[Federal Register Volume 61, Number 19 (Monday, January 29, 1996)]
[Proposed Rules]
[Pages 2733-2739]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-1582]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 600 and 601

[Docket No. 95N-0411]
RIN 0910-AA68


Well-Characterized Biotechnology Products; Elimination of 
Establishment License Application

AGENCY:  Food and Drug Administration, HHS.

ACTION:  Proposed rule.

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SUMMARY:  The Food and Drug Administration (FDA) is proposing to amend 
the biologics regulations to eliminate the establishment license 
application (ELA) requirement for well-characterized biotechnology 
products licensed under the Public Health Service Act (PHS Act). The 
proposed rule would also exempt well-characterized biotechnology 
products licensed under the PHS Act from certain biologics regulations 
and harmonize the requirements applicable to these products with those 
applicable to similar drug products which are approved under the 
Federal Food, Drug, and Cosmetic Act (the act).
    This action is part of FDA's continuing effort to achieve the 
objectives of the President's ``Reinventing Government'' initiatives, 
and it is intended to reduce unnecessary burdens for industry without 
diminishing public health protection.

DATES: Written comments on this proposed rule by February 28, 1996. 
Submit written comments on the information collection requirements by 
February 28, 1996, but not later than March 29, 1996. The agency 
proposes that any final rule that may issue based on this proposal 
become effective upon its date of publication in the Federal Register.

ADDRESSES: Submit written comments on this proposed rule to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Submit written comments on 
the information collection requirements to the Office of Information 
and Regulatory Affairs, OMB, New Executive Office Bldg., 725 17th St. 
NW., rm. 10235, Washington, DC 20503.

FOR FURTHER INFORMATION CONTACT: Tracey H. Forfa, Center for Biologics 
Evaluation and Research (HFM-630), Food and Drug Administration, 1401 
Rockville Pike, suite 200N, Rockville, MD 20852-1448, 301-594-3074.

SUPPLEMENTARY INFORMATION

I. Background

    In the Federal Register of December 8, 1995 (60 FR 63048), the 
agency announced its interim definition of a well-characterized 
therapeutic recombinant DNA-derived and monoclonal antibody 
biotechnology product, as follows:
    A chemical entity(ies) whose identity, purity, impurities, 
potency, and quantity can be determined and controlled.
    Identity:
    a. Recombinant DNA Biotechnology Products
    The primary structure is known (i.e., amino acid sequence), and
    The secondary structure is known (e.g. disulfide linkage), and
    Post-translational modifications are known (e.g., 
glycosylation), or
    b. Monoclonal Antibodies
    The identity can be determined by rigorous physicochemical and 
immunochemical characterization without fully knowing its chemical 
structure.
    Purity and impurities:
    The purity is quantifiable.
    The impurities are quantifiable, and identified if feasible.
    Potency and quantity:
    The biological activity is measurable.
    The quantity is measurable.
    A well-characterized therapeutic recombinant DNA-derived and 
monoclonal antibody product requires proper raw material controls, 
process validation and controls, and sensitive and validated test 
methods and specifications.
    As announced in the Federal Register of October 25, 1995 (60 FR 
54695), FDA held a scientific workshop on December 11, 12, and 13, 
1995, to discuss the definition of a well-characterized therapeutic 
recombinant DNA-derived and monoclonal antibody product and to identify 
the information necessary to characterize such products. FDA intends to 
consider information received at the workshop, as well as comments 
received in response to this proposed rule, to determine whether the 
definition previously given in this document should be expanded to 
include other categories of products that would be considered to be 
well-characterized, such as certain vaccines and biologic devices, 
e.g., test kits for screening blood.
    FDA is proposing to use the phrase ``well-characterized 
biotechnology product,'' to describe the products that would be 
eligible for a single license application so that the regulatory 
language would accommodate such additional categories of products. FDA 
has not included a definition of a well-characterized biotechnology 
product in the proposed regulations because the agency intends to 
clarify the definition in a guidance document that can be more readily 
modified to reflect changes that may be warranted as scientific 
knowledge progresses. FDA specifically invites public comment on 
whether a definition of a well-characterized biotechnology product 
should be included in the regulations and, if so, what the scope of 
such a definition should be.
    Well-characterized therapeutic recombinant DNA-derived and 
monoclonal antibody products that are viruses, therapeutic sera, 
toxins, antitoxins, vaccines, blood, blood components or derivatives, 
allergenic products, or analogous products applicable to the 
prevention, treatment, or cure of human diseases or injuries are 
``biologics'' within the meaning of 

[[Page 2734]]
section 351 of the PHS Act (42 U.S.C. 262). They are also ``drugs'' as 
the term is defined in section 201(g) of the act (21 U.S.C. 321(g)). 
Additional well-characterized biotechnology products identified in the 
future may be ``devices'' as defined in section 201(h) of the act (21 
U.S.C. 321(h)). Therefore, such products are subject to the provisions 
of the act applicable to drugs and/or devices, including, but not 
limited to, the adulteration and misbranding provisions (21 U.S.C. 351 
and 352).
    At the present time, these products are regulated by either FDA's 
Center for Biologics Evaluation and Research (CBER) or Center for Drug 
Evaluation and Research (CDER). CBER and CDER have entered into an 
intercenter agreement announced in the Federal Register of November 21, 
1991 (56 FR 58760), with respect to the regulation of drugs and 
biological products. The intercenter agreement assigns jurisdiction to 
CBER or CDER based on product class. A product class is defined as a 
distinct category of agents recognizable by physical characteristics, 
source materials, or pharmacologic properties. Examples of product 
classes include: antibiotics, vaccines, hormones, and human blood 
derivatives. Under the agreement, some well-characterized biotechnology 
products, such as recombinant insulin and human growth hormone, are 
assigned to CDER, while other similar recombinant products, such as 
erythropoietin, colony stimulating factor, and interferon, are assigned 
to CBER.
    Currently, when approved under the PHS Act as biological products, 
well-characterized biotechnology products are reviewed like any other 
biologic; that is, both a product license application (PLA) and an ELA 
are submitted to and approved by FDA before the well-characterized 
biotechnology product may be shipped. When approved under the act as a 
drug product, a well-characterized biotechnology product must have an 
approved new drug application (NDA) in place of a PLA and ELA. Much of 
the information provided in a PLA is similar to that included in an 
NDA. Some of the information provided in an ELA is included in the 
chemistry, manufacturing and controls section of the NDA (see 
Sec. 314.50(d)(1)(21 CFR 314.50(d)(1))); however, much of the 
information concerning the manufacturing facility that is included in 
an ELA is not included in an NDA.
    Technical advances over the last 15 years have greatly increased 
the ability of manufacturers to control and analyze the manufacture of 
many biotechnology-derived biological products. After over a decade of 
experience with these products, the agency has found that it can review 
the safety, purity, potency, and effectiveness of most well-
characterized biotechnology products without requiring submission of a 
separate ELA. Accordingly, FDA is proposing procedures under which CBER 
would approve well-characterized biotechnology products by requiring a 
single biologics license application. CDER would continue to approve 
NDA's for well-characterized biotechnology products. The single 
biologics license application and the NDA would have an identical 
format and include the same information. FDA would continue to inspect 
manufacturing facilities for compliance with good manufacturing 
practice requirements before approving either a biologics license 
application or NDA.
    FDA has determined that the review standards for well-characterized 
biotechnology products across the agency are substantially identical, 
notwithstanding that such standards may be specified in separate 
regulations, but the manner in which information is submitted to FDA is 
more burdensome when done through the ELA mechanism. Accordingly, the 
agency believes that the proposed procedures will significantly reduce 
burdens without reducing the safety or effectiveness of these products.

II. Legal Authority

    This proposal would establish a licensing scheme for well-
characterized biotechnology products that differs from the current 
licensing scheme in four fundamental ways. First, an applicant seeking 
marketing approval of a well-characterized biotechnology product would 
submit a single biologics license application to CBER and be issued a 
single license. Second, for these products, many of the establishment 
standards set forth in part 600 (21 CFR part 600) would be exempted 
from applicability and the current good manufacturing practice 
requirements found at parts 210 and 211 (21 CFR parts 210 and 211) 
would constitute the bulk of the applicable establishment standards. 
Some of the product standards set forth in part 610 (21 CFR part 610) 
would also be eliminated for these products. Third, in lieu of 
submitting an ELA to CBER showing compliance with establishment 
standards, FDA would evaluate whether establishment standards had been 
met by reviewing information submitted in the biologics license 
application and by inspecting the facilities in which the product is 
manufactured. Fourth, the term ``manufacturer'' as it is used in parts 
600 through 680 (21 CFR parts 600 through 680) would be broadened to 
include an applicant for a license for a well-characterized 
biotechnology product who may or may not own the facilities engaged in 
significant production steps. This would allow a single license 
applicant to take responsibility for compliance with the requirements 
in parts 600 through 680 applicable to manufacturers and eliminate the 
requirement that each separate contract facility engaging in 
significant manufacturing obtain a separate license.
    These licensing procedures for well-characterized biotechnology-
derived biological products are authorized by section 351 of the PHS 
Act. The proposed rule would establish an administrative approach to 
enforce the requirements in sections 351(a) and (d) of the PHS Act 
appropriate for current scientific and technological methods applied in 
the manufacture of these products.
    FDA's current regulations to administer and enforce the statutory 
requirements embody a dual licensing scheme: Applicants must submit to 
CBER an ELA and a PLA and obtain agency approval of both applications 
before they may distribute a biological product. Parts 600 through 680 
set out establishment and product standards that applicants must meet 
before FDA issues an establishment or product license. However, a dual 
licensing scheme is not compelled by the PHS Act.
    Section 351(a) of the PHS Act restricts the interstate sale, 
barter, and exchange of biologics to products manufactured in 
establishments that have been licensed. Section 351(a) requires that a 
biologic product be ``propagated or manufactured and prepared at an 
establishment holding an unsuspended and unrevoked license.'' Section 
351(d) authorizes the agency to prescribe regulations for the issuance, 
suspension, and revocation of licenses: ``Licenses for the maintenance 
of establishments for the propagation or manufacture and preparation of 
[biological] products
* * * may be issued only upon a showing that the establishment and the 
products for which a license is desired meet standards, designed to 
insure the continued safety, purity, and potency of such products, 
prescribed in regulations, and licenses for new products may be issued 
only upon a showing that they meet such standards.'' The sole 
limitation on the agency's discretion to issue biologic licenses is 
that licenses may only be 

[[Page 2735]]
issued upon a showing that both the establishment in which the product 
is prepared and the product meet regulatory standards designed to 
insure the continued safety, purity, and potency of such products.
    The PHS Act does not prescribe requirements for the format or 
content of license applications. Nor does it direct that there be two 
forms of license. The clear import of section 351(a) is that the entity 
responsible for the product and its manufacture should be licensed.
    The agency believes that the single biologics license application 
scheme that FDA is proposing for well-characterized biotechnology 
products is authorized by the PHS Act because licenses would continue 
to be issued only after the agency has made a determination that the 
product and the establishment(s) in which it is manufactured meet 
applicable regulatory standards. FDA would make its determination as to 
whether the product and establishment(s) meet applicable regulatory 
standards after reviewing the information submitted in the biologics 
license application and after inspecting the manufacturing facilities.
    FDA believes that a license holder need not be the legal owner of 
each facility in which the product is manufactured as long as he or she 
is responsible for assuring FDA that the product and establishment 
standards are met. Accordingly, the proposed rule would permit a single 
license holder to assume control of the production of a well-
characterized biotechnology product regardless of whether he or she 
owns the manufacturing facilities.
    FDA also believes that its administrative approach to enforcing the 
PHS Act can and should change to respond to changing knowledge and 
experience in reviewing the safety, purity, and potency of biological 
products.

III. Summary of Proposed Rule

A. Biologics License Application.

    The proposed rule would be applicable to applicants seeking 
marketing approval of well-characterized biotechnology products that 
are currently licensed under the provisions of the PHS Act.
    In an effort to further harmonize the manner in which well-
characterized biotechnology products are regulated, the agency is 
proposing in new Sec. 601.2(c) to eliminate the requirement for a 
separate ELA for well-characterized biotechnology products licensed 
under the PHS Act. This proposed regulation would require that an 
applicant seeking marketing approval of a well-characterized 
biotechnology product file a single application on a form prescribed by 
CBER. The form will include a section that is the same as the 
chemistry, manufacturing, and controls (CMC) section found in an NDA. 
(See Sec. 314.50(d)(1)). CBER and CDER have prepared a draft form that 
has been made available for comment. This draft form may be used in the 
interim until a final form is available. Both CBER and CDER intend to 
prepare and use the same guidance documents to aid in the preparation 
of the chemistry, manufacturing, and controls section of an application 
for a well-characterized biotechnology product. FDA intends that this 
guidance will be made available to the public by the time of issuance 
of any final rule resulting from this proposal.
    The CMC section of a license application for a well-characterized 
biotechnology product, like an NDA for a well-characterized 
biotechnology product, would include the following elements, at a 
minimum: A full description and characterization of the well-
characterized biotechnology product; the names, addresses, and 
responsibilities of all manufacturers involved in the manufacture and 
testing of the product; the method of manufacture, including raw 
materials, solvents, and reagents; process controls and tests; 
reference standards; specifications and analytical methods; a 
description of the container and closure system and its compatibility 
with the well-characterized biotechnology product drug substance; a 
description of the storage conditions, stability study protocols, and 
results; a tabulated list of all components; specifications and methods 
for the drug product's ingredients; methods of manufacturing and 
packaging of the well-characterized drug product including a floor plan 
which designates rooms in the manufacturing facilities and operations 
in each room; specifications and methods for the drug product; any 
microbiology and drug product stability data; description of any 
investigational formulation; environmental assessment and method 
validation.
    This proposal would also expand the definition in Sec. 600.3(t) of 
``manufacturer'' to include a license applicant for a well-
characterized biotechnology product regardless of whether the applicant 
is personally engaged in significant manufacturing steps.
    These proposed changes would facilitate a company's ability to 
contract out manufacture of its well-characterized biotechnology 
products. The proposed rule would eliminate the requirement that each 
separate contract facility engaging in significant production steps 
submit an ELA and a PLA. Instead, a well-characterized biotechnology 
product would be covered by a single biologics license application, 
which lists all manufacturing locations, regardless of how many 
separate companies are involved in its manufacture. FDA is seeking 
comment on whether the definition of ``manufacturer'' in Sec. 600.3(t) 
should also be expanded to include license applicants for products 
other than well-characterized biotechnology products.

B. Good Manufacturing Practice Requirements.

    The establishment standards for well-characterized biotechnology 
products would continue to include the CGMP regulations found in parts 
210 and 211 (21 CFR parts 210 and 211). FDA would review compliance 
with good manufacturing practice requirements upon inspection and 
applicants would be required to demonstrate such compliance in order to 
obtain approval of a biologics license application.
    Should well-characterized devices licensed under the PHS Act be 
identified and be eligible for the new procedures, applicable CGMP 
regulations would include parts 606 and 820 (21 CFR parts 606 and 820) 
(for blood and blood components). FDA requests comments on whether a 
specific reference to part 820 should be included in the rule.
    Under section 501(a)(2)(B) of the act, the methods used in, and the 
facilities or controls used for the manufacture, processing, packing, 
or holding of a drug must conform to current good manufacturing 
practice. Because the bulk drug substance, drug component, and bulk 
drug product meet the definition of ``drug'' in section 201(g)(1) of 
the act (21 U.S.C. 321(g)(1)), their manufacture also must conform to 
good manufacturing practice. The CGMP regulations set forth in parts 
210 and 211 are intended to apply to the preparation of a finished 
dosage form, whether or not in packaged form. (See 
Sec. Sec. 210.3(b)(4) and 211.1(a).) Although these CGMP regulations 
are not applied to the manufacture of bulk drug components, there are 
numerous instances where good manufacturing practice for bulk drug 
substances and bulk drug product components would parallel the 
requirements set forth in part 211. (See 43 FR 45076.) Because well-
characterized biotechnology products can be susceptible to 
contamination, adequate control over 

[[Page 2736]]
bulk manufacturing is important. FDA intends to use the standards of 
part 211 as guidelines during inspections of manufacturers of bulk drug 
substance and bulk drug product components, under the jurisdiction of 
the act, to help ensure that a well-characterized biotechnology product 
will have the proper raw materials controls, process validation and 
controls, and sensitive and validated test methods and specifications 
that are necessary to assure the safety, purity, potency, and 
effectiveness of the product.

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

    In order to harmonize the regulatory standards applied by CBER and 
CDER in their review of applications for well-characterized 
biotechnology products, FDA is proposing to exempt well-characterized 
biotechnology products licensed under the PHS Act from certain 
requirements found in parts 600 through 680. The regulations that have 
not been excluded in this proposed rule are those that FDA believes are 
necessary to ensure the safety, purity, and potency of well-
characterized biotechnology products; are essentially the same as those 
found in comparable regulations governing drug products; may not be 
applicable by their terms to well-characterized biotechnology products; 
or are ones that are targeted for revision. FDA requests comments on 
whether well-characterized biotechnology products should be exempted 
from requirements in parts 600 through 680 not identified for exclusion 
in this proposal, or whether certain regulations exempted in this 
proposed rule should remain applicable. FDA also requests comments on 
whether well-characterized devices licensed under the PHS Act, should 
such products be identified, would need to be exempted from the same or 
different requirements in parts 600 through 680.
    The following lists set forth those provisions that FDA proposes 
would remain applicable, those that FDA proposes to exempt from 
applicability to well-characterized biotechnology products, and those 
that would not be applicable by their terms to well-characterized 
biotechnology products.
    The following sections would remain applicable to well-
characterized biotechnology products: Sec. Sec. 600.3, 600.10(a), 
600.14, 600.20, 600.21, 600.22, 600.80, 600.81, 600.90, 601.2, 
601.3(b), 601.4, 601.5, 601.6, 601.7, 601.8, 601.9, 601.12, 601.20, 
601.21, 601.22, 601.33, 601.40, 601.41, 601.42, 601.43, 601.44, 601.45, 
601.46, 601.50, 601.51, 610.1, 610.2 (Lot-by-lot release eliminated for 
licensed well-characterized therapeutic recombinant DNA-derived and 
monoclonal antibody products per letters to manufacturers and notice in 
the Federal Register of December 8, 1995, (60 FR 63048.)), 610.9, 
610.10, 610.11a, 610.12 (Equivalent methods or processes possible under 
Sec. 610.9.), 610.13, 610.14, 610.15, 610.17, 610.18, 610.30, 610.40, 
610.41, 610.45 (Sections 610.40 through 610.45 apply to blood and blood 
components used in the manufacture of a well-characterized 
biotechnology product.), 610.50, 610.60, 610.61, 610.63, 610.64, 
610.65, and parts 606 (potential applicability to blood and blood 
components only); 640 (potential applicability to blood and blood 
products only); and 680 (would apply only to a well-characterized 
biotechnology allergenic product).-
    The following sections would be exempted from applicability to 
well-characterized biotechnology products: Secs. 600.10(b) and (c), 
600.11, 600.12, 600.13, 601.1, 601.30, 601.31, 601.32, 610.11, 610.53, 
and 610.62.
    The following sections by their terms would not be applicable to 
well-characterized biotechnology products: Secs. 600.15, 601.3(a), 
601.10, 601.25, 601.26, 610.16, 610.19, 610.20, 610.21, and parts 607, 
620, 630, 650, and 660.
    FDA is proposing to exempt well-characterized biotechnology 
products from the requirements of Sec. 610.11, which sets out 
procedures for a general safety test for biological products. FDA 
believes that a general safety test requirement is not necessary to 
ensure the safety, purity, and potency of a well-characterized 
biotechnology product. With in-process control and process validation 
and product testing, the identity of the well-characterized 
biotechnology product can be determined, its purity can be controlled 
and quantified, its activity and quantity can be measured, and the end-
product release specifications can be validated. The agency believes 
that specific analytical tests that are available for these products 
will provide a better assessment of safety than the general safety 
test.
    FDA is also proposing to exempt well-characterized biotechnology 
products from Sec. 610.62, which sets out requirements for position and 
prominence of the proper name of the product on the package label. FDA 
believes that the requirements in Sec. 201.10(g) are adequate to assure 
the appropriate identification of these products. -

D. Transition Issues.

    Any well-characterized biotechnology product for which a PLA and an 
ELA are pending on the effective date of these regulations would be 
reviewed as submitted. No new submission would be necessary to 
implement this rule change for these products. If found acceptable for 
licensure, FDA would issue a biologics license in lieu of issuing both 
a product and establishment license. Any company planning to file a PLA 
or an ELA prior to April 1996 should contact the agency for guidance. 
FDA specifically asks for comments on how transition issues should be 
handled.
    FDA anticipates that applicants already holding an approved ELA and 
PLA for a well-characterized biotechnology product would not be 
required to file supplements to comply with the new requirements. The 
approved PLA for a well-characterized biotechnology product, together 
with the limited portions of the approved ELA relevant to the new 
requirements for the biologics license application, would be deemed to 
constitute an approved biologics license application under the new 
regulations.

IV. Proposed Effective Date

    FDA proposes that a final rule resulting from this proposal become 
effective upon its date of publication in the Federal Register. As 
provided under 5 U.S.C. 553(d) and 21 CFR 10.40(c)(4), the effective 
date of a final rule may not be less than 30 days after publication, 
except for, among other things, ``a regulation that grants an exemption 
or relieves a restriction'' (Sec. 10.40(c)(4)(i)). Because, as 
described below, this rule would decrease the regulatory burdens for 
well-characterized biotechnology products, FDA believes that an 
immediate effective date is appropriate.

V. Analysis of Impacts

A. Reduction in Burden

    The proposed harmonization of the requirements would reduce burden 
on industry because companies manufacturing well-characterized 
biotechnology products that are regulated by both CBER and CDER would 
be able to submit applications for products in a consistent format.
    Companies developing and manufacturing well-characterized 
biotechnology products regulated by CBER would no longer have to 
prepare an ELA to submit to the agency for approval. The amount of 
information that applicants would need to provide in a biologics 
license application would be less than that currently required in a PLA 
and ELA. These proposed changes would enable companies to devote more 
resources to ensuring that 

[[Page 2737]]
manufacturing processes are properly validated and fewer resources to 
submitting documentation to the agency. These changes would especially 
benefit biotechnology companies that lack experience preparing ELA's 
and PLA's. According to the biotechnology industry, preparation and 
submission of an ELA may add substantially to the cost of obtaining 
approval of a well-characterized biotechnology product.
    The inclusion of parts 210 and 211 in the proposed rule as 
establishment standards would not impose any additional burden on 
industry. Human drugs, including well-characterized biotechnology 
products, are already subject to the CGMP's in parts 210 and 211.

B. Review Under Executive Order 12866 and the Regulatory Flexibility 
Act-

    FDA has examined the impact of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (Pub. L. 96-354). 
Executive Order 12866 directs agencies to assess all costs and benefits 
of available regulatory alternatives and, when regulation is necessary, 
to select regulatory approaches that maximize net benefits (including 
potential economic, environmental, public health and safety, and other 
advantages; distributive impact; and equity). The agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order. In addition, the proposed 
rule is a significant regulatory action as defined by the Executive 
Order and is subject to review under the Executive Order because it 
deals with a novel policy issue.
    In accordance with the principles of Executive Order 12866, the 
overall result of the proposed rule would be a substantial reduction in 
burdens on applicants filing for approval of a well-characterized 
biotechnology product. In addition, FDA anticipates that the proposed 
rule would facilitate applicants' ability to improve their licensed 
products and methods of manufacture by decreasing the burden and cost 
associated with filing an application.
    The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. Because, as stated previously, the overall result of 
the proposed rule would be a substantial reduction of the regulatory 
and reporting burdens, the agency certifies that the proposed rule 
would not have a significant negative economic impact on a substantial 
number of small entities. Therefore, under the Regulatory Flexibility 
Act, no further analysis is required.

C. Review Under the Paperwork Reduction Act of 1995

    This proposed rule contains information collection requirements 
which are subject to review by the Office of Management and Budget 
(OMB) under the Paperwork Reduction Act of 1995. The title, description 
and respondent description of the information collection are shown 
below with an estimate of the annual reporting burden. Included in the 
estimate is the time for reviewing instructions, gathering and 
maintaining the data needed, and completing and reviewing the 
collection of information.
    With respect to the following collection of information, FDA 
invites comments on: (1) Whether the proposed collection of information 
is necessary for the proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Well-characterized Biotechnology Products; Elimination of 
Establishment License Application.
    Description: FDA is proposing to eliminate the requirement that an 
ELA be submitted and approved by FDA for those well-characterized 
biotechnology products that are licensed by CBER. For these products, 
in place of the ELA, a company would be required to prepare and submit 
additional information for inclusion in a single biologics license 
application, which would be the same as the information included in the 
``Chemistry, manufacturing, and controls'' (CMC) section of a NDA. This 
proposed regulation would harmonize the approval and other regulatory 
requirements for all well-characterized biotechnology product under the 
PHS Act or approved as a drug under the new drug provisions of the act.
    Description of Respondents: All applicants for a biological product 
license to be approved under the Public Health Service Act.

                                                                                                                
----------------------------------------------------------------------------------------------------------------
                                        Estimated Annual Reporting Burden                                       
-----------------------------------------------------------------------------------------------------------------
                    Number of         Frequency of         Total Annual         Hours per                       
 CFR Section       Respondents          Responses           Responses            Response         Total Hours   
----------------------------------------------------------------------------------------------------------------
601.2(c)       1                   1                   1                    40                 40               
                                                                                                                
                                                                                                                
                                                                                                                
                                                                                                                
                                                                                                                
----------------------------------------------------------------------------------------------------------------

    Reporting or Disclosure: These estimates are an approximation of 
the average time expected to be necessary for a collection of 
information. They are based on such information as is available to FDA. 
There are no capital costs or operating and maintenance costs 
associated with this information collection. The number of respondents 
is dependent in part, on the definition of ``well-characterized 
biotechnology products,'' now under review by the agency. At the 
present time, FDA estimates the number of respondents at one a year. 
The agency seeks comment on these estimates, particularly the 
industry's view of the number of firms and products affected by the 
collections of information requirements contained in this proposed 
rule.
    The agency has submitted a copy of this proposed rule to OMB for 
its review of these information collections. Interested persons are 
requested to send 

[[Page 2738]]
comments regarding this information collection, including suggestions 
for reducing this burden, to the Office of Information and Regulatory 
Affairs, OMB, New Executive Office Bldg., 725 17th St. NW., rm. 10235, 
Washington, DC 20503, Attn: Desk Officer for FDA. Submit written 
comments on the information collection by February 28, 1996 but not 
later than March 29, 1996.

D. Environmental Impact

    The agency has determined under 21 CFR 25.24(a)(8) that this action 
is of a type that does not individually or cumulatively have a 
significant effect on the human environment. Therefore, neither an 
environmental assessment nor an environmental impact statement is 
required.

    Interested persons may, on or before February 28, 1996, submit to 
the Dockets Management Branch (address above) written comments 
regarding the proposal. Two copies of any comments are to be submitted, 
except that individuals may submit one copy. Comments are to be 
identified with the docket number found in brackets in the heading of 
this document. Two copies of all comments are to be submitted, except 
that individuals may submit one copy. The comments received are 
available for public examination in the Dockets Management Branch 
between 9 a.m. and 4 p.m., Monday through Friday. Submit written 
comments on the information collection requirements to the Office of 
Information and Regulatory Management, OMB (address above).

List of Subjects

21 CFR Part 600

    Biologics, Reporting and recordkeeping requirements.

21 CFR Part 601

    Administrative practice and procedure, Biologics, Confidential 
business information.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and the 
Public Health Service Act, and under authority delegated to the 
Commissioner of Food and Drugs, it is proposed that 21 CFR parts 600 
and 601 be amended as follows:

PART 600--BIOLOGICAL PRODUCTS: GENERAL

    3. The authority citation for 21 CFR part 600 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352, 
353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125 
of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a, 
264, 300aa-25).

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


Sec. 600.3  Definitions.

* * * * *
    (t) Manufacturer means any legal person or entity engaged in the 
manufacture of a product subject to license under the act; 
``Manufacturer'' also includes an applicant for a license for a well-
characterized biotechnology product.
* * * * *

PART 601--LICENSING

    5. The authority citation for 21 CFR part 601 continues to read as 
follows:

    Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520, 
701, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21 
U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374, 
379e, 381); secs. 215, 301, 351, 352 of the Public Health Service 
Act (42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging 
and Labeling Act (15 U.S.C. 1451-1461).

    6. Section 601.2 is amended by adding a sentence at the end of 
paragraph (a) and by adding a new paragraph (c) to read as follows:


Sec. 601.2  Applications for establishment and product licenses; 
procedures for filing.

    (a) * * * In lieu of the procedures described in this paragraph, 
applications for well-characterized biotechnology products shall be 
handled as set forth in paragraph (c) of this section.
* * * * *
    (c) Well-characterized biotechnology products. (1) To obtain 
marketing approval for a well-characterized biotechnology product, an 
applicant shall submit to the Director, Center for Biologics Evaluation 
and Research, a biologics license application on a form prescribed by 
the Director, Center for Biologics Evaluation and Research. For such 
well-characterized biotechnology products, a separate establishment 
license application shall not be required. An application for a license 
for a well-characterized biotechnology product shall include: Data 
derived from nonclinical laboratory and clinical studies that 
demonstrate that the manufactured product meets prescribed standards of 
safety, purity, and potency; with respect to each nonclinical 
laboratory study, either a statement that the study was conducted in 
compliance with the requirements set forth in part 58 of this chapter, 
or, if the study was not conducted in compliance with such regulations, 
a brief statement of the reason for the noncompliance; statements 
regarding each clinical investigation involving human subjects 
contained in the application, that it either was conducted in 
compliance with the requirements for institutional review set forth in 
part 56 of this chapter or was not subject to such requirements in 
accordance with Secs. 56.104 or 56.105 of this chapter, and was 
conducted in compliance with requirements for informed consent set 
forth in part 50 of this chapter; a full description of manufacturing 
methods; data establishing stability of the product through the dating 
period; sample(s) representative of the product to be sold, bartered, 
or exchanged or offered, sent, carried or brought for sale, barter, or 
exchange; summaries of results of tests performed on the lot(s) 
represented by the submitted samples; and specimens of the labels, 
enclosures, and containers proposed to be used for the product. An 
application for license shall not be considered as filed until all 
pertinent information and data have been received from the applicant by 
the Center for Biologics Evaluation and Research. The applicant shall 
also include either a claim for categorical exclusion under Sec. 25.24 
of this chapter or an environmental assessment under Sec. 25.31 of this 
chapter.
    (2) Approval of the biologics license application and issuance of 
the biologics license shall constitute a determination that the 
establishment and the product meet applicable standards established in 
this chapter to ensure the continued safety, purity, and potency of 
such products. Applicable standards for the maintenance of 
establishments for the manufacture of well-characterized biotechnology 
product shall include the good manufacturing practice requirements set 
forth in parts 210 and 211 of this chapter. The following sections in 
parts 600 through 680 of this chapter shall not be applicable to well-
characterized biotechnology products: Sec. Sec.  600.10(b)
and (c), 600.11, 600.12, 600.13, 601.1, 601.30, 601.31, 601.32, 610.11, 
610.53, and 610.62 of this chapter.




[[Page 2739]]

    (3) The term ``product license application,'' as it is used in 
those sections of parts 600 through 680 of this chapter that are 
applicable to well-characterized biotechnology products, shall include 
a biologics license application for a well-characterized biotechnology 
product.
    (4) To the extent that the requirements in this paragraph conflict 
with other requirements in this subchapter, this paragraph (c) shall 
supercede such other requirements.

    Dated: January 8, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 96-1582 Filed 1-25-96; 10:42 am]
BILLING CODE 4160-01-F