[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