[Federal Register Volume 61, Number 94 (Tuesday, May 14, 1996)]
[Rules and Regulations]
[Pages 24226-24233]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-12144]
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[[Page 24227]]
DEPARTMENT OF HEALTH AND HUMAN SERVICES
21 CFR Parts 600 and 601
[Docket No. 95N-0411]
RIN 0910-AA71
Elimination of Establishment License Application for Specified
Biotechnology and Specified Synthetic Biological Products
AGENCY: Food and Drug Administration, HHS.
ACTION: Final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the
biologics regulations to eliminate the establishment license
application (ELA) requirement for certain biotechnology and synthetic
biological products subject to licensing under the Public Health
Service Act (PHS Act). This final rule also exempts these biotechnology
and synthetic biological products from certain biologics regulations
and harmonizes the requirements applicable to these products with those
applicable to similar drug products which are approved under the
Federal Food, Drug, and Cosmetic Act (the act). This final rule is part
of FDA's continuing effort to achieve the objectives of the President's
``Reinventing Government'' initiatives, and it is intended to reduce
unnecessary burdens for industry without diminishing public health
protection.
EFFECTIVE DATE: May 24, 1996.
FOR FURTHER INFORMATION CONTACT: Sharon A. Carayiannis, Center for
Biologics Evaluation and Research (HFM-630), Food and Drug
Administration, 1401 Rockville Pike, suite 400S, Rockville, MD 20852-
1448, 301-594-3074.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of January 29, 1996, FDA proposed to amend
the biologics regulations to eliminate the ELA requirement for well-
characterized biotechnology products licensed under the PHS Act. In
that document, FDA proposed to use the general phrase ``well-
characterized biotechnology product,'' to describe products that would
be eligible for a single license application so that the regulatory
language would accommodate categories of products that might later be
considered to be well-characterized as scientific knowledge progresses.
FDA requested specific comments on whether a definition of a well-
characterized biotechnology product should be included in the
regulations and, if so, what the scope of such a definition should be.
The agency noted that technical advances over the last 15 years
have greatly increased the ability of manufacturers to control and
analyze the manufacture of many 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 proposed
procedures under which CBER would approve most well-characterized
biotechnology products by requiring a single biologics license
application. FDA noted that the proposed procedures would significantly
reduce burdens without reducing the safety or effectiveness of these
products.
In the Federal Register of December 8, 1995 (60 FR 63048), the
agency first published an interim definition of a well-characterized
therapeutic recombinant DNA-derived and monoclonal antibody
biotechnology product and announced that, under Sec. 610.2, the
Director of CBER was no longer requiring that manufacturers of these
products submit samples and protocols to CBER for lot-by-lot release.
While the interim definition was intended to be used as a basis for
determining which products would be exempted from CBER lot-by-lot
release, FDA also used the interim definition to prepare draft guidance
on reporting post-approval changes for biotechnology products (as
published in the Federal Register of January 29, 1996 (61 FR 2739 at
2748), ``Draft Guidance; Changes to An Approved Application for Well-
Characterized Therapeutic Recombinant DNA-Derived and Monoclonal
Antibody Biotechnology Products''.)
In addition, FDA held a scientific workshop on December 11 through
13, 1995, to discuss the characterization of therapeutic recombinant
DNA-derived and monoclonal antibody products, including whether FDA's
interim definition should be changed or expanded to include other
categories of products that would be considered well-characterized.
After considering the public comments received on the interim
definition, the discussion at the workshop, and the many requests the
agency has received for further clarification of the term ``well-
characterized,'' FDA has determined that it may not be possible to
achieve a sufficiently clear and specific understanding of this term to
adequately apprise potential applicants of the applicability of the new
procedures. Accordingly, in this final rule, FDA is specifying, in lieu
of the term ``well characterized biotechnology product,'' the
categories of products to which this final rule will be applicable (see
comment Nos. 1 and 6).
FDA intends to evaluate the application of lot-by-lot release for
additional products and to announce in the Federal Register a revised
determination of which products will be exempted from lot-by-lot
release. FDA also plans to issue guidance on the characterization of
product categories specified in this rule. FDA anticipates that these
documents will replace the notice published in the Federal Register of
December 8, 1995 (60 FR 63048).
This final rule is part of FDA's continuing effort to achieve the
objectives of the President's ``Reinventing Government'' initiatives.
One goal of these initiatives is to harmonize regulations administered
by FDA's Center for Biologics Evaluation and Research (CBER) and Center
for Drug Evaluation and Research (CDER), to reduce unnecessary burdens
for industry without diminishing public health protection.
II. Proposed Rule
In the January 29, 1996, proposed rule, FDA proposed to amend
Sec. 601.2(a) and to add a new paragraph (c) to create a licensing
scheme for well-characterized biotechnology products that differs from
the current licensing scheme for biological products in four
fundamental ways. First, an applicant seeking marketing approval for a
product that falls within the scope of the rule would submit a single
biologics license application to CBER and would be issued a single
license. Second, for these products, many of the establishment and
product standards set forth in parts 600 through 680 (21 CFR parts 600
through 680) would not be applied. The current good manufacturing
practice (CGMP) regulations found at parts 210 and 211 (21 CFR parts
210 and 211), in addition to the information included in a chemistry,
manufacturing, and controls (CMC) section of the biologics license
application, would constitute the bulk of the applicable establishment
standards for these products. Third, in lieu of reviewing an ELA, FDA
proposed to evaluate whether establishment standards had been met by
reviewing information submitted in the biologics license application
and by inspecting the facilities in which the product is manufactured
for compliance with applicable requirements, including CGMP's. Fourth,
FDA proposed to amend Sec. 600.3(t) to broaden the term
[[Page 24228]]
``manufacturer'' as it is used in parts 600 through 680 to include an
applicant for a license for a well-characterized biotechnology product
who may or may not own the facilities engaged in significant
manufacturing steps. This amendment would allow a single license
applicant to take responsibility for compliance with the requirements
in parts 600 through 680 applicable to manufacturers and would
eliminate the requirement that each contract facility engaged in
significant manufacturing obtain its own license. Instead, each well-
characterized biotechnology product could be covered by a single
biologics license application, which lists all manufacturing locations,
regardless of how many separate companies are involved in its
manufacture. In addition, FDA requested comments on whether the
definition of ``manufacturer''in Sec. 600.3(t) should also be expanded
to include license applicants for products other than well-
characterized biotechnology products.
III. Responses to Letters of Comment
FDA allowed 30 days for comment on the proposal of January 29,
1996. Written comments received in response to the proposal are on file
in the Dockets Management Branch (HFA-305), Food and Drug
Administration, 12420 Parklawn Dr., rm. 1-23, Rockville, MD 20857.
FDA received seven comments in response to the proposed rule. The
comments, which addressed a number of issues, were received from
manufacturers of biotechnology products, a blood establishment, and a
biotechnology trade association. Comments received and FDA's responses
to the comments are discussed below. All of the comments supported the
proposal, although many comments contained suggestions or requests for
clarification. All of the letters supported FDA's efforts to achieve
the President's ``Reinventing Government'' initiatives and agreed that
the proposed changes will contribute to the goal of reducing
unnecessary burdens for industry and the agency without diminishing
public health protection.
1. Two comments requested that FDA define well-characterized
products in the final rule to clearly identify those entities subject
to the rule and to allow for public comment and administrative review.
However, one of these comments also suggested that FDA publish a
companion guidance document, updated as necessary, to provide
interpretation of this definition based on current technology and
scientific knowledge. Two comments requested that a definition be
included in a guideline rather than the regulation so that it can be
readily revised as the technology advances. One comment stated that the
proposal left uncertainty as to which products would be eligible for
the single license application.
In response to comments received, FDA has revised its proposed
administrative approach and is specifying, in Sec. 601.2(a) and new
paragraph (c), the categories of products subject to the rule. FDA has
decided to list the product categories in the regulation in order to
minimize uncertainty about which products are eligible for the new
procedures.
2. Five comments suggested that products in addition to those
identified in FDA's interim definition of a well-characterized
therapeutic recombinant deoxyribonucleic acid (DNA) derived and
monoclonal antibody biotechnology product could be considered well-
characterized and requested that FDA broaden the scope of the proposed
rule to include additional product categories. Particular categories
suggested by one or more comments include: Proteins, including those
isolated from natural sources; products (including vaccines and in
vitro diagnostics) made using synthetic peptides, recombinant DNA
technology and monoclonal antibody technology; products made using
chemical synthesis; DNA plasmid products; highly purified and
inactivated vaccines; polysaccharides; and any other biologic product
for which the applicant submits data from studies that demonstrate that
the manufactured product meets prescribed standards of safety, purity,
and potency. One comment suggested that in vitro diagnostic products
using biotechnology components should not be treated differently than
well-characterized biotechnology drugs. One comment requested that FDA
specify that blood, blood components (including plasma and stem cells),
and plasma derivatives (where the raw material is human based) are
products which should not be included.
FDA agrees that the elimination of the ELA requirement should apply
to product categories beyond those originally identified in the
agency's interim definition of a well-characterized therapeutic
recombinant DNA-derived and monoclonal antibody biotechnology product.
FDA is expanding the scope of this final rule to include additional
products, based on the technology of the manufacturing process and the
proposed use of the products. At this time, FDA has determined that it
has sufficient experience in reviewing investigational and product
applications to eliminate the ELA requirements for the following
categories of products: Therapeutic DNA plasmid products; therapeutic
synthetic peptide products of 40 or fewer amino acids; monoclonal
antibody products for in vivo use; and therapeutic recombinant DNA-
derived products. Methodologies are now available to characterize these
products in a much more rigorous fashion, allowing the products to be
more clearly evaluated by end product testing. FDA believes that
eliminating the submission for the facility and establishment
information will not adversely affect the public health.
FDA disagrees that vaccines and in vitro diagnostic (IVD) products
should be included within the scope of this rule at this time because
these products raise additional concerns in assessing safety, purity,
and potency. For vaccines, safety is a critical concern due to the
intended use in a healthy population. For IVD products, FDA believes
that the product and establishment standards necessary to ensure
continued safety, purity, and potency may differ from those applicable
to products included in this rule.
FDA agrees that blood and blood components, including plasma,
plasma derivatives, and stem cells, are products which should not fall
within the scope of this rule. FDA believes that license applications
for these and other naturally derived products should continue to
include establishment information at this time. FDA believes that a
license application that includes detailed information on the
facilities and controls may be necessary to assess the continued
safety, purity, and potency of these products. Because these products
involve complex issues, such as a risk of contamination with infectious
agents, their review requires special expertise and adequate time in
order to assess the adequacy of controls in place at the facility. In
addition, end product testing of naturally derived products may not be
sufficient to detect contamination with infectious agents. FDA intends
to continue to assess the need to expand the scope of the rule to
include additional categories of products as science and technology
advance and as the agency gains experience in regulating biological
products under this new scheme.
3. One comment suggested that the use of a single biologics
application be applied to all biologic products. Another comment
suggested that IVD products be eligible for the single license
application.
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As outlined in the President's November, 1995, National Performance
Review, ``Reinventing the Regulation of Drugs Made From
Biotechnology,'' FDA will use a standardized, single application form
for all biological and drug product approvals, regardless of which
Center regulates them. FDA will make the harmonized form available for
public comment through a subsequent rulemaking and will develop
guidance to assist applicants in completing the new application form
when it is available.
4. One comment suggested that FDA develop a guideline delineating
the responsibilities of center and field inspection personnel to avoid
confusion. One comment suggested that FDA application reviewers
participate in facility inspections to provide continuity.
FDA recognizes that close cooperation between center and field is
essential to the success of this approach. CBER and the field offices
intend to coordinate pre- and post-licensure inspections to provide
consistency in program and policy approaches. In addition, FDA plans to
develop guidance on facility standards for biotechnology manufacturing
facilities to clarify regulatory requirements and FDA policy.
5. One comment requested that companies have the option to submit
descriptions of systems design, equipment validation, etc., for FDA
review and comment prior to the time of inspection because it would be
advantageous to both industry and FDA.
FDA agrees that the submission of facility information, such as
systems design, and early dialogue is advantageous to both industry and
FDA. Accordingly, the agency intends to continue to review this
information, when requested, and provide comments early in the
development process, prior to and after the submission of the license
application. Companies should contact the Division of Establishment
Licensing, CBER, to arrange such reviews.
6. One comment stated that the use of an interim definition of
products that would be eligible for single license application under
Sec. 601.2(c) creates the possibility that FDA might refuse to file a
biologics license application for a product that the applicant believes
is well-characterized, even though the application might include
sufficient data to demonstrate that the product meets prescribed
standards for safety, purity, and potency. Another comment suggested
that the determination as to whether a product is well-characterized
should be made during the Phase 2 clinical trials or as early in the
process as is practical.
As discussed above in the response to comment No. 1 of this
document, FDA has decided to clearly identify, by category, those
products subject to the rule, and thereby reduce uncertainty as to
whether a product falls within the scope of the rule. This clear
identification of products should also eliminate the concerns regarding
a refusal to file action and the need to provide sufficient data to
support an applicant's claim that its product is ``well-
characterized.'' Applicants seeking licensure of a product that falls
within a category listed in 601.2(c) will not be required to make an
initial showing that the product is ``well-characterized'' to use the
new procedures. Companies may seek guidance from FDA at any time on the
type of application that should be submitted, and FDA encourages early
communication.
7. One comment agreed with FDA's proposal to exempt well-
characterized products from Sec. 610.62, which sets out requirements
for position and prominence of the proper name of the product on the
package label. The comment suggested that this labeling change should
be voluntary for currently licensed products, that companies should be
allowed to phase in changes over a 24 month time period, and that
preapproval should not be required.
The comment may have misunderstood the applicability of
Sec. 201.10(g) (21 CFR 201.10(g)). Section 201.10(g) applies to
biological products licensed under section 351 of the PHS Act, as well
as to drugs approved under the act. Accordingly, labels that comply
with preexisting requirements should not require revisions to comply
with the requirements in this final rule.
8. One comment suggested that manufacturers submitting a biologics
license application should be permitted to cross-reference information
already supplied in an approved ELA.
FDA agrees that avoiding unnecessary duplication of information in
applications is desirable. FDA will permit a biologics license
applicant to cross-reference information already submitted in an
approved ELA at this time. However, the agency may reassess the
viability of this approach in the future. Should the information in the
approved ELA become outdated, cross-reference may no longer be
appropriate.
9. One comment agreed with FDA's proposed revision of the
definition of ``manufacturer'' in Sec. 600.3(t). Three comments
requested that FDA apply an expanded definition of ``manufacturer'' to
all biologic license applicants and not limit application of this
definition exclusively to well-characterized products. One of the
comments favoring a broader definition suggested the following language
for Sec. 600.3(t): ``Manufacturer'' means any legal person or entity
engaged in the manufacture of a product subject to license under the
act; ``Manufacturer'' also includes an applicant for a license for a
product, or a license holder, who is responsible for assuring that the
product and establishment standards are met.
FDA agrees with the comments requesting the broader definition of
``manufacturer'' and is revising Sec. 600.3(t) to include any license
applicant who assumes responsibility for compliance with the applicable
product and establishment standards in parts 600 through 680. FDA
believes that this change will facilitate contract manufacturing
arrangements for all biological products by allowing an applicant who
does not own all the facilities where significant manufacturing is
performed to apply for licensure. The revised Sec. 600.3(t) will define
``manufacturer'' as the term is used in parts 600 through 680. Contract
firms engaged in the manufacture, processing, packing, or holding of a
biological drug will continue to be subject to applicable CGMP
requirements and the amendment to Sec. 600.3(t) will not affect other
definitions of ``manufacturer'' contained in other applicable statutes
and regulations. FDA intends to revise current guidance on contract
manufacturing arrangements for applicants interested in pursuing such
arrangements under the new definition.
10. One comment requested that Sec. 610.63, which addresses package
label and container label requirements for products manufactured under
an arrangement involving two or more establishments, be exempted from
applicability to well-characterized biotechnology products because such
products would involve a single license holder. The comment suggested
that it would be unnecessary to require that the labeling show the
names of multiple participating manufacturers.
The agency does not agree that Sec. 610.63 should be exempted from
applicability to the products covered in this rule. Divided or shared
manufacturing arrangements could still exist between holders of
biologics licenses for products subject to this rule if this was an
arrangement the companies desired, and in these cases Sec. 610.63 would
apply.
However, FDA agrees that it is unnecessary to identify contract
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manufacturers on the package label and container label of a biological
product subject to this final rule. FDA has applied Sec. 610.63 to
require label identification of licensed manufacturers only. As
discussed below, FDA intends to consider the need for revisions to
Sec. 610.63 in separate rulemaking. FDA also intends to revise the
November 25, 1992, Policy Statement Concerning Cooperative
Manufacturing Arrangements for Licensed Biological Products to address
contract, divided, and shared manufacturing arrangements under the new
regulatory scheme.
11. One comment suggested that Secs. 610.60, 610.61, 610.63,
610.64, and 610.65 be eliminated for all biologic products and be
replaced by labeling requirements described in part 201 (21 CFR part
201), subpart A.
FDA agrees that harmonizing the labeling requirements for biologics
and drugs approved under the act, where appropriate, is desirable. It
is important to note that biologic products are already subject to most
provisions in subpart A of part 201. FDA is considering revising the
labeling requirements in Secs. 610.60 through 610.65 as part of the
agency's comprehensive review and rewrite of the general biologics
regulations.
12. One comment stated that Sec. 600.10(a), which describes the
requirements for an establishments to designate a ``responsible head,''
should not apply to well-characterized products as currently written.
FDA agrees that Sec. 600.10(a), as currently written, imposes
unnecessary burdens for many modern biological manufacturers and has
made a commitment to publish a proposed rule to revise this regulation
within 9 months of the publication of the President's November, 1995,
National Performance Review, ``Reinventing the Regulation of Drugs Made
From Biotechnology.'' FDA intends to revise the requirements to allow
more flexibility to assign control and oversight responsibility within
a company.
13. One comment requested that Sec. 600.22(g), which authorizes
inspectors to inspect and copy, as circumstances may require, any
records to be kept under to Sec. 600.12, be amended because Sec. 600.12
will not apply to well-characterized biotechnology products under this
rule.
The agency believes that it is not necessary to amend
Sec. 600.22(g) because the CGMP requirements in parts 210 and 211 that
apply to products subject to this rule include recordkeeping
requirements and state that records are subject to photocopying as part
of an FDA inspection (see Sec. 211.180(b)).
14. One comment requested clarification of Sec. 601.3(b), which
describes the information required on the product license form. One
comment requested that FDA eliminate the requirement for an
establishment license number in the product license application (PLA)
for well-characterized products because a contract manufacturing site
engaged in multiproduct manufacture for different manufacturers may
produce several licensed products. The comment stated that the
establishment number would not be meaningful under such circumstances.
FDA believes that it is unnecessary to include an exemption for
Sec. 601.3(b)(4) in this rule. Elsewhere in this issue of the Federal
Register, FDA is announcing the availability of an interim form, FDA
3439, which contains a section in which all locations performing
manufacturing or testing of the product are to be identified. If a
location has a license number, that number should be included as part
of that identification, as should the location's registration number.
If there is no license number for the location, it cannot be included,
as is currently the case for a new establishment filing its first PLA
and ELA.
15. One comment requested that Sec. 601.22, which permits initial
and partial manufacturing of products in short supply at other than a
licensed establishment, be amended to include a statement clarifying
the relevant referenced regulations when Sec. 601.22 is applied to
well-characterized products.
FDA agrees and is making conforming amendments to Sec. 601.22 to
specify that persons conducting the initial and partial manufacturing
of a product that is subject to this rule shall be subject to all
regulations of subchapter F except Secs. 601.1 to 601.6, 601.9, 601.10,
601.20, 601.21; 601.30 to 601.33; 610.60 to 610.65, 600.10(b) and (c),
600.11, 600.12, 600.13, 610.11, and 610.53.
16. One comment stated that Sec. 601.45, which requires, for
certain products, submission of promotional materials to the agency,
should not apply to well-characterized biotechnology products. The
comment suggested that the proposed rule under which promotional
labeling materials would not have to be submitted for agency
consideration within 120 days following marketing approval be applied
to well-characterized products. The comment also suggested that
submission of advertisements and promotional labeling be regulated
under Sec. 314.81(b)(3)(i) (21 CFR 314.81(b)(3)(i)).
The comment may have misunderstood the applicability of
Sec. 601.45. Section 601.45 applies solely to biological products
subject to subpart E, Accelerated Approval of Biological Products for
Serious or Life Threatening Illnesses. For biological products not
subject to subpart E, FDA has proposed to revise requirements for
submission of advertisements and promotional labeling to CBER to
reflect procedures found in Sec. 314.81(b)(3)(i), in the proposal of
January 29, 1996 (61 FR 2733 at 2739).
17. One comment requested that Sec. 610.9, which permits
manufacturers, under certain conditions, to modify a particular test
method or manufacturing process, be exempted from applicability to
well-characterized biotechnology products. The comment also suggested
that this regulation be eliminated as part of the proposed revisions to
Sec. 601.12, published in the Federal Register (61 FR 2739).
FDA disagrees with the comment. The comment may have misunderstood
Sec. 610.9. This regulation allows manufacturers the flexibility to
modify methods or processes specified in regulations, if the
modification can be shown to provide equivalent assurance of safety,
purity, potency, and effectiveness. Because this regulation adds
flexibility without compromising the safety, purity, potency, or
effectiveness of biological products, FDA believes that it should apply
to all biological products.
18. One comment suggested that a broad interpretation of
Sec. 610.15, which describes the requirements for use of constituent
materials, may require development of sophisticated purification
methods to reduce the level of ``contaminating'' immunoglobulins to the
one part per million level if applied to cell culture products such as
monoclonal antibodies. The comment suggested that Sec. 610.15 be
amended to be applicable only to vaccine products and products intended
to be antigenic.
Section 610.15(b) applies by its terms to cell culture-produced
vaccines intended for injection. For guidance on the use of a serum in
the medium for production of monoclonal antibodies, consult the Draft
``Points to Consider in the Manufacture and Testing of Monoclonal
Antibody Products for Human Use,'' announced in the Federal Register of
August 3, 1994 (59 FR 39571).
19. One comment suggested that Sec. 600.81 (the comment references
``Sec. 601.81,'' but the subject is consistent with Sec. 600.81), which
describes the requirements for product distribution reports, is
duplicative, provides no
[[Page 24231]]
value to the manufacturer or to FDA in ensuring the public health, and
should be eliminated. The comment requested that distribution
information for well-characterized biotechnology products be regulated
under Sec. 314.81(b)(2)(ii).
FDA disagrees with this comment. Section 600.81 differs from
Sec. 314.81(b)(2)(ii) in that Sec. 600.81 requires submission of
product distribution reports every 6 months; requires information on
bulk lot number, fill lot number and label lot number; states that FDA
may require more detailed information, as needed; and states that FDA
may require, on written notice, submission of reports at times other
than those stated in the regulation. FDA believes that the requirements
in Sec. 600.81 assist the agency in determining adverse reaction rates
for vaccines and other biological products, and are of use in
monitoring product safety. It should be noted that Sec. 600.90 permits
a licensed manufacturer to apply to FDA for a waiver from any of the
requirements of Sec. 600.81.
20. Several comments addressed issues beyond the scope of this
rulemaking. Comments included issues related to reporting of errors and
accidents (Sec. 600.14), lot release, methods for evaluating product
characteristics, and establishing product specifications.
Revisions to Sec. 600.14 Reporting of errors and other biologics
regulations are currently under consideration and are outside the scope
of this rulemaking. However, FDA will consider all comments received as
a part of the agency's comprehensive rewrite of the general biologics
regulations.
IV. Summary of Changes for the Final Rule
In response to comments received, FDA is making the following
changes in this final rule:
In lieu of the term ``well-characterized biotechnology
product,'' FDA is specifying, in Sec. 601.2(a) (21 CFR 601.2(a)) and
new paragraph (c), the categories of products to which the rule will
be applicable, including therapeutic DNA plasmid products;
therapeutic synthetic peptide products of 40 or fewer amino acids;
monoclonal antibody products for in vivo use; and therapeutic
recombinant DNA-derived products. The definition of manufacturer has
been modified to include an applicant for a license for any
biological product where the applicant assumes responsibility for
compliance with the applicable product and establishment standards.
The final rule also sets forth an amendment to 21 CFR 601.22
clarifying that section's applicability to the categories of
products specified in new Sec. 601.2(c).
V. Implementation Issues
Any therapeutic DNA plasmid product, therapeutic synthetic peptide
product of 40 or fewer amino acids, monoclonal antibody product for in
vivo use, and therapeutic recombinant DNA-derived product for which a
PLA and an ELA are pending on the effective date of these regulations,
will be reviewed as submitted. No new submission will be necessary to
implement this rule change for these products. If found acceptable for
licensure, FDA will issue a biologics license in lieu of issuing both a
product and establishment license.
Applicants already holding an approved ELA and PLA for a product
within the scope of this rule will not be required to file supplements
to comply with the new requirements. The approved PLA for the product,
together with the limited portions of the approved ELA relevant to the
new requirements for the biologics license application, will be deemed
to constitute an approved biologics license application under the new
regulations.
The agency recognizes that there are a variety of contractual
arrangements that could be affected by this rule. For example, an
innovator company may have contracted with another company to make a
product. Under the previous regulatory scheme, a contract manufacturer
could hold both the establishment license and the product license.
Under the new regulatory scheme, an innovator company may wish to hold
the license. FDA anticipates that firms desiring an arrangement where
the innovator holds the license could surrender the original licenses
to the agency and request reissuance of a new biological license to the
innovator under the provisions of this final rule. FDA urges license
holders or those wishing to change their licensing arrangements to
contact the agency for additional guidance on how this can be
accomplished.
VI. Effective Date
The final rule is effective May 24, 1996. As provided under 5
U.S.C. 553(d) and 21 CFR 10.40(c)(4), the effective date of a final
rule may not be less than 30 days after publication, except for, among
other things, ``a regulation that grants an exemption or relieves a
restriction'' (Sec. 10.40(c)(4)(i)). Because, as described below, this
rule will decrease the regulatory burdens for specified biotechnology
and synthetic biological products, FDA believes that an immediate
effective date is appropriate.
VII. Analysis of Impacts
A. Reduction in Burden
The harmonization of the requirements will reduce burden on
industry because companies manufacturing specified biotechnology and
synthetic products that are regulated by both CBER and CDER will be
able to submit applications for products in a consistent format.
Companies developing and manufacturing products within the scope of
this rule will no longer have to prepare an ELA to submit to the agency
for approval. The amount of information that applicants will need to
provide in a biologics license application will be less than that
currently required in a PLA and ELA. These changes will enable
companies to devote more resources to ensuring that manufacturing
processes are properly validated and fewer resources to submitting
documentation to the agency. These changes will especially benefit
biotechnology companies that lack experience preparing ELA's and PLA's.
According to the biotechnology industry, preparation and submission of
an ELA may add substantially to the cost of obtaining approval of a
biotechnology product.
The inclusion of parts 210 and 211 in this final rule as
establishment standards will not impose any additional burden on
industry. Human drugs, including products subject to this rule, are
already subject to the CGMP's in parts 210 and 211.
B. Review Under Executive Order 12866 and the Regulatory Flexibility
Act
FDA has examined the impact of the final rule under Executive Order
12866 and the Regulatory Flexibility Act (Pub. L. 96-354). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impact; and equity). The agency believes that
this final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. In addition, the final
rule is a significant regulatory action as defined by the Executive
Order and is subject to review under the Executive Order because it
deals with a novel policy issue.
In accordance with the principles of Executive Order 12866, the
overall result of the final rule will be a substantial reduction in
burdens on
[[Page 24232]]
applicants filing for approval of a product subject to this rule. In
addition, FDA anticipates that the final rule will facilitate
applicants' ability to improve their licensed products and methods of
manufacture by decreasing the burden and cost associated with filing an
application.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because, as stated above, the overall result of the
final rule will be a substantial reduction of the regulatory and
reporting burdens, the agency certifies that the final rule will not
have a significant negative economic impact on a substantial number of
small entities. Therefore, under the Regulatory Flexibility Act, no
further analysis is required.
C. Review Under the Paperwork Reduction Act of 1995
This final rule contains information collection requirements that
were submitted for review and approval to the Director of the Office of
Management and Budget (OMB) as required by section 3504(b) of the
Paperwork Reduction Act of 1995. As part of this review, FDA provided
individuals and organizations an opportunity to comment to OMB on the
information collection requirements in the proposed rule. All comments
received agreed that FDA's proposal to eliminate the ELA requirements
for certain biotechnology products would reduce the burden to industry
without diminishing the public health protection. As a result of
information provided, FDA has revised the number of estimated
applicants yearly from 1 to 15. The estimate for completing the
application has not changed, however. This number remains at 40. These
information collection requirements were approved and assigned OMB
control number OMB No. 0910-0316. The expiration date for this approval
is December 31, 1997. An agency may not conduct or sponsor, and a
person is not required to respond to, a collection of information
unless it displays a currently valid OMB control number.
The title, description and respondent description of the
information collection are shown below with an estimate of the annual
reporting burden. Included in the estimate is the time for reviewing
instructions, gathering and maintaining the data needed, and completing
and reviewing the collection of information.
Title: Elimination of Establishment License Application for
Specified Biotechnology and Synthetic Biological Products.
Description: FDA is eliminating the requirement that an ELA be
submitted and approved by FDA for specified biotechnology and synthetic
biological products that are licensed by CBER. For these products, in
place of the ELA, a company would be required to prepare and submit
additional information for inclusion in a single biologics license
application, which will be the same as the information included in the
``Chemistry, manufacturing, and controls'' (CMC) section of a new drug
application. This regulation will harmonize the approval and other
regulatory requirements applicable to specified biotechnology and
synthetic biological products licensed under the PHS Act and drugs
approved under the new drug provisions of the act.
Description of Respondents: All applicants for a biological product
license to be approved under the Public Health Service Act.
Estimated Annual Reporting Burden
----------------------------------------------------------------------------------------------------------------
Number of Frequency of Total Annual Hours per
CFR Section Respondents Responses Responses Response Total Hours
----------------------------------------------------------------------------------------------------------------
601.2(c) 15 1 15 40 600
----------------------------------------------------------------------------------------------------------------
There are no capital costs or operating and maintenance costs associated with this information collection.
Reporting or Disclosure: These estimates are an approximation of
the average time expected to be necessary for the collection of
information. They are based on such information as is available to FDA.
-
D. Environmental Impact
The agency has determined under 21 CFR 25.24(a)(8) that this action
is of a type that does not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.
List of Subjects
21 CFR Part 600
Biologics, Reporting and recordkeeping requirements.
21 CFR Part 601
Administrative practice and procedure, Biologics, Confidential
business information.
Therefore, under the Federal Food, Drug, and Cosmetic Act and the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR parts 600 and 601 are amended as
follows:
PART 600--BIOLOGICAL PRODUCTS: GENERAL
1. The authority citation for 21 CFR part 600 continues to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 519, 701, 704 of
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 351, 352,
353, 355, 360, 360i, 371, 374); secs. 215, 351, 352, 353, 361, 2125
of the Public Health Service Act (42 U.S.C. 216, 262, 263, 263a,
264, 300aa-25).
2. Section 600.3 is amended by revising paragraph (t) to read as
follows:
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 any legal person or entity who is an
applicant for a license where the applicant assumes responsibility for
compliance with the applicable product and establishment standards.
* * * * *
PART 601--LICENSING
3. The authority citation for 21 CFR part 601 continues to read as
follows:
Authority: Secs. 201, 501, 502, 503, 505, 510, 513-516, 518-520,
701, 704, 721, 801 of the Federal Food, Drug, and Cosmetic Act (21
U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f, 360h-360j, 371, 374,
379e, 381); secs. 215, 301, 351, 352 of the Public Health Service
Act (42 U.S.C. 216, 241, 262, 263); secs. 2-12 of the Fair Packaging
and Labeling Act (15 U.S.C. 1451-1461).
4. Section 601.2 is amended by designating the text of paragraph
(a) as introductory text of (a) and by adding a clause at the end of
the introductory text, new paragraphs (a)(1) through (a)(4), and (c) to
read as follows:
Sec. 601.2 Applications for establishment, product, and biologics
licenses; procedures for filing.
(a) * * * In lieu of the procedures described in this paragraph,
applications for the following specified
[[Page 24233]]
categories of products shall be handled as set forth in paragraph (c)
of this section:
(1) Therapeutic DNA plasmid products;
(2) Therapeutic synthetic peptide products of 40 or fewer amino
acids;
(3) Monoclonal antibody products for in vivo use; and
(4) Therapeutic recombinant DNA-derived products.
* * * * * -
(c)(1) To obtain marketing approval for a therapeutic DNA plasmid
product, therapeutic synthetic peptide product of 40 or fewer amino
acids, monoclonal antibody product for in vivo use, or therapeutic
recombinant DNA-derived product, an applicant shall submit to the
Director, Center for Biologics Evaluation and Research, a biologics
license application on a form prescribed by the Director, Center for
Biologics Evaluation and Research. For such products, a separate
establishment license application shall not be required. An application
for a license for such a product shall include:
(i) Data derived from nonclinical laboratory and clinical studies
that demonstrate that the manufactured product meets prescribed
standards of safety, purity, and potency; with respect to each
nonclinical laboratory study, either a statement that the study was
conducted in compliance with the requirements set forth in part 58 of
this chapter, or,
(ii) If the study was not conducted in compliance with such
regulations, a brief statement of the reason for the noncompliance;
(iii) Statements regarding each clinical investigation involving
human subjects contained in the application, that it either was
conducted in compliance with the requirements for institutional review
set forth in part 56 of this chapter or was not subject to such
requirements in accordance with 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;
(iv) A full description of manufacturing methods;
(v) Data establishing stability of the product through the dating
period;
(vi) Sample(s) representative of the product to be sold, bartered,
or exchanged or offered, sent, carried or brought for sale, barter, or
exchange;
(vii) Summaries of results of tests performed on the lot(s)
represented by the submitted samples; and
(viii) Specimens of the labels, enclosures, and containers proposed
to be used for the product.
(2) An application for license shall not be considered as filed
until all pertinent information and data have been received from the
applicant by the Center for Biologics Evaluation and Research. The
applicant shall also include either a claim for categorical exclusion
under Sec. 25.24 of this chapter or an environmental assessment under
Sec. 25.31 of this chapter.
(3) Approval of the biologics license application and issuance of
the biologics license shall constitute a determination that the
establishment and the product meet applicable standards established in
this chapter to ensure the continued safety, purity, and potency of
such products. Applicable standards for the maintenance of
establishments for the manufacture of a product subject to this
paragraph (c) shall include the good manufacturing practice
requirements set forth in parts 210 and 211 of this chapter. The
following sections in parts 600 through 680 of this chapter shall not
be applicable to such products: 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 of this chapter.
(4) The term ``product license application,'' as it is used in
those sections of parts 600 through 680 of this chapter that are
applicable to products subject to this paragraph (c) shall include a
biologics license application for a therapeutic DNA plasmid product,
therapeutic synthetic peptide product of 40 or fewer amino acids,
monoclonal antibody product for in vivo use, or therapeutic recombinant
DNA-derived product.
(5) To the extent that the requirements in this paragraph (c)
conflict with other requirements in this subchapter, this paragraph (c)
shall supersede such other requirements.
5. Section 601.22 is amended by adding a sentence after the second
sentence to read as follows:
Sec. 601.22 Products in short supply; initial manufacturing at other
than licensed establishment.
* * *For persons and places authorized under this section to conduct
the initial and partial manufacturing of a product for shipment solely
to a manufacturer of a product subject to licensure under
Sec. 601.2(c), the following additional regulations shall not be
applicable: Secs. 600.10(b) and (c), 600.11, 600.12, 600.13, 610.11,
and 610.53 of this chapter * * *.
Dated: May 6, 1996.
William B. Schultz,
Deputy Commissioner for Policy.
[FR Doc. 96-12144 Filed 5-10-96; 10:13 am]
BILLING CODE 4160-01-F
