shall submit a new drug

application to the Center for Drug Evaluation and Research, Food and

Drug Administration.

(c)(1) To obtain marketing approval for a biological product

subject to licensure which is a therapeutic DNA plasmid product,

therapeutic synthetic peptide product of 40 or fewer amino acids,

monoclonal antibody product for in vivo use, or therapeutic recombinant

DNA-derived product, an applicant shall submit a biologics license

application in accordance with paragraph (a) of this section except

that the following sections in parts 600 through 680 of this chapter

shall not be applicable to such products: Secs. 600.10(b) and (c),

600.11, 600.12, 600.13, 610.11, 610.53, and 610.62 of this chapter.

(2) To the extent that the requirements in this paragraph (c)

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

shall supersede other requirements.

(d) Approval of a biologics license application or issuance of a

biologics license shall constitute a determination that the

establishment(s) and the product meet applicable requirements to ensure

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

requirements for the maintenance of establishments for the manufacture

of a product subject to this section shall include but not be limited

to the good manufacturing practice requirements set forth in parts 210,

211, 600, 606, and 820 of this chapter.

(e) Any establishment and product license for a biological product

issued under section 351 of the Public Health Service Act (42 U.S.C.

201 et seq.) that has not been revoked or suspended as of (insert

effective date of final rule), shall constitute an approved biologics

license application in effect under the same terms and conditions set

forth in such product license and such portions of the establishment

license relating to such product.

Sec. 601.3 [Removed]

28. Section 601.3 License forms is removed.

29. Section 601.4 is amended by revising paragraph (a) and the

first sentence of paragraph (b) to read as follows:

Sec. 601.4 Issuance and denial of license.

(a) A biologics license shall be issued upon a determination by

the Director, Center for Biologics Evaluation and Research that the

establishment(s) and the product meet the applicable requirements

established in this chapter. A biologics license shall be valid until

suspended or revoked.

(b) If the Commissioner, determines that the establishment or

product does not meet the requirements established in this chapter, the

biologics license application shall be denied and the applicant shall

be informed of the grounds for, and of an opportunity for a hearing on,

the decision. * * *

30. Section 601.5 is revised to read as follows:

Sec. 601.5 Revocation of license.

(a) A biologics license shall be revoked upon application of the

manufacturer giving notice of intention to discontinue the manufacture

of all products manufactured under such license or to discontinue the

manufacture of a particular product for which a license is held and

waiving an opportunity for a hearing on the matter.

(b)(1) The Commissioner shall notify the licensed manufacturer of

the intention to revoke the biologics license, setting forth the

grounds for, and offering an opportunity for a hearing on, the proposed

revocation if the Commissioner finds any of the following:

(i) Authorized Food and Drug Administration employees after

reasonable efforts have been unable to gain access to an establishment

or a location for the purpose of carrying out the inspection required

under Sec. 600.21 of this chapter,

(ii) Manufacturing of products or of a product has been

discontinued to an extent that a meaningful inspection or evaluation

cannot be made,

(iii) The manufacturer has failed to report a change as required by

Sec. 601.12,

(iv) The establishment or any location thereof, or the product for

which the license has been issued, fails to conform to the applicable

standards established in the license and in this chapter designed to

ensure the continued safety, purity, and potency of the manufactured

product,

(v) The establishment or the manufacturing methods have been so

changed as to require a new showing that the establishment or product

meets the requirements established in this chapter in order to protect

the public health, or

(vi) The licensed product is not safe and effective for all of its

intended uses or is misbranded with respect to any such use.

(2) Except as provided in Sec. 601.6 or in cases involving

willfulness, the notification required in this paragraph shall provide

a reasonable period for the licensed manufacturer to demonstrate or

achieve compliance with the requirements of this chapter, before

proceedings will be instituted for the revocation of the license. If

compliance is not demonstrated or achieved and the licensed

manufacturer does not waive the opportunity for a hearing, the

Commissioner shall issue a notice of opportunity for hearing on the

matter under Sec. 12.21(b) of this chapter.

31. Section 601.6 is revised to read as follows:

Sec. 601.6 Suspension of license.

(a) Whenever the Commissioner has reasonable grounds to believe

that any of the grounds for revocation of a license exist and that by

reason thereof there is a danger to health, the Commissioner may notify

the licensed manufacturer that the biologics license is suspended and

require that the licensed manufacturer do the following:

(1) Notify the selling agents and distributors to whom such product

or products have been delivered of such suspension, and

(2) Furnish to the Director, Center for Biologics Evaluation and

Research, complete records of such deliveries and notice of suspension.

(b) Upon suspension of a license, the Commissioner shall either:

(1) Proceed under the provisions of Sec. 601.5(b) to revoke the

license, or

(2) If the licensed manufacturer agrees, hold revocation in

abeyance pending resolution of the matters involved.

32. Section 601.9 is revised to read as follows:

Sec. 601.9 Licenses; reissuance.

(a) Compliance with requirements. A biologics license, previously

suspended or revoked, may be reissued or reinstated upon a showing of

compliance with requirements and upon such inspection and examination

as may be considered necessary by the Director, Center for Biologics

Evaluation and Research.

(b) Exclusion of noncomplying location. A biologics license,

excluding a location or locations that fail to

[[Page 40869]]

comply with the requirements in this chapter, may be issued without

further application and concurrently with the suspension or revocation

of the license for noncompliance at the excluded location or locations.

(c) Exclusion of noncomplying product(s). In the case of multiple

products included under a single biologics license application, a

biologics license may be issued, excluding the noncompliant product(s),

without further application and concurrently with the suspension or

revocation of the biologics license for a noncompliant product(s).

Sec. 601.10 [Removed]

33. Section 601.10 Establishment licenses; issuance and conditions

is removed.

34. Section 601.20 is revised to read as follows:

Sec. 601.20 Biologics licenses; issuance and conditions.

(a) Examination--compliance with requirements. A biologics license

application shall be approved only upon examination of the product and

upon a determination that the product complies with the standards

established in biologics license application and the requirements

prescribed in the regulations in this chapter including but not limited

to the good manufacturing practice requirements set forth in parts 210,

211, 600, 606, and 820 of this chapter.

(b) Availability of product. No biologics license shall be issued

unless:

(1) The product intended for introduction into interstate commerce

is available for examination, and

(2) Such product is available for inspection during all phases of

manufacture.

(c) Manufacturing process--impairment of assurances. No product

shall be licensed if any part of the process of or relating to the

manufacture of such product, in the judgment of the Director, Center

for Biologics Evaluation and Research, would impair the assurances of

continued safety, purity, and potency as provided by the regulations

contained in this chapter.

(d) Inspection--compliance with requirements. A biologics license

shall be issued or a biologics license application approved only after

inspection of the establishment(s) listed in the biologics license

application and upon a determination that the establishment(s) complies

with the standards established in the biologics license application and

the requirements prescribed in applicable regulations.

(e) One biologics license to cover all locations. One biologics

license shall be issued to cover all locations meeting the

establishment standards identified in the approved biologics license

application and each location shall be subject to inspection by FDA

officials.

35. Section 601.21 is revised to read as follows:

Sec. 601.21 Products under development.

A biological product undergoing development, but not yet ready

for a biologics license, may be shipped or otherwise delivered from one

State or possession into another State or possession provided such

shipment or delivery is not for sale, barter, or exchange, except as

provided in section 505(i) of the Federal Food, Drug, and Cosmetic Act,

as amended, and the regulations thereunder (21 CFR parts 312 and 812).

36. Section 601.22 is amended by revising the section heading and

the first and second sentences to read as follows:

Sec. 601.22 Products in short supply; initial manufacturing at other

than licensed location.

A biologics license issued to a manufacturer and covering all

locations of manufacture shall authorize persons other than such

manufacturer to conduct at places other than such locations the

initial, and partial manufacturing of a product for shipment solely to

such manufacturer only to the extent that the names of such persons and

places are registered with the Commissioner of Food and Drugs and

either of the following is found upon application of such manufacturer,

that the product is in short supply due either to the peculiar growth

requirements of the organism involved or to the scarcity of the animal

required for manufacturing purposes, and such manufacturer has

established with respect to such persons and places such procedures,

inspections, tests or other arrangements as will assure full compliance

with the applicable regulations of this subchapter related to continued

safety, purity, and potency. Such persons and places shall be subject

to all regulations of this subchapter except Secs. 601.2 to 601.6,

601.9, 601.10, 601.20, 601.21 to 601.33, and Secs. 610.60 to 610.65 of

this chapter. * * *

37. Sections 601.25 is amended in paragraph (b)(3) under

``Biological Products Review Information'' by revising section VIII and

by revising the third sentence of paragraph (f)(3) to read as follows:

Sec. 601.25 Review procedures to determine that licensed biological

products are safe, effective, and not misbranded under prescribed,

recommended, or suggested conditions of use.

* * * * *

(b) * * *

(3) * * *

BIOLOGICAL PRODUCTS REVIEW INFORMATION

* * * * *

VIII. If the submission is by a licensed manufacturer, a

statement signed by the authorized official of the licensed

manufacturer shall be included, stating that to the best of his or

her knowledge and belief, it includes all information, favorable and

unfavorable, pertinent to an evaluation of the safety,

effectiveness, and labeling of the product, including information

derived from investigation, commercial marketing, or published

literature. If the submission is by an interested person other than

a licensed manufacturer, a statement signed by the person

responsible for such submission shall be included, stating that to

the best of his knowledge and belief, it fairly reflects a balance

of all the available information, favorable and unfavorable

available to him, pertinent to an evaluation of the safety,

effectiveness, and labeling of the product.

* * * * *

(f) * * *

(3) * * * Where the Commissioner determines that the potential

benefits outweigh the potential risks, the proposed order shall provide

that the biologics license for any biological product, falling within

this paragraph will not be revoked but will remain in effect on an

interim basis while the data necessary to support its continued

marketing are being obtained for evaluation by the Food and Drug

Administration. * * *

* * * * *

38. Section 601.26 is amended by revising the second sentence of

the introductory text of paragraph (e), the first, fourth and fifth

sentences of paragraph (f)(1), the second sentence of paragraph (f)(2),

and the first sentence of paragraph (f)(3) to read as follows:

Sec. 601.26 Reclassification procedures to determine that licensed

biological products are safe, effective, and not misbranded under

prescribed, recommended, or suggested conditions of use.

* * * * *

(e) * * * Where the Commissioner determines that there is a

compelling medical need and no suitable alternative therapeutic,

prophylactic, or diagnostic agent for any biological product that is

available in sufficient quantities to meet current medical needs, the

final order shall provide that the biologics license application for

that biological product will not be revoked, but will remain in effect

on an interim basis while the data

[[Page 40870]]

necessary to support its continued marketing are being obtained for

evaluation by the Food and Drug Administration. * * *

(f) Additional studies and labeling. (1) Within 60 days following

publication of the final order, each licensed manufacturer for a

biological product designated as requiring further study to justify

continued marketing on an interim basis, under paragraph (e) of this

section, shall submit to the Commissioner a written statement intended

to show that studies adequate and appropriate to resolve the questions

raised about the product have been undertaken. * * * The Commissioner

may extend this 60-day period if necessary, either to review and act on

proposed protocols or upon indication from the licensed manufacturer

that the studies will commence at a specified reasonable time. If no

such commitment is made, or adequate and appropriate studies are not

undertaken, the biologics license or licenses shall be revoked. * * *

(2) * * * If the progress report is inadequate or if the

Commissioner concludes that the studies are not being pursued promptly

and diligently, or if interim results indicate the product is not a

medical necessity, the biologics license or licenses shall be revoked.

(3) Promptly upon completion of the studies undertaken on the

product, the Commissioner will review all available data and will

either retain or revoke the biologics license or licenses involved. * *

*

* * * * *

39. Section 601.51 is amended by revising the section heading, the

first sentence of paragraph (a), and paragraph (b) to read as follows:

Sec. 601.51 Confidentiality of data and information in applications

for biologics licenses.

(a) For purposes of this section the biological product file

includes all data and information submitted with or incorporated by

reference in any application for a biologics license, IND's

incorporated into any such application, master files, and other related

submissions. * * *

(b) The existence of a biological product file will not be

disclosed by the Food and Drug Administration before a biologics

license application has been approved unless it has previously been

publicly disclosed or acknowledged. The Director of the Center for

Biologics Evaluation and Research will maintain a list available for

public disclosure of biological products for which a license

application has been approved.

* * * * *

PART 607--ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR

MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS

40. The authority citation for 21 CFR part 607 continues to read

as follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374; 42

U.S.C. 216, 262.

41. Section 607.20 is amended by revising paragraph (b) to read as

follows:

Sec. 607.20 Who must register and submit a blood product list.

* * * * *

(b) Preparatory to engaging in the manufacture of blood products,

owners or operators of establishments who are submitting a biologics

license application to manufacture blood products are required to

register before the biologics license application is approved.

* * * * *

42. Section 607.21 is amended by revising the second sentence to

read as follows:

Sec. 607.21 Times for establishment registration and blood product

listing.

* * * If the owner or operator of the establishment has not

previously entered into such operation (defined in Sec. 607.3(d)) for

which a license is required, registration shall follow within 5 days

after the submission of a biologics license application in order to

manufacture blood products. * * *

PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS

43. The authority citation for 21 CFR part 610 continues to read as

follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42

U.S.C. 216, 262, 263, 263a, 264.

44. Section 610.13 is amended by revising the introductory

paragraph and the first sentence of paragraph (a)(1) to read as

follows:

Sec. 610.13 Purity.

Products shall be free of extraneous material except that which is

unavoidable in the manufacturing process described in the approved

biologics license application. In addition, products shall be tested as

provided in paragraphs (a) and (b) of this section.

(a)(1) Test for residual moisture. Each lot of dried product shall

be tested for residual moisture and shall meet and not exceed

established limits as specified by an approved method on file in the

biologics license application. * * *

* * * * *

45. Section 610.53 is amended by revising paragraph (d) to read as

follows:

Sec. 610.53 Dating periods for licensed biological products.

* * * * *

(d) Exemptions. Exemptions or modifications shall be made only upon

written approval, in the form of a supplement to the biologics license

application, issued by the Director, Center for Biologics Evaluation

and Research.

46. Section 610.63 is revised to read as follows:

Sec. 610.63 Divided manufacturing responsibility to be shown.

If two or more licensed manufacturers participate in the

manufacture of a biological product, the name, address, and license

number of each must appear on the package label, and on the label of

the container if capable of bearing a full label.

PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS

47. The authority citation for 21 CFR part 640 continues to read as

follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42

U.S.C. 216, 262, 263, 263a, 264.

48. Section 640.6 is amended by revising the introductory text to

read as follows:

Sec. 640.6 Modifications of Whole Blood.

Upon approval by the Director, Center for Biologics Evaluation

and Research, of a supplement to the biologics license application for

Whole Blood a manufacturer may prepare Whole Blood from which the

antihemophilic factor has been removed, provided the Whole Blood meets

the applicable requirements of this subchapter and the following

conditions are met:

* * * * *

49. Section 640.21 is amended by revising paragraph (c) to read as

follows:

Sec. 640.21 Suitability of donors.

* * * * *

(c) Plateletpheresis donors shall meet criteria for suitability as

described in a biologics license application or a supplement to the

biologics license application, and must have the written approval of

the Director, Center for Biologics Evaluation and Research, Food and

Drug Administration.

[[Page 40871]]

50. Section 640.22 is amended by revising paragraph (c) to read as

follows:

Sec. 640.22 Collection of source material.

* * * * *

(c) If plateletpheresis is used, the procedure for collection shall

be as described in a biologics license application or a supplement to a

biologics license application, and must have the written approval of

the Director, Center for Biologics Evaluation and Research, Food and

Drug Administration.

* * * * *

51. Section 640.64 is amended by revising the second sentence of

the introductory text of paragraph (c) to read as follows:

Sec. 640.64 Collection of blood for Source Plasma.

* * * * *

(c) * * * One of the following formulas shall be used in the

indicated volumes, except that a different formula may be used for

plasma for manufacture into noninjectable products if prior written

approval is obtained from the Director of the Center for Biologics

Evaluation and Research at the time of licensing or in the form of a

supplement to the biologics license application for Source Plasma.

* * * * *

52. Section 640.65 is amended by revising the last sentence of

paragraph (a) to read as follows:

Sec. 640.65 Plasmapheresis.

(a) * * * This procedure shall be described in detail in the

biologics license application.

* * * * *

53. Section 640.71 is amended by revising the introductory text of

paragraphs (a) and (b) and by revising paragraph (b)(1) to read as

follows:

Sec. 640.71 Manufacturing responsibility.

(a) All steps in the manufacture of Source Plasma, including donor

examination, blood collection, plasmapheresis, laboratory testing,

labeling, storage, and issuing shall be performed by personnel of the

licensed manufacturer of the Source Plasma, except that the following

tests may be performed by personnel of a manufacturer licensed for

blood or blood derivatives under section 351(a) of the Public Health

Service Act, or by a clinical laboratory that meets the standards of

the Clinical Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C.

263a): Provided, The establishment or the clinical laboratory is

qualified to perform the assigned test(s).

* * * * *

(b) Such testing shall not be considered divided manufacturing,

which requires two biologics licenses for Source Plasma: Provided, That

(1) The results of such tests are maintained by the licensed

manufacturer of the Source Plasma whereby such results may be reviewed

by a licensed physician as required in Sec. 640.65(b)(2) and by an

authorized representative of the Food and Drug Administration.

* * * * *

54. Section 640.74 is amended by revising paragraph (a) and the

last sentence of paragraph (b)(2) to read as follows:

Sec. 640.74 Modification of Source Plasma.

(a) Upon approval by the Director, Center for Biologics Evaluation

and Research, Food and Drug Administration, of a supplement to the

biologics license application for Source Plasma, a manufacturer may

prepare Source Plasma as a liquid product for a licensed blood

derivative manufacturer who has indicated a need for a liquid product.

(b) * * *

(2) * * * Such evidence may be submitted by either the licensed

manufacturer of the Source Plasma Liquid or the manufacturer of the

final blood derivative product who has requested the Source Plasma

Liquid.

* * * * *

PART 660--ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR

LABORATORY TESTS

55. The authority citation for 21 CFR part 660 continues to read as

follows:

Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42

U.S.C. 216, 262, 263, 263a, 264.

56. Section 660.21 is amended by revising paragraphs (a)(3) and (d)

to read as follows:

Sec. 660.21 Processing.

(a) * * *

(3) A lot may be subdivided into clean, sterile vessels. Each

subdivision shall constitute a sublot. If lots are to be subdivided,

the manufacturer shall include this information in the biologics

license application. The manufacturer shall describe the test

specifications to verify that each sublot is identical to other sublots

of the lot.

* * * * *

(d) Volume of final product. Each manufacturer shall identify the

possible final container volumes in the biologics license application.

* * * * *

57. Section 660.30 is amended by revising paragraph (b) to read as

follows:

Sec. 660.30 Reagent Red Blood Cells.

* * * * *

(b) Source. Reagent Red Blood Cells shall be prepared from human

peripheral blood meeting the criteria of Secs. 660.31 and 660.32, or

from umbilical cord cells which shall be collected and prepared

according to the manufacturer's biologics license application.

58. Section 660.33 is amended by revising the fifth sentence to

read as follows:

Sec. 660.33 Testing of source material.

* * * Where fewer than three donor sources of an antibody

specificity are available, test discrepancies shall be resolved in

accordance with the manufacturer's biologics license application. * * *

Dated: July 22, 1998.

Michael A. Friedman,

Acting Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

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

BILLING CODE 4160-01-F