[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.

[[Page 24229]]

    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