[Federal Register Volume 64, Number 202 (Wednesday, October 20, 1999)]
[Rules and Regulations]
[Pages 56441-56454]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 99-27159]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Parts 3, 5, 10, 20, 50, 56, 58, 207, 310, 312, 316, 600,
601, 607, 610, 640, and 660
[Docket No. 98N-0144]
RIN 0910-AB29
Biological Products Regulated Under Section 351 of the Public
Health Service Act; Implementation of Biologics License; Elimination of
Establishment License and Product License
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 references to establishment licenses
and product licenses for all products regulated under the Public Health
Service Act (the PHS Act). In lieu of filing an establishment license
application (ELA) and product license application (PLA) in order to
market a biological product in interstate commerce, a manufacturer will
file a single biologics license application (BLA) with the agency. Upon
approval of the BLA, a manufacturer will receive a biologics license to
market the product in interstate commerce. This action is part of FDA's
continuing effort to achieve the objectives of the President's
``Reinventing Government'' initiatives and is intended to reduce
unnecessary burdens for industry without diminishing public health
protection. This action implements certain sections of the FDA
Modernization Act of 1997 (FDAMA).
DATES: Effective date: The regulation is effective December 20, 1999.
Compliance Date: Submit all applications with the Form FDA 356h by
December 20, 1999, and submit any application for licensure as a BLA by
October 20, 2000.
FOR FURTHER INFORMATION CONTACT: Robert A. Yetter, Center for
Biologics Evaluation and Research (CBER) (HFM-10), Food and Drug
Administration, 1401 Rockville Pike, suite 200N, Rockville, MD 20852-
1448, 301-827-0373.
SUPPLEMENTARY INFORMATION:
I. Background
In the Federal Register of July 31, 1998 (63 FR 40858), FDA
proposed to amend the biologics and other drug regulations to eliminate
references to the PLA and ELA and to replace such references with the
BLA. FDA provided 75 days for comments on the proposed rule. FDA held a
public meeting, announced in the Federal Register of August 11, 1998
(63 FR 42773), on September 2, 1998, to discuss the BLA/biologics
license scheme. FDA also invited the submission of written comments to
the docket at the public meeting. The transcript of the public meeting
and written comments to the proposed rule are on file in the Dockets
Management Branch (HFA-305), 5630 Fishers Lane, rm. 1061, Rockville, MD
20852.
Prior to the issuance of the proposed rule, FDA had already
reviewed its process of licensing biological products and had taken a
number of actions to reduce the regulatory burdens imposed by the
licensing process and to make the licensing process more consistent
with the process for the approval of new drugs. In the Federal Register
of May 14, 1996 (61 FR 24227), FDA issued a final rule to amend the
biologics regulations by eliminating the ELA requirement for the
following specified biotechnology and synthetic biological products
licensed under section 351 of the PHS Act (42 U.S.C. 262 et seq.): (1)
Therapeutic deoxyribonucleic acid (DNA) plasmid products; (2)
therapeutic synthetic peptide products of 40 or fewer amino acids; (3)
monoclonal antibody products for in vivo use; and (4) therapeutic
recombinant DNA-derived products. That provision applied only to those
products that FDA determined under principles articulated in the
``Intercenter Agreement Between the Center for Drug Evaluation and
Research and the Center for Biologics Evaluation and Research''
(effective on October 31, 1991) to be subject to licensure under
section 351 of the PHS Act. Thus, upon approval, manufacturers of the
specified biotechnology and synthetic biological products received a
single biologics license instead of a product license and an
establishment license (see Sec. 601.2(c) (21 CFR 601.2(c))).
In the Federal Register of July 8, 1997 (62 FR 36558), FDA
announced the availability of a revised Form FDA 356h entitled
``Application to Market a New Drug, Biologic, or an Antibiotic Drug for
Human Use.'' Form FDA 356h was revised as a ``Reinventing Government''
initiative to harmonize application procedures between CBER and the
Center for Drug Evaluation and Research (CDER) as outlined in the
President's November 1995 National Performance Review Report entitled
``Reinventing the Regulation of Drugs Made From Biotechnology.'' In the
notice, FDA advised that applicants for biologics licenses for products
specified in Sec. 601.2(c) as well as autologous somatic cell therapy
products could begin to use Form FDA 356h immediately and were required
to do so beginning January 8, 1998. FDA advised applicants for licenses
for other biological products that the agency would announce in the
future when they can voluntarily begin to use and will be required to
use Form FDA 356h. Upon approval of a BLA submitted on Form FDA 356h,
FDA will issue a single biologics license. FDA believes that this
licensing procedure will greatly simplify the application process,
harmonize application procedures with those of CDER, and reduce
industry and agency paperwork burdens. As a consequence of this final
[[Page 56442]]
rule, all manufacturers requesting approval to introduce, or deliver
for introduction, a biological product into interstate commerce must
use Form FDA 356h to submit a BLA in lieu of separate establishment and
product applications.
On November 21, 1997, the President signed into law FDAMA (Pub. L.
105-115). Section 123 of FDAMA, in pertinent part, amended section 351
of the PHS Act to specify that a biologics license shall be in effect
for a biological product prior to such product's introduction into
interstate commerce. FDAMA thereby statutorily codified FDA's
administrative BLA/biologics license ``Reinventing Government''
initiative. Section 123(a)(1) of FDAMA further states that the
Secretary of Health and Human Services (the Secretary) (delegated to
the Commissioner of Food and Drugs at 21 CFR 5.10(a)(5)) shall approve
a ``biologics license application'' on the basis of a demonstration
that the biological product that is the subject of the application is
safe, pure, and potent; and the facility in which the biological
product is manufactured, processed, packed, or held meets standards
designed to ensure that the biological product continues to be safe,
pure, and potent.
With the consolidation of the ELA's and PLA's into a single BLA,
the amount of information formerly included in the ELA will be reduced,
but not eliminated. Much of the information previously reviewed in an
ELA at FDA will be reviewed by FDA investigators at the manufacturing
site during a preapproval inspection. Some information formerly
included in the ELA will now be submitted as ``chemistry,
manufacturing, and controls'' (CMC) information or under the
``establishment description'' section of Form FDA 356h. The type and
amount of information related to the establishment will vary according
to the specific biological product for which licensure is being
requested. To describe what information should be included for each
type of biological product, CBER has prepared a series of guidance
documents. The following guidance documents are available: (1)
``Guidance for Industry for the Submission of Chemistry, Manufacturing,
and Controls Information for a Therapeutic Recombinant DNA-Derived
Product or a Monoclonal Antibody Product for In Vivo Use'' (61 FR
56243, October 31, 1996); (2) ``Guidance for the Submission of
Chemistry, Manufacturing, and Controls Information and Establishment
Description for Autologous Somatic Cell Therapy Products'' (62 FR 1460,
January 10, 1997); (3) ``Guidance for Industry for the Submission of
Chemistry, Manufacturing and Controls Information for Synthetic Peptide
Substances'' (issued on the internet, November 1994); (4) ``Guidance
for Industry: Content and Format of Chemistry, Manufacturing and
Controls and Establishment Description Information for a Vaccine or
Related Product'' (64 FR 518, January 5, 1999); (5) ``Guidance for
Industry for the Submission of Chemistry, Manufacturing and Controls
and Establishment Description Information for Human Plasma-Derived
Biological Products, Animal Plasma, or Serum-Derived Products'' (64 FR
7896, February 17, 1999); (6) ``Guidance for Industry: Content and
Format of Chemistry, Manufacturing and Controls, and Establishment
Description Information for a Biological In Vitro Diagnostic Product''
(64 FR 11023, March 8, 1999); (7) ``Guidance for Industry: On the
Content and Format of Chemistry, Manufacturing and Controls, and
Establishment Description Information for an Allergenic Extract or
Allergen Patch Test'' (64 FR 20006, April 23, 1999); and (8) ``Guidance
for Industry: For the Submission of Chemistry, Manufacturing and
Controls, and Establishment Description Information for Human Blood and
Blood Components Intended for Transfusion or for Further Manufacture
and for the Completion of the Form FDA 356h Application to Market a New
Drug, Biologic or an Antibiotic Drug for Human Use'' (64 FR 25049, May
10, 1999). All of these guidance documents can be downloaded from the
CBER Guidelines/Guidance document World Wide Web page at ``http://
www.fda.gov/cber/guidelines.htm''. These guidance documents can also be
obtained by written request to the Office of Communication, Training,
and Manufacturers Assistance (HFM-40), Center for Biologics Evaluation
and Research, Food and Drug Administration, 1401 Rockville Pike,
Rockville, MD 20852-1448. Send one self-addressed adhesive label to
assist the office in processing your requests. These documents may also
be obtained by mail by calling the CBER Voice Information System at 1-
800-835-4709 or 301-827-1800, or by fax by calling the FAX Information
System at 1-888-CBER-FAX or 301-827-3844.
II. Highlights of Proposed Rule
A. Introduction
FDA licenses biological products under the authority of section
351(a) of the PHS Act. The PHS Act requires that biological products be
licensed and be safe, pure, potent, and manufactured in facilities
designed to ensure that the product continues to be safe, pure, and
potent. The PHS Act does not specify the license application forms that
manufacturers must submit to FDA. Except for the biological products
listed under Sec. 601.2(c), FDA, in the past, has required
manufacturers to submit a PLA and an ELA (or a PLA and a supplement to
an existing ELA) for each biological product. Accordingly, upon
approval, FDA issued two licenses for each product.
In the proposed rule of July 31, 1998, FDA proposed changes to the
regulations intended to implement use of the BLA and to implement
FDAMA. The proposed rule would also change certain definitions to be
more consistent with FDAMA and eliminate references to the PLA and ELA.
In the following sections of this document, FDA outlines in greater
detail the provisions of the proposed rule.
B. Definitions and Deletion of Terms
In order to reduce any confusion that may result from use of the
term ``facility'' in section 351 of the PHS Act as amended by FDAMA,
FDA proposed to amend the definition of ``establishment'' in
Sec. 600.3(w) (21 CFR 600.3(w)) to clarify that the term has the same
meaning as ``facility'' in section 351 of the PHS Act. FDA also
proposed to amend the definition of ``standards'' in Sec. 600.3(n) to
indicate that the term refers to specifications and procedures
established in BLA's designed to ensure the continued safety, purity,
and potency of biological products as well as adherence to
specifications and procedures in applicable regulations. Establishing
standards in the BLA is consistent with FDA's previous effort to
streamline the license review process by deleting certain additional
standards in the biologics regulations (see 61 FR 40153, August 1,
1996). This proposed change to Sec. 600.3(n) also would reduce
confusion in the biologics regulations by establishing consistency with
FDA's current regulation at 21 CFR 601.5(b)(4) regarding the revocation
of licenses. FDA proposed to delete the term ``licensee'' as used in
the biologics regulations in order to reduce confusion and to make
clear that it is the licensed manufacturer who is responsible for
compliance with product and establishment requirements. The term
``licensed manufacturer'' would be inserted in all instances that
currently read ``licensee.''
[[Page 56443]]
C. Elimination of PLA/ELA and Implementation of BLA
FDA proposed that the terms ``biologics license'' or ``biologics
license application'' be substituted in lieu of references to PLA's and
ELA's and product and establishment licenses in all regulations in 21
CFR chapter I. In a few instances, references to product and
establishment licenses would be retained for historical accuracy, e.g.,
Sec. 601.25 (21 CFR 601.25) and 21 CFR 601.26.
Under the proposed rule, a manufacturer applying for approval to
market a biological product under section 351 of the PHS Act would
submit to FDA the appropriate establishment and product information on
the recently approved Form FDA 356h. Manufacturers would no longer be
required to submit product or establishment information on one of the
many different PLA and ELA forms formerly in use. Upon approval of the
BLA, FDA would issue an approval letter that in general terms states
that FDA grants the licensed manufacturer a biologics license to
manufacture the particular biological product. FDA would not issue
license certificates separate from the approval letter as is current
agency practice. The approval letter would serve as the functional
equivalent of a biologics license within the meaning of section 351 of
the PHS Act.
Under proposed Sec. 601.2(a), manufacturers would list in the BLA
the addresses of all locations of manufacture of a biological product.
FDA believes this will simplify and clarify the licensing processes by
having necessary establishment information in the BLA and also by
allowing FDA to approve all locations involved in the manufacture of
the product without having to issue an establishment license for each
location.
Under proposed Sec. 601.9(c), for manufacturers of some biological
products that would be able to list multiple products in a single BLA,
(such as blood and blood components and nonstandardized allergenic
products) and for which FDA will issue a single biologics license to
the manufacturer for more than one product, FDA would be able to
license compliant locations and products and exclude noncompliant
locations.
D. Radioactive Biological Products
FDA proposed to amend Sec. 601.2(b) to clarify procedures for
submitting an application for marketing approval for a radioactive
biological product in order to help ensure consistency with current
CBER and CDER policies and procedures. The regulation would clarify
when a manufacturer of a radioactive biological product should submit a
new drug application (NDA) to CDER or a BLA to CBER. The regulation
provides that when the biological component of a radioactive coupled
antibody determines the site of action, normally a BLA would be
submitted. The regulation will provide sufficient flexibility to take
into account situations that may arise in the future where the
scientific issues associated with a radionuclide or other chemically
synthesized component are more significant than the scientific issues
associated with the biological component. In such cases, jurisdiction
will be determined in accordance with principles articulated in the
``Intercenter Agreement Between the Center for Drug Evaluation and
Research and the Center for Biologics Evaluation and Research'' of
October 31, 1991. The proposed changes should not be construed as an
attempt to address or implement the requirements of section 122 of
FDAMA, ``Requirements for Radiopharmaceuticals.''
FDA is also amending Sec. 310.4 (21 CFR 310.4) to make it
consistent with Sec. 601.2(b). Revisions to the proposed changes to
Sec. 310.4 have been made for clarity. Certain changes to both
Sec. 310.4(a) and (b) are necessary in order to make congruous the
regulations that describe whether CBER or CDER will have primary
jurisdiction over a radioactive biological product. The amendment to
Sec. 310.4(b) is prospective and does not alter the approval mechanism
of any currently approved radioactive biological products that have
approved NDA's or approved establishment and product licenses. Section
310.4(a) is amended to make it consistent with Sec. 601.2(b) and to
clarify that if any biological product has an approved license under
section 351 of the PHS Act, it is not required to have an approved
application under section 505 of the Federal Food, Drug, and Cosmetic
Act (the act) (21 U.S.C. 355).
E. Current Good Manufacturing Practice Requirements
FDA discussed in the preamble to the proposed rule the
applicability of current good manufacturing practices (CGMP)
requirements for biological products. For clarity FDA proposed in
Sec. 601.2(d) that the CGMP requirements in parts 210, 211, 600, 606,
and 820 (21 CFR parts 210, 211, 600, 606, and 820) are included, as
applicable, as part of the establishment requirements for the
production of a biological product.
III. Comments on the Proposed Rule and FDA Responses
FDA received two letters of comment in response to the proposed
rule; one letter from an organization representing the blood and blood
component industry and another from a manufacturer of biological
products. Comments received and FDA's responses to the comments are
discussed below. There were also a few technical changes, to be
consistent with other changes in this rulemaking or to be consistent
with statutory language in FDAMA, made to the following regulations: 21
CFR 50.3(b)(12), 56.102(b)(11), 58.3(e)(13); Secs. 600.81, 601.2, and
601.21 (21 CFR 601.21). FDA is also revising 21 CFR 601.22 to remove
wording that was inadvertently added to the regulation in the proposed
rule that implied that either of two requirements must be met. The
change eliminates this ambiguity and reinstates the original intent
that both requirements must be met.
1. A comment was supportive of the concept of a BLA and use of the
Form FDA 356h but strongly urged FDA to ensure that the intended
paperwork reduction and efficiency goals are achieved. The comment
stated that the simplification of the BLA will be affected by how
supplemental applications are handled and expressed concern that this
be adequately addressed. The comment specifically requested that in
implementing the BLA for blood and blood components that one supplement
to the BLA be acceptable to report a change in the manufacturing of
Platelets, Pheresis for all manufacturing locations.
FDA agrees that it is important to implement the rule in a manner
that will reduce unnecessary burdens; accordingly the agency is
implementing several mechanisms for ensuring that this is the case.
Manufacturers of some biological products will be able to list multiple
products in a BLA and FDA will issue a single biologics license to the
manufacturer for more than one product. FDA intends to use this
approach generally with products that both have been on the market for
a long period of time and that FDA has considerable knowledge and
expertise regulating. Currently, only products such as blood and blood
components and nonstandardized allergenic products will be handled in a
single BLA. Therefore, a manufacturer of blood and blood components
will only need to submit one BLA to request approval to market one or
more blood or blood components, (e.g., Whole Blood, Platelets, Plasma,
Red Blood Cells, and
[[Page 56444]]
Cryoprecipitated AHF). FDA believes this consolidation of forms and
submissions will result in a reduced regulatory burden for the blood
industry because information previously duplicated in the many blood
and blood component product and establishment applications would be
submitted only once in the BLA.
With regard to manufacturing changes, the BLA system will simplify
submission of supplements to blood and blood component applications.
Currently, manufacturers desiring to make a single manufacturing change
that would affect multiple products are required to submit a supplement
to each individual product and establishment application. Under the
final rule, a manufacturer would only need to submit one supplement to
the BLA. For example, under the current PLA/ELA system if a
manufacturer desired to make a single change to the irradiation
procedure for its Whole Blood, Red Blood Cells, Platelets, and Plasma
products manufactured at 3 locations, the manufacturer would be
required to submit 12 supplements to 4 PLA's, i.e., a separate
supplement for each blood component manufactured at each location.
Under the final rule, the manufacturer would only be required to submit
one supplement to the BLA describing the change for all of the products
and locations involved. Of course, all data (including applicable
validation and quality control testing) and information related to all
the affected products and locations would be expected to be present in
the supplement. Section 123 of FDAMA states, in part, that the
Secretary shall approve a BLA on the basis of a demonstration that the
biological product that is the subject of the application is safe,
pure, and potent; and the facility in which the biological product is
manufactured, processed, packed, or held meets standards designed to
ensure that the biological product continues to be safe, pure, and
potent. FDA intends to ensure that the final rule will be properly
implemented and is providing adequate training and management oversight
to ensure that this happens.
2. One comment requested the elimination of the use of the Form FDA
2567, Transmittal of Labels and Circulars, as being duplicative of Form
FDA 356h.
FDA disagrees that the form is duplicative. FDA Form 2567 is used
for any submission of labeling, including promotional labeling. This
form (OMB Control No. 0910-0039) contains information that is not
requested in the Form FDA 356h, which is necessary for the adequate
tracking of labeling submissions to FDA. It provides specific
identification of the labeling changes, including revision number and
the type of labeling and provides a check list for the type of changes
that have been made to the labeling. The form provides a clear, simple
method for transmitting comments on the labeling to and from the
manufacturers allowing for quick return of comments and easy
identification of sequential revisions.
3. One comment stated that the ``Draft Guidance for Industry: For
the Submission of Chemistry, Manufacturing and Controls and
Establishment Description Information for Human Blood and Blood
Components Intended for Transfusion or for Further Manufacture and For
the Completion of the Form FDA 356h, `Application to Market a New Drug,
Biologic or an Antibiotic Drug for Human Use''' (63 FR 37401, July 10,
1998) requires, for the first time, submission of information regarding
certain manufacturing standard operating procedures (SOP's), contracts,
organizational characteristics, organization diagrams, physical plant,
major equipment, and quality assurance.
FDA disagrees in part with this comment. Guidance documents do not
set forth requirements; they provide the agency's current thinking on a
topic and are nonbinding. A review of SOP's, physical plant
information, and information on contracts have always been part of an
assessment of a product's safety, purity, and potency. FDA has the
authority to require sponsors to submit such information in license
applications under section 351 of the PHS Act and 21 CFR part 601. In
the more recent past, FDA has found that inadequate organizational/
managerial oversight and quality assurance problems at firms have
resulted in firms being out of compliance with the regulations
applicable to blood and blood components and have been the cause of
problems leading to significant enforcement action by the agency. FDA
believes it is important to review information related to the
managerial/organizational oversight and quality assurance in order to
ensure that a firm can manufacture products that meet the applicable
regulatory and statutory requirements. Therefore, FDA will review such
information as part of the BLA. FDA believes that the burden associated
with the submission of such information will be minimal. Describing
organizational aspects can be done through the use of organizational
charts, and under CGMP regulations, quality assurance is already a
requirement. The submission of descriptions of such organizations
should require minimal time for gathering and preparing the
information. In addition, since other information previously reviewed
as part of the PLA and ELA will not be required to be included in a
BLA, FDA estimates that the net effect is no increase in burden or a
slightly lower burden. For example, information that will no longer be
submitted in a BLA but should, as appropriate, be available for an
establishment inspection includes, but is not limited, to such
information as: (1) Floor plans of facilities, auxiliary facilities and
self-contained mobile units to show locations of major equipment, hand
washing facilities and restrooms; (2) Heating, ventilation, and air
conditioning information; (3) curriculum vitae for physicians,
physician substitutes, authorized officials and their alternates, and
managers; (4) ``statement of understanding'' from physicians and
authorized officials; (5) proof of state licensure of physicians; (6)
physician substitute certification of training and cardiopulmonary
resuscitation; (7) supervisor qualifications and number of people
supervised in the areas of donor suitability, blood collection,
laboratory processing, and testing; (8) description of any other uses
for the area where blood collection or processing occurs; (9)
description of provisions for housekeeping, pest control, and lighting;
(10) description of records maintenance method, including when they are
made, how long they are stored, and how they are maintained to permit
effective recall; and (11) copy of the certificate of incorporation.
FDA is currently reviewing comments on the draft CMC guidance and will
consider the comments in any revision made to the ``Draft Guidance for
Industry: For the Submission of Chemistry, Manufacturing and Controls
and Establishment Description Information for Human Blood and Blood
Components Intended for Transfusion or for Further Manufacture and for
the Completion of the Form FDA 356h, `Application to Market a New Drug,
Biologic or an Antibiotic Drug for Human Use.'''
4. One comment supported the proposed revision to Sec. 601.21 but
recommended that the regulation reference the appropriate section of
the act applicable to investigational device exemptions.
FDA agrees with the comment and is amending Sec. 601.21 in the
final rule to reference section 520(g) of the act (21 U.S.C. 360j(g))
that provides for exemption of devices for investigational use.
[[Page 56445]]
FDA has considered all comments received in response to the
proposed rule and has determined that the proposed rule should be
issued as a final rule. Accordingly, FDA is issuing as a final rule
changes to the biologics regulations that provide for the use of a
``biologics license application'' and ``biologics license'' for the
licensure of all products under section 351 of the PHS Act.
IV. Effective Dates and Other Implementation Issues
FDA is providing a 10-month transition period for implementation of
the BLA. FDA recognizes that it may take applicants time to switch
format from PLA's and ELA's to BLA's. Any PLA and ELA for a biological
product pending on the effective date of these regulations will be
reviewed as submitted. Notwithstanding the new regulations, new
submissions by the manufacturer will not be necessary for these
products. FDA will continue to accept PLA's and ELA's in lieu of a BLA
until October 20, 2000, of this final rule. However, all applications
submitted to the agency after the effective date of the final rule will
be required to include all information indicated in Form FDA 356h in
order for the application to be considered as complete. PLA's and ELA's
received after the effective date of the final rule will be
administratively handled by FDA as a BLA. If the PLA and ELA are
sufficient for licensure, FDA will issue a biologics license. Any
manufacturer planning to file a PLA and an ELA during the 10-month time
period after the effective date of these regulations should contact FDA
for further guidance.
Under new Sec. 601.2(e), a manufacturer already holding an approved
ELA and PLA for a biological product will not be required to file
supplements to comply with the amended regulations. The approved PLA
together with portions of the approved ELA relevant to the new
requirements for the BLA, will be deemed to constitute a BLA under
section 351 of the PHS Act .
V. Analysis of Impacts
A. Reduction in Burden
The use of the harmonized Form FDA 356h for all biological products
and drugs regulated by CBER and CDER will reduce burden on industry by
enabling manufacturers to submit applications for biological products
and drugs in a consistent format.
Manufacturers intending to introduce biological products into
interstate commerce will no longer have to prepare a PLA and an ELA to
submit to the agency for approval. The amount of information that
manufacturers will need to provide in a BLA will be less than that
previously required in a PLA and ELA. These changes will enable
manufacturers to devote fewer resources to submitting documentation to
the agency. Much of the information previously reviewed in an ELA at
FDA will be reviewed by FDA investigators at the manufacturing site
during a preapproval inspection. According to many biological product
manufacturers, preparation, submission, and approval of a separate PLA
and ELA for each biological product added substantially to the cost of
licensing the product.
The inclusion of reference to parts 210, 211, 600, 606, and 820 in
the final rule as establishment requirements only serve to clarify
existing requirements and will not impose any additional burden on
industry. Biological products regulated under section 351 of the PHS
Act, are already subject to the CGMP's in parts 600, 606 and, as
applicable, parts 210 and 211, or 820.
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 (5 U.S.C. 601-612). Executive
Order 12866 directs agencies to assess all costs and benefits of
available regulatory alternatives and, when regulation is necessary, to
select regulatory approaches that maximize net benefits (including
potential economic, environmental, public health and safety, and other
advantages; distributive impact; and equity). The agency believes that
this rule is consistent with the regulatory philosophy and principles
identified in Executive Order 12866. In addition, the rule is a
significant regulatory action as defined in Executive Order 12866 and
is subject to review because it deals with a novel policy issue.
In accordance with the principles of Executive Order 12866, the
overall result of the rule will be a substantial reduction in burdens
on a manufacturer filing an application to market a biological product.
In addition, FDA anticipates that the rule will facilitate a
manufacturer's ability to improve its licensed products and methods of
manufacture by decreasing the burden and cost associated with filing
applications and supplements.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small entities. Because, as stated previously, the overall result of
the rule will be a substantial reduction in reporting burdens, the
agency certifies that the rule would not have a significant negative
economic impact on a substantial number of small entities. Therefore,
under the Regulatory Flexibility Act, no further analysis is required.
C. The Paperwork Reduction Act of 1995
This final rule contains information collection provisions that
are subject to review by the Office of Management and Budget (OMB)
under the Paperwork Reduction Act of 1995 (the PRA) (44 U.S.C. 3501-
3520). The title, description, and the respondent description of the
information collection provisions are shown below with an estimate of
the annual reporting burden. Included in the estimate is the time for
reviewing the instructions, searching existing data sources, gathering
and maintaining the data needed, and completing and reviewing each
collection of information.
Title: Biological Products Regulated Under Section 351 of the
Public Health Service Act; Implementation of Biologics License;
Elimination of Establishment License and Product License.
Description: This final rule revises the regulations regarding the
procedures for application for approval to market a biological product
regulated under section 351 of the PHS Act. Under the regulations, a
manufacturer will submit to FDA the appropriate establishment and
product information in a single BLA in lieu of filing a separate ELA
and PLA. Upon approval of the BLA, a manufacturer would receive a
single biologics license to market the product in interstate commerce.
Description of Respondents: Manufacturers of biological products.
The final rule amends the regulations for filing an application to
market a biological product under Sec. 601.2 to eliminate references to
establishment licenses and product licenses for all products regulated
under the PHS Act. The final rule will require biologics manufacturers
to file a single BLA, rather than either an ELA or PLA, to market a
biological product. The agency estimates that the total average
paperwork burden for manufacturers filing one application that
consolidates the information currently required under both the PLA and
ELA will decrease approximately 10 percent. The estimate reduces the
number of annual responses from a combined PLA/BLA/ELA total of 76 to a
BLA total of 60. This estimate is derived from the total number of
license applications received
[[Page 56446]]
by FDA in fiscal year (FY) 1997 (76) minus the total number of ELA's
filed in the same period (17). Based on information provided by
industry, the time estimated to prepare an application for FDA approval
to market a product is approximately 1,600 hours. In addition to
Sec. 601.2, there are other regulations in the final rule that relate
to certain information to be included in a license application
including Sec. 640.21(c) (21 CFR 640.21(c)), Sec. 640.22(c) (21 CFR
640.22(c)), 21 CFR 640.65(a), and 660.21(a)(3) and (d). The burden
associated with the information collection requirements in these
regulations is included in the following reporting burden estimate for
Sec. 601.2.
The regulation also makes several technical amendments to conform
the language throughout the biological product regulations to the
changes made final here for Sec. 601.2. Specifically, the final rule
makes the following technical term changes: References to product and
establishment license, and product and establishment applications are
replaced with ``biologics license'' or ``biologics license
application;'' and ``licensee'' is replaced with ``licensed
manufacturer.'' These technical changes do not have an impact on either
the substantive requirements or the paperwork burden of these
requirements, each of which carry OMB clearance numbers as follows: 21
CFR 207.20(c) and 207.21(a) (0910-0045); Secs. 600.80(c)(2) and 600.81
(0910-0308); Sec. 601.25(b)(3) (0910-0039); 21 CFR 607.20(b) and 607.21
(0910-0052); and 21 CFR 610.63 and 640.71(b)(1) (0910-0116).
The following regulations relate to the submission of additional
information in certain supplements to a BLA. Regulations in 21 CFR
600.15(b) and 610.53(d) require submission of a request for an
exemption or modification regarding the temperature requirements during
shipment and from dating periods, respectively, for certain biological
products. The preparation of an exemption request is estimated to be 8
hours; however, no requests were received by the agency under either
regulation in FY 1997. To account for the rare instance in which a
request for an exemption may be made, the agency has estimated one
respondent per year in Table 1 of this document. Section 640.6 (21 CFR
640.6) requires that an applicant submit a request to make a certain
modification of Whole Blood. The number of supplements relating to
Whole Blood filed by an applicant in FY 1997 totaled 74. Because the
agency could not easily determine the number of supplements filed
specific to Sec. 640.6, the estimate below is based on last year's
total number of supplements related to Whole Blood, regardless of
whether the supplement was filed specific to Sec. 640.6.
The remaining regulations, Secs. 640.21(c), 640.22(c), 21 CFR
640.64(c), and 640.74(a) and (b)(2), refer to information that is
collected under Sec. 601.12, (OMB Control No. 0910-0315) under which
the collection of information burden is calculated. Moreover, the final
rule makes only technical changes to these regulations. For example,
the term ``product license'' is changed to ``biologics license,'' and
the term ``product licensee'' is changed to ``licensed manufacturer.''
As required by section 3506(c)(2)(B) of the PRA, FDA provided an
opportunity for public comment on the information collection provisions
of the proposed rule (63 FR 40858). One letter of comment on the
information collection provisions was submitted to OMB. Most of the
comments submitted to OMB were the same as those submitted directly to
FDA in response to the proposed rule. FDA's responses to these comments
are found above in section III of this document. Responses to
additional comments in the letter received by OMB that were not
addressed previously are addressed in the following paragraphs.
1. A comment pointed out that few new BLA's for blood and blood
components will be submitted to the agency. More frequently changes to
already approved applications are submitted as supplements. These
supplements will now use Form FDA 356h for submission to the agency.
The comment stated if Form FDA 356h is merely substituted for the
current forms and manufacturers must continue to file a supplement for
each product at each location, the paperwork will actually increase
because of the increased CMC and establishment requirements.
FDA agrees that few new BLA's for blood and blood components are
submitted to the agency. However, FDA disagrees that the burden will
increase. Previously, manufacturers desiring to make a single
manufacturing change that would affect multiple products were required
to submit a supplement to each individual product and establishment
application. Under this final rule a manufacturer would only need to
submit one supplement to the BLA. For example, under the current PLA/
ELA system, if a manufacturer desired to make a single change to the
irradiation procedure for its Whole Blood, Red Blood Cells, Platelets,
and Plasma products manufactured at 3 locations, the manufacturer would
be required to submit 12 supplements to 4 PLA's. Under the proposed BLA
system, the manufacturer would only be required to submit one
supplement to the BLA describing the change for all of the products and
locations involved. Therefore, fewer supplements should be submitted by
applicants. The size of the decrease in supplements will depend on how
the applicant bundles the submissions. At the time of submission of a
supplement, FDA expects that all data and information pertinent to the
supplement be present or the FDA may refuse to file the application
(see the guidance entitled ``Center for Biologics Evaluation and
Research (CBER): Refusal to File (RTF) Guidance for Product License
Applications (PLA's) and Establishment License Applications (ELA's)''
(58 FR 38770, July 20, 1993)). Therefore, if an applicant wishes to
submit a change affecting multiple locations in one supplement, and all
data and information supporting the change at those locations are
present in the supplement, FDA will accept such a submission. FDA,
therefore, estimates that there will be an overall reduction in burden
associated with this final rule.
2. Another comment stated that the number of respondents and
supplement submissions, and the hours per submission were severely
underestimated by FDA. The comment expressed concern that FDA was
unable to specifically enumerate the number of submissions made under
Sec. 640.6 and suggested that this was ``indicative of a larger
problem.'' The comment described FDA's approach to burden estimates as
disturbing for other reasons such as not addressing supplements for
products other than Whole Blood, and because the agency's internal
tracking, accounting, and documentation systems may be inadequate. The
comment stated that FDA had trouble distinguishing between supplemental
license applications submitted under Secs. 640.6 and 601.12. For the
purposes of burden hour development, the distinction between
supplements submitted under Sec. 640.6 and those under Sec. 601.12 is
somewhat artificial because the burden for the regulated community to
prepare the supplement is identical regardless of the section under
which such information is submitted.
The comment has misinterpreted the estimate. In preparing this
burden estimate, FDA estimated the burden for those sections of the
regulations being amended, including Sec. 640.6. No changes in
Sec. 601.12 were included in this rulemaking, therefore FDA has not
estimated the burden of this section which already has an approved OMB
control number (0910-0315). The burden associated with the preparation
of supplemental applications is also
[[Page 56447]]
included in the estimate for Sec. 601.12 and is outside the scope of
this rule. Since Sec. 640.6 applies specifically to Whole Blood, an
estimate as seen in Table 1 of this document is limited to only Whole
Blood submissions and the associated reporting burden hours. The number
of respondents reflects the number of FY 1997 supplements submitted
specifically for Whole Blood, and the 8 hours is an accurate estimate
for this type of submission. For purposes of carrying out its
obligations for the review of applications, FDA continues to believe
that it is unnecessary to keep separate track of those applications
submitted under Sec. 640.6, because review of these supplemental
applications is not different from other supplemental applications
submitted under Sec. 601.12. Because FDA's current tracking system does
not allow a search of the data base that would identify accurately the
number of Whole Blood supplements submitted under Sec. 640.6, FDA
looked at the number of all supplements related only to Whole Blood,
which is the scope of this regulation, and conservatively estimated the
burden to account for more rather than fewer burden hours. Therefore,
the estimated burden hours are likely to be higher than those that may
actually occur.
Table 1.--Estimated Annual Reporting Burden1
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of Frequency per Total Annual Hours per Total Hours
Respondents Response Responses Response
----------------------------------------------------------------------------------------------------------------
601.2 60 1 60 1,600 96,000
600.15(b) 1 1 1 8 8
610.53(d) 1 1 1 8 8
640.6 74 1 74 8 592
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
The information collection provisions of the final rule have been
submitted to OMB for review. Prior to the effective date of the final
rule, FDA will publish a document in the Federal Register announcing
OMB's decision to approve, modify, or disapprove the information
collection provisions in the final rule. 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.
D. Environmental Impact
The agency has determined under 21 CFR 25.30(h) 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 3
Administrative practice and procedure, Biologics, Drugs, Medical
devices.
21 CFR Part 5
Authority delegations (Government agencies), Imports, Organization
and functions (Government agencies).
21 CFR Part 10
Administrative practice and procedure, News media.
21 CFR Part 20
Confidential business information, Courts, Freedom of information,
Government employees.
21 CFR Part 50
Human research subjects, Prisoners, Reporting and recordkeeping
requirements, Safety.
21 CFR Part 56
Human research subjects, Reporting and recordkeeping requirements,
Safety.
21 CFR Part 58
Laboratories, Reporting and recordkeeping requirements.
21 CFR Part 207
Drugs, Reporting and recordkeeping requirements.
21 CFR Part 310
Administrative practice and procedure, Drugs, Labeling, Medical
devices, Reporting and recordkeeping requirements.
21 CFR Part 312
Drugs, Exports, Imports, Investigations, Labeling, Medical
research, Reporting and recordkeeping requirements, Safety.
21 CFR Part 316
Administrative practice and procedure, Drugs, Reporting and
recordkeeping requirements.
21 CFR Part 600
Biologics, Reporting and recordkeeping requirements.
21 CFR Part 601
Administrative practice and procedure, Biologics, Confidential
business information.
21 CFR Part 607
Blood.
21 CFR Parts 610 and 660
Biologics, Labeling, Reporting and recordkeeping requirements.
21 CFR Part 640
Blood, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and authority delegated to the Commissioner
of Food and Drugs, 21 CFR parts 3, 5, 10, 20, 50, 56, 58, 207, 310,
312, 316, 600, 601, 607, 610, 640, and 660 are amended as follows:
PART 3--PRODUCT JURISDICTION
1. The authority citation for 21 CFR part 3 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360c-360f,
360h-360j, 360gg-360ss, 371(a), 379e, 381, 394; 42 U.S.C. 216, 262.
2. Section 3.2 is amended by revising paragraph (k) to read as
follows:
Sec. 3.2 Definitions.
* * * * *
(k) Premarket review includes the examination of data and
information in an application for premarket review described in
sections 505, 510(k), 513(f), 515, or 520(g) or 520(l) of the act or
section 351 of the Public Health Service Act of data and information
contained in any investigational new drug (IND) application,
investigational device exemption (IDE), new drug application (NDA),
biologics license application, device premarket notification, device
reclassification petition, and premarket approval application (PMA).
* * * * *
[[Page 56448]]
PART 5--DELEGATIONS OF AUTHORITY AND ORGANIZATION
3. The authority citation for 21 CFR part 5 continues to read as
follows:
Authority: 5 U.S.C. 504, 552, App. 2; 7 U.S.C. 138a, 2271; 15
U.S.C. 638, 1261-1282, 3701-3711a; 15 U.S.C. 1451-1461; 21 U.S.C.
41-50, 61-63, 141-149, 321-394, 467f, 679(b), 801-886, 1031-1309; 35
U.S.C. 156; 42 U.S.C. 241, 242, 242a, 242l, 242n, 243, 262, 263,
264, 265, 300u-300u-5, 300aa-1; 1395y, 3246b, 4332, 4831(a), 10007-
10008; E.O. 11921, 41 FR 24294, 3 CFR, 1977 Comp., p. 124-131; E.O.
12591, 52 FR 13414, 3 CFR, 1988 Comp., p. 220-223.
4. Section 5.58 is amended by revising paragraph (a)(3) to read as
follows:
Sec. 5.58 Orphan products.
(a) * * *
(3) Applications for biologics licenses for biological products; or
* * * * *
5. Section 5.67 is amended by revising paragraphs (a), (b), and (c)
to read as follows:
Sec. 5.67 Issuance of notices of opportunity for a hearing on
proposals for denial of approval of applications for licenses or
revocation of licenses and certain notices of revocation of licenses.
* * * * *
(a) Notices of opportunity for a hearing on proposals to deny
approval or filing of applications for biologics licenses under
Sec. 601.4(b) of this chapter.
(b) Notices of opportunity for a hearing on proposals to revoke
biologics licenses under Sec. 601.5(b) of this chapter.
(c) Notices of revocation, at the manufacturer's request, of
biologics licenses under Secs. 601.5(a) and 601.8 of this chapter.
* * * * *
PART 10--ADMINISTRATIVE PRACTICES AND PROCEDURES
6. The authority citation for 21 CFR part 10 continues to read as
follows:
Authority: 5 U.S.C. 551-558, 701-706; 15 U.S.C. 1451-1461; 21
U.S.C. 141-149, 321-397, 467f, 679, 821, 1034; 28 U.S.C. 2112; 42
U.S.C. 201, 262, 263b, 264.
7. Section 10.50 is amended by revising paragraph (c)(19) to read
as follows:
Sec. 10.50 Promulgation of regulations and orders after an
opportunity for a formal evidentiary public hearing.
* * * * *
(c) * * *
(19) Section 351(a) of the Public Health Service Act on a biologics
license for a biological product.
* * * * *
PART 20--PUBLIC INFORMATION
8. The authority citation for 21 CFR part 20 continues to read as
follows:
Authority: 5 U.S.C. 552; 18 U.S.C. 1905; 19 U.S.C. 2531-2582;
21 U.S.C. 321-393, 1401-1403; 42 U.S.C. 241, 242, 242a, 242l, 242n,
243, 262, 263, 263b-263n, 264, 265, 300u-300u-5, 300aa-1.
9. Section 20.100 is amended by revising paragraph (c)(24) to read
as follows:
Sec. 20.100 Applicability; cross-reference to other regulations.
* * * * *
(c) * * *
(24) Applications for biologics licenses for biological products,
in Sec. 601.51 of this chapter.
* * * * *
PART 50--PROTECTION OF HUMAN SUBJECTS
10. The authority citation for 21 CFR part 50 continues to read as
follows:
Authority: 21 U.S.C. 321, 346, 346a, 348, 352, 353, 355, 360,
360c-360f, 360h-360j, 371, 379e; 42 U.S.C. 216, 241, 262, 263b-263n.
11. Section 50.3 is amended by revising paragraph (b)(12) to read
as follows:
Sec. 50.3 Definitions.
* * * * *
(b) * * *
(12) An application for a biologics license, described in part 601
of this chapter.
* * * * *
PART 56--INSTITUTIONAL REVIEW BOARDS
12. The authority citation for 21 CFR part 56 continues to read as
follows:
Authority: 21 U.S.C. 321, 346, 346a, 348, 351, 352, 353, 355,
360, 360c-360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 216, 241, 262,
263b-263n.
13. Section 56.102 is amended by revising paragraph (b)(11) to read
as follows:
Sec. 56.102 Definitions.
* * * * *
(b) * * *
(11) An application for a biologics license, described in part 601
of this chapter.
* * * * *
PART 58--GOOD LABORATORY PRACTICE FOR NONCLINICAL LABORATORY
STUDIES
14. The authority citation for 21 CFR part 58 continues to read as
follows:
Authority: 21 U.S.C. 342, 346, 346a, 348, 351, 352, 353, 355,
360, 360b-360f, 360h-360j, 371, 379e, 381; 42 U.S.C. 216, 262, 263b-
263n.
15. Section 58.3 is amended by revising paragraph (e)(13) to read
as follows:
* * * * *
(e) * * *
(13) An application for a biologics license, described in part 601
of this chapter.
* * * * *
PART 207--REGISTRATION OF PRODUCERS OF DRUGS AND LISTING OF DRUGS
IN COMMERCIAL DISTRIBUTION
16. The authority citation for 21 CFR part 207 continues to read as
follows:
Authority: 21 U.S.C. 331, 351, 352, 355, 360, 360b, 371, 374;
42 U.S.C. 262.
17. Section 207.20 is amended by revising paragraph (c) to read as
follows:
Sec. 207.20 Who must register and submit a drug list.
* * * * *
(c) Before beginning manufacture or processing of a drug subject to
one of the following applications, an owner or operator of an
establishment is required to register before the agency approves it: A
new drug application, a new animal drug application, a medicated feed
application, or a biologics license application.
* * * * *
18. Section 207.21 is amended by revising the second sentence of
paragraph (a) to read as follows:
Sec. 207.21 Times for registration and drug listing.
(a) * * * If the owner or operator of the establishment has not
previously entered into such an operation, the owner or operator shall
register within 5 days after submitting a new drug application, new
animal drug application, medicated feed application, or a biologics
license application. * * *
* * * * *
PART 310--NEW DRUGS
19. The authority citation for 21 CFR part 310 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360b-360f,
360j, 361(a), 371, 374, 375, 379e; 42 U.S.C. 216, 241, 242(a), 262,
263b-263n.
20. Section 310.4 is revised to read as follows:
Sec. 310.4 Biologics; products subject to license control.
(a) If a drug has an approved license under section 351 of the
Public Health
[[Page 56449]]
Service Act (42 U.S.C. 262 et seq.) or under the animal virus, serum,
and toxin law of March 4, 1913 (21 U.S.C. 151 et seq.), it is not
required to have an approved application under section 505 of the act.
(b) To obtain marketing approval for radioactive biological
products for human use, as defined in Sec. 600.3(ee) of this chapter,
manufacturers must comply with the provisions of 601.2(b) of this
chapter.
21. Section 310.503 is amended by revising the first sentence of
paragraph (b) to read as follows:
Sec. 310.503 Requirements regarding certain radioactive drugs.
* * * * *
(b) It is the opinion of the Nuclear Regulatory Commission, and the
Food and Drug Administration that this exemption should not apply for
certain specific drugs and that these drugs should be appropriately
labeled for uses for which safety and effectiveness can be demonstrated
by new drug applications or through licensing under the Public Health
Service Act (42 U.S.C. 262 et seq.) in the case of biologics. * * *
* * * * *
PART 312--INVESTIGATIONAL NEW DRUG APPLICATION
22. The authority citation for 21 CFR part 312 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 371; 42
U.S.C. 262.
23. Section 312.3 is amended in paragraph (b) by revising the
definition for Marketing application to read as follows:
Sec. 312.3 Definitions and interpretations.
* * * * *
(b) * * *
Marketing application means an application for a new drug submitted
under section 505(b) of the act or a biologics license application for
a biological product submitted under the Public Health Service Act.
* * * * *
PART 316--ORPHAN DRUGS
24. The authority citation for 21 CFR part 316 continues to read as
follows:
Authority: 21 U.S.C. 360aa, 360bb, 360cc, 360dd, 371.
25. Section 316.3 is amended by revising paragraph (b)(9) to read
as follows:
Sec. 316.3 Definitions.
* * * * *
(b) * * *
(9) Marketing application means an application for approval of a
new drug filed under section 505(b) of the act or an application for a
biologics license submitted under section 351 of the Public Health
Service Act (42 U.S.C. 262).
* * * * *
PART 600--BIOLOGICAL PRODUCTS: GENERAL
26. The authority citation for 21 CFR part 600 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 360i, 371,
374; 42 U.S.C. 216, 262, 263, 263a, 264, 300aa-25.
27. Section 600.3 is amended by revising paragraphs (n) and (w) to
read as follows:
Sec. 600.3 Definitions.
* * * * *
(n) The word standards means specifications and procedures
applicable to an establishment or to the manufacture or release of
products, which are prescribed in this subchapter or established in the
biologics license application designed to insure the continued safety,
purity, and potency of such products.
* * * * *
(w) Establishment has the same meaning as ``facility'' in section
351 of the Public Health Service Act and includes all locations.
* * * * *
28. Section 600.15 is amended by revising paragraph (b) to read as
follows:
Sec. 600.15 Temperatures during shipment.
* * * * *
(b) Exemptions. Exemptions or modifications shall be made only upon
written approval, in the form of a supplement to the biologics license
application, approved by the Director, Center for Biologics Evaluation
and Research.
29. Section 600.21 is amended by revising the first sentence to
read as follows:
Sec. 600.21 Time of inspection.
The inspection of an establishment for which a biologics license
application is pending need not be made until the establishment is in
operation and is manufacturing the complete product for which a
biologics license is desired. * * *
30. Section 600.80 is amended by revising the first sentence of
paragraph (b), the first and second sentences of paragraph (c)(2)(i),
and by revising paragraphs (g) and (j) to read as follows:
Sec. 600.80 Postmarketing reporting of adverse experiences.
* * * * *
(b) Review of adverse experiences. Any person having a biologics
license under Sec. 601.20 of this chapter shall promptly review all
adverse experience information pertaining to its product obtained or
otherwise received by the licensed manufacturer from any source,
foreign or domestic, including information derived from commercial
marketing experience, postmarketing clinical investigations,
postmarketing epidemiological/surveillance studies, reports in the
scientific literature, and unpublished scientific papers. * * *
* * * * *
(c) * * *
(2) Periodic adverse experience reports. (i) The licensed
manufacturer shall report each adverse experience not reported under
paragraph (c)(1)(i) of this section at quarterly intervals, for 3 years
from the date of issuance of the biologics license, and then at annual
intervals. The licensed manufacturer shall submit each quarterly report
within 30 days of the close of the quarter (the first quarter beginning
on the date of issuance of the biologics license) and each annual
report within 60 days of the anniversary date of the issuance of the
biologics license. * * *
* * * * *
(g) Multiple reports. A licensed manufacturer should not include in
reports under this section any adverse experience that occurred in
clinical trials if they were previously submitted as part of the
biologics license application. If a report refers to more than one
biological product marketed by a licensed manufacturer, the licensed
manufacturer should submit the report to the biologics license
application for the product listed first in the report.
* * * * *
(j) Revocation of biologics license. If a licensed manufacturer
fails to establish and maintain records and make reports required under
this section with respect to a licensed biological product, FDA may
revoke the biologics license for such a product in accordance with the
procedures of 601.5 of this chapter.
* * * * *
31. Section 600.81 is amended by revising the first sentence to
read as follows:
Sec. 600.81 Distribution reports.
The licensed manufacturer shall submit information about the
quantity of the product distributed under the biologics license,
including the quantity distributed to distributors. * * *
[[Page 56450]]
PART 601--LICENSING
32. The authority citation for 21 CFR part 601 continues to read as
follows:
Authority: 15 U.S.C. 1451-1561; 21 U.S.C. 321, 351, 352, 353,
355, 360, 360c-360f, 360h-360j, 371, 374, 379e, 381; 42 U.S.C. 216,
241, 262, 263; sec.122, Pub. L. 105-115, 111 Stat. 2322 (21 U.S.C.
355 note).
Sec. 601.1 [Removed]
33. Section 601.1 Two forms of licenses is removed.
34. Section 601.2 is revised to read as follows:
Sec. 601.2 Applications for biologics licenses; procedures for
filing.
(a) General. To obtain a biologics license under section 351 of the
Public Health Service Act for any biological product, the manufacturer
shall submit an application to the Director, Center for Biologics
Evaluation and Research, on forms prescribed for such purposes, and
shall submit data derived from nonclinical laboratory and clinical
studies which demonstrate that the manufactured product meets
prescribed requirements of safety, purity, and potency; with respect to
each nonclinical laboratory study, either a statement that the study
was conducted in compliance with the requirements set forth in part 58
of this chapter, or, if the study was not conducted in compliance with
such regulations, a brief statement of the reason for the
noncompliance; statements regarding each clinical investigation
involving human subjects contained in the application, that it either
was conducted in compliance with the requirements for institutional
review set forth in part 56 of this chapter; or was not subject to such
requirements in accordance with Sec. 56.104 or Sec. 56.105, and was
conducted in compliance with requirements for informed consent set
forth in part 50 of this chapter. A full description of manufacturing
methods; data establishing stability of the product through the dating
period; sample(s) representative of the product for introduction or
delivery for introduction into interstate commerce; summaries of
results of tests performed on the lot(s) represented by the submitted
sample(s); specimens of the labels, enclosures, and containers, and if
applicable, any Medication Guide required under part 208 of this
chapter proposed to be used for the product; and the address of each
location involved in the manufacture of the biological product shall be
listed in the biologics license application. The applicant shall also
include a financial certification or disclosure statement(s) or both
for clinical investigators as required by part 54 of this chapter. An
application for a biologics license shall not be considered as filed
until all pertinent information and data have been received from the
manufacturer by the Center for Biologics Evaluation and Research. The
applicant shall also include either a claim for categorical exclusion
under Sec. 25.30 or Sec. 25.31 of this chapter or an environmental
assessment under Sec. 25.40 of this chapter. In lieu of the procedures
described in this paragraph, applications for radioactive biological
products shall be handled as set forth in paragraph (b) of this
section. The applicant, or the applicant's attorney, agent, or other
authorized official shall sign the application. An application for any
of the following specified categories of biological products subject to
licensure shall be handled as set forth in paragraph (c) of this
section:
(1) Therapeutic DNA plasmid products;
(2) Therapeutic synthetic peptide products of 40 or fewer amino
acids;
(3) Monoclonal antibody products for in vivo use; and
(4) Therapeutic recombinant DNA-derived products.
(b) Radioactive biological products. To obtain marketing approval
for a radioactive biological product, as defined in Sec. 600.3(ee) of
this chapter, the manufacturer of such product shall comply with the
following:
(1) An applicant for a radioactive coupled antibody, which means a
product that consists of an antibody component coupled with a
radionuclide component (or an antibody component intended solely to be
coupled with a radionuclide) in which both components provide a
pharmacological effect but the biological component determines the site
of action, shall submit a biologics license application to the
Director, Center for Biologics Evaluation and Research, Food and Drug
Administration, except if, as determined by FDA, there are significant
scientific issues associated with the radionuclide or other chemically
synthesized component, in which case a new drug application shall be
submitted to the Center for Drug Evaluation and Research, Food and Drug
Administration;
(2) An applicant for a radioactive biological product other than as
described in paragraph (b)(1) of this section, shall submit a new drug
application to the Center for Drug Evaluation and Research, Food and
Drug Administration.
(c)(1) To obtain marketing approval for a biological product
subject to licensure which is a therapeutic DNA plasmid product,
therapeutic synthetic peptide product of 40 or fewer amino acids,
monoclonal antibody product for in vivo use, or therapeutic recombinant
DNA-derived product, an applicant shall submit a biologics license
application in accordance with paragraph (a) of this section except
that the following sections in parts 600 through 680 of this chapter
shall not be applicable to such products: Secs. 600.10(b) and (c),
600.11, 600.12, 600.13, 610.11, 610.53, and 610.62 of this chapter.
(2) To the extent that the requirements in this paragraph (c)
conflict with other requirements in this subchapter (except for those
products described in paragraph (b) of this section for which a new
drug application is required), this paragraph (c) shall supersede other
requirements.
(d) Approval of a biologics license application or issuance of a
biologics license shall constitute a determination that the
establishment(s) and the product meet applicable requirements to ensure
the continued safety, purity, and potency of such products. Applicable
requirements for the maintenance of establishments for the manufacture
of a product subject to this section shall include but not be limited
to the good manufacturing practice requirements set forth in parts 210,
211, 600, 606, and 820 of this chapter.
(e) Any establishment and product license for a biological product
issued under section 351 of the Public Health Service Act (42 U.S.C.
201 et seq.) that has not been revoked or suspended as of December 20,
1999, shall constitute an approved biologics license application in
effect under the same terms and conditions set forth in such product
license and such portions of the establishment license relating to such
product.
Sec. 601.3 [Removed]
35. Section 601.3 License forms is removed.
36. Section 601.4 is amended by revising paragraph (a) and the
first sentence of paragraph (b) to read as follows:
Sec. 601.4 Issuance and denial of license.
(a) A biologics license shall be issued upon a determination by the
Director, Center for Biologics Evaluation and Research that the
establishment(s) and the product meet the applicable requirements
established in this chapter. A biologics license shall be valid until
suspended or revoked.
(b) If the Commissioner determines that the establishment or
product does not meet the requirements established
[[Page 56451]]
in this chapter, the biologics license application shall be denied and
the applicant shall be informed of the grounds for, and of an
opportunity for a hearing on, the decision. * * *
37. Section 601.5 is revised to read as follows:
Sec. 601.5 Revocation of license.
(a) A biologics license shall be revoked upon application of the
manufacturer giving notice of intention to discontinue the manufacture
of all products manufactured under such license or to discontinue the
manufacture of a particular product for which a license is held and
waiving an opportunity for a hearing on the matter.
(b)(1) The Commissioner shall notify the licensed manufacturer of
the intention to revoke the biologics license, setting forth the
grounds for, and offering an opportunity for a hearing on the proposed
revocation if the Commissioner finds any of the following:
(i) Authorized Food and Drug Administration employees after
reasonable efforts have been unable to gain access to an establishment
or a location for the purpose of carrying out the inspection required
under Sec. 600.21 of this chapter,
(ii) Manufacturing of products or of a product has been
discontinued to an extent that a meaningful inspection or evaluation
cannot be made,
(iii) The manufacturer has failed to report a change as required by
Sec. 601.12 of this chapter,
(iv) The establishment or any location thereof, or the product for
which the license has been issued, fails to conform to the applicable
standards established in the license and in this chapter designed to
ensure the continued safety, purity, and potency of the manufactured
product,
(v) The establishment or the manufacturing methods have been so
changed as to require a new showing that the establishment or product
meets the requirements established in this chapter in order to protect
the public health, or
(vi) The licensed product is not safe and effective for all of its
intended uses or is misbranded with respect to any such use.
(2) Except as provided in Sec. 601.6 of this chapter, or in cases
involving willfulness, the notification required in this paragraph
shall provide a reasonable period for the licensed manufacturer to
demonstrate or achieve compliance with the requirements of this
chapter, before proceedings will be instituted for the revocation of
the license. If compliance is not demonstrated or achieved and the
licensed manufacturer does not waive the opportunity for a hearing, the
Commissioner shall issue a notice of opportunity for hearing on the
matter under Sec. 12.21(b) of this chapter.
38. Section 601.6 is revised to read as follows:
Sec. 601.6 Suspension of license.
(a) Whenever the Commissioner has reasonable grounds to believe
that any of the grounds for revocation of a license exist and that by
reason thereof there is a danger to health, the Commissioner may notify
the licensed manufacturer that the biologics license is suspended and
require that the licensed manufacturer do the following:
(1) Notify the selling agents and distributors to whom such product
or products have been delivered of such suspension, and
(2) Furnish to the Director, Center for Biologics Evaluation and
Research, complete records of such deliveries and notice of suspension.
(b) Upon suspension of a license, the Commissioner shall either:
(1) Proceed under the provisions of Sec. 601.5(b) of this chapter
to revoke the license, or
(2) If the licensed manufacturer agrees, hold revocation in
abeyance pending resolution of the matters involved.
39. Section 601.9 is revised to read as follows:
Sec. 601.9 Licenses; reissuance.
(a) Compliance with requirements. A biologics license, previously
suspended or revoked, may be reissued or reinstated upon a showing of
compliance with requirements and upon such inspection and examination
as may be considered necessary by the Director, Center for Biologics
Evaluation and Research.
(b) Exclusion of noncomplying location. A biologics license,
excluding a location or locations that fail to comply with the
requirements in this chapter, may be issued without further application
and concurrently with the suspension or revocation of the license for
noncompliance at the excluded location or locations.
(c) Exclusion of noncomplying product(s). In the case of multiple
products included under a single biologics license application, a
biologics license may be issued, excluding the noncompliant product(s),
without further application and concurrently with the suspension or
revocation of the biologics license for a noncompliant product(s).
Sec. 601.10 [Removed]
40. Section 601.10 Establishment licenses; issuance and conditions
is removed.
41. Section 601.20 is revised to read as follows:
Sec. 601.20 Biologics licenses; issuance and conditions.
(a) Examination--compliance with requirements. A biologics license
application shall be approved only upon examination of the product and
upon a determination that the product complies with the standards
established in the biologics license application and the requirements
prescribed in the regulations in this chapter including but not limited
to the good manufacturing practice requirements set forth in parts 210,
211, 600, 606, and 820 of this chapter.
(b) Availability of product. No biologics license shall be issued
unless:
(1) The product intended for introduction into interstate commerce
is available for examination, and
(2) Such product is available for inspection during all phases of
manufacture.
(c) Manufacturing process--impairment of assurances. No product
shall be licensed if any part of the process of or relating to the
manufacture of such product, in the judgment of the Director, Center
for Biologics Evaluation and Research, would impair the assurances of
continued safety, purity, and potency as provided by the regulations
contained in this chapter.
(d) Inspection--compliance with requirements. A biologics license
shall be issued or a biologics license application approved only after
inspection of the establishment(s) listed in the biologics license
application and upon a determination that the establishment(s) complies
with the standards established in the biologics license application and
the requirements prescribed in applicable regulations.
(e) One biologics license to cover all locations. One biologics
license shall be issued to cover all locations meeting the
establishment standards identified in the approved biologics license
application and each location shall be subject to inspection by FDA
officials.
42. Section 601.21 is revised to read as follows:
Sec. 601.21 Products under development.
A biological product undergoing development, but not yet ready for
a biologics license, may be shipped or otherwise delivered from one
State or possession into another State or possession provided such
shipment or
[[Page 56452]]
delivery is not for introduction or delivery for introduction into
interstate commerce, except as provided in sections 505(i) and 520(g)
of the Federal Food, Drug, and Cosmetic Act, as amended, and the
regulations thereunder (21 CFR parts 312 and 812).
43. Section 601.22 is amended by revising the section heading and
the first and second sentences to read as follows:
Sec. 601.22 Products in short supply; initial manufacturing at other
than licensed location.
A biologics license issued to a manufacturer and covering all
locations of manufacture shall authorize persons other than such
manufacturer to conduct at places other than such locations the
initial, and partial manufacturing of a product for shipment solely to
such manufacturer only to the extent that the names of such persons and
places are registered with the Commissioner of Food and Drugs and it is
found upon application of such manufacturer, that the product is in
short supply due either to the peculiar growth requirements of the
organism involved or to the scarcity of the animal required for
manufacturing purposes, and such manufacturer has established with
respect to such persons and places such procedures, inspections, tests
or other arrangements as will ensure full compliance with the
applicable regulations of this subchapter related to continued safety,
purity, and potency. Such persons and places shall be subject to all
regulations of this subchapter except Secs. 601.2 to 601.6, 601.9,
601.10, 601.20, 601.21 to 601.33, and 610.60 to 610.65 of this chapter.
* * *
44. Section 601.25 is amended in paragraph (b)(3) under
``Biological Products Review Information'' by revising section VIII and
by revising the third sentence of paragraph (f)(3) to read as follows:
Sec. 601.25 Review procedures to determine that licensed biological
products are safe, effective, and not misbranded under prescribed,
recommended, or suggested conditions of use.
* * * * *
(b) * * *
(3) * * *
BIOLOGICAL PRODUCTS REVIEW INFORMATION
* * * * *
VIII. If the submission is by a licensed manufacturer, a
statement signed by the authorized official of the licensed
manufacturer shall be included, stating that to the best of his or
her knowledge and belief, it includes all information, favorable and
unfavorable, pertinent to an evaluation of the safety,
effectiveness, and labeling of the product, including information
derived from investigation, commercial marketing, or published
literature. If the submission is by an interested person other than
a licensed manufacturer, a statement signed by the person
responsible for such submission shall be included, stating that to
the best of his knowledge and belief, it fairly reflects a balance
of all the available information, favorable and unfavorable
available to him, pertinent to an evaluation of the safety,
effectiveness, and labeling of the product.
* * * * *
(f) * * *
(3) * * * Where the Commissioner determines that the potential
benefits outweigh the potential risks, the proposed order shall provide
that the biologics license for any biological product, falling within
this paragraph, will not be revoked but will remain in effect on an
interim basis while the data necessary to support its continued
marketing are being obtained for evaluation by the Food and Drug
Administration. * * *
* * * * *
45. Section 601.26 is amended by revising the second sentence of
the introductory text of paragraph (e), the first, fifth, and sixth
sentences of paragraph (f)(1), the second sentence of paragraph (f)(2),
and the first sentence of paragraph (f)(3) to read as follows:
Sec. 601.26 Reclassification procedures to determine that licensed
biological products are safe, effective, and not misbranded under
prescribed, recommended, or suggested conditions of use.
* * * * *
(e) * * * Where the Commissioner determines that there is a
compelling medical need and no suitable alternative therapeutic,
prophylactic, or diagnostic agent for any biological product that is
available in sufficient quantities to meet current medical needs, the
final order shall provide that the biologics license application for
that biological product will not be revoked, but will remain in effect
on an interim basis while the data necessary to support its continued
marketing are being obtained for evaluation by the Food and Drug
Administration. * * *
(f) Additional studies and labeling. (1) Within 60 days following
publication of the final order, each licensed manufacturer for a
biological product designated as requiring further study to justify
continued marketing on an interim basis, under paragraph (e) of this
section, shall submit to the Commissioner a written statement intended
to show that studies adequate and appropriate to resolve the questions
raised about the product have been undertaken. * * * The Commissioner
may extend this 60-day period if necessary, either to review and act on
proposed protocols or upon indication from the licensed manufacturer
that the studies will commence at a specified reasonable time. If no
such commitment is made, or adequate and appropriate studies are not
undertaken, the biologics license or licenses shall be revoked.
(2) * * * If the progress report is inadequate or if the
Commissioner concludes that the studies are not being pursued promptly
and diligently, or if interim results indicate the product is not a
medical necessity, the biologics license or licenses shall be revoked.
(3) Promptly upon completion of the studies undertaken on the
product, the Commissioner will review all available data and will
either retain or revoke the biologics license or licenses involved. * *
*
* * * * *
46. Section 601.51 is amended by revising the section heading, the
first sentence of paragraph (a), and paragraph (b) to read as follows:
Sec. 601.51 Confidentiality of data and information in applications
for biologics licenses.
(a) For purposes of this section the biological product file
includes all data and information submitted with or incorporated by
reference in any application for a biologics license, IND's
incorporated into any such application, master files, and other related
submissions. * * *
(b) The existence of a biological product file will not be
disclosed by the Food and Drug Administration before a biologics
license application has been approved unless it has previously been
publicly disclosed or acknowledged. The Director of the Center for
Biologics Evaluation and Research will maintain a list available for
public disclosure of biological products for which a license
application has been approved.
* * * * *
PART 607--ESTABLISHMENT REGISTRATION AND PRODUCT LISTING FOR
MANUFACTURERS OF HUMAN BLOOD AND BLOOD PRODUCTS
47. The authority citation for 21 CFR part 607 continues to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 355, 360, 371, 374; 42
U.S.C. 216, 262.
48. Section 607.20 is amended by revising paragraph (b) to read as
follows:
Sec. 607.20 Who must register and submit a blood product list.
* * * * *
(b) Preparatory to engaging in the manufacture of blood products,
owners
[[Page 56453]]
or operators of establishments who are submitting a biologics license
application to manufacture blood products are required to register
before the biologics license application is approved.
* * * * *
49. Section 607.21 is amended by revising the second sentence to
read as follows:
Sec. 607.21 Times for establishment registration and blood product
listing.
* * * If the owner or operator of the establishment has not
previously entered into such operation (defined in Sec. 607.3(d) of
this chapter) for which a license is required, registration shall
follow within 5 days after the submission of a biologics license
application in order to manufacture blood products. * * *
PART 610--GENERAL BIOLOGICAL PRODUCTS STANDARDS
50. The authority citation for 21 CFR part 610 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42
U.S.C. 216, 262, 263, 263a, 264.
51. Section 610.13 is amended by revising the introductory
paragraph and the first sentence of paragraph (a)(1) to read as
follows:
Sec. 610.13 Purity.
Products shall be free of extraneous material except that which is
unavoidable in the manufacturing process described in the approved
biologics license application. In addition, products shall be tested as
provided in paragraphs (a) and (b) of this section.
(a)(1) Test for residual moisture. Each lot of dried product shall
be tested for residual moisture and shall meet and not exceed
established limits as specified by an approved method on file in the
biologics license application. * * *
* * * * *
52. Section 610.53 is amended by revising paragraph (d) to read as
follows:
Sec. 610.53 Dating periods for licensed biological products.
* * * * *
(d) Exemptions. Exemptions or modifications shall be made only
upon written approval, in the form of a supplement to the biologics
license application, issued by the Director, Center for Biologics
Evaluation and Research.
53. Section 610.63 is revised to read as follows:
Sec. 610.63 Divided manufacturing responsibility to be shown.
If two or more licensed manufacturers participate in the
manufacture of a biological product, the name, address, and license
number of each must appear on the package label, and on the label of
the container if capable of bearing a full label.
PART 640--ADDITIONAL STANDARDS FOR HUMAN BLOOD AND BLOOD PRODUCTS
54. The authority citation for 21 CFR part 640 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42
U.S.C. 216, 262, 263, 263a, 264.
55. Section 640.6 is amended by revising the introductory text to
read as follows:
Sec. 640.6 Modifications of Whole Blood.
Upon approval by the Director, Center for Biologics Evaluation and
Research, of a supplement to the biologics license application for
Whole Blood a manufacturer may prepare Whole Blood from which the
antihemophilic factor has been removed, provided the Whole Blood meets
the applicable requirements of this subchapter and the following
conditions are met:
* * * * *
56. Section 640.21 is amended by revising paragraph (c) to read as
follows:
Sec. 640.21 Suitability of donors.
* * * * *
(c) Plateletpheresis donors shall meet criteria for suitability as
described in a biologics license application or a supplement to the
biologics license application, and must have the written approval of
the Director, Center for Biologics Evaluation and Research, Food and
Drug Administration.
57. Section 640.22 is amended by revising paragraph (c) to read as
follows:
Sec. 640.22 Collection of source material.
* * * * *
(c) If plateletpheresis is used, the procedure for collection shall
be as described in a biologics license application or a supplement to a
biologics license application, and must have the written approval of
the Director, Center for Biologics Evaluation and Research, Food and
Drug Administration.
* * * * *
58. Section 640.64 is amended by revising the second sentence of
the introductory text of paragraph (c) to read as follows:
Sec. 640.64 Collection of blood for Source Plasma.
* * * * *
(c) * * * One of the following formulas shall be used in the
indicated volumes, except that a different formula may be used for
plasma for manufacture into noninjectable products if prior written
approval is obtained from the Director of the Center for Biologics
Evaluation and Research at the time of licensing or in the form of a
supplement to the biologics license application for Source Plasma.
* * * * *
59. Section 640.65 is amended by revising the last sentence of
paragraph (a) to read as follows:
Sec. 640.65 Plasmapheresis.
(a) * * * This procedure shall be described in detail in the
biologics license application.
* * * * *
60. Section 640.71 is amended by revising the introductory text of
paragraphs (a) and (b) and by revising paragraph (b)(1) to read as
follows:
Sec. 640.71 Manufacturing responsibility.
(a) All steps in the manufacture of Source Plasma, including donor
examination, blood collection, plasmapheresis, laboratory testing,
labeling, storage, and issuing shall be performed by personnel of the
licensed manufacturer of the Source Plasma, except that the following
tests may be performed by personnel of a manufacturer licensed for
blood or blood derivatives under section 351(a) of the Public Health
Service Act, or by a clinical laboratory that meets the standards of
the Clinical Laboratories Improvement Act of 1967 (CLIA) (42 U.S.C.
263a): Provided, The establishment or the clinical laboratory is
qualified to perform the assigned test(s).
* * * * *
(b) Such testing shall not be considered divided manufacturing,
which requires two biologics licenses for Source Plasma: Provided, That
(1) The results of such tests are maintained by the licensed
manufacturer of the Source Plasma whereby such results may be reviewed
by a licensed physician as required in Sec. 640.65(b)(2) of this
chapter and by an authorized representative of the Food and Drug
Administration.
* * * * *
61. Section 640.74 is amended by revising paragraph (a) and the
last sentence of paragraph (b)(2) to read as follows:
[[Page 56454]]
Sec. 640.74 Modification of Source Plasma.
(a) Upon approval by the Director, Center for Biologics Evaluation
and Research, Food and Drug Administration, of a supplement to the
biologics license application for Source Plasma, a manufacturer may
prepare Source Plasma as a liquid product for a licensed blood
derivative manufacturer who has indicated a need for a liquid product.
(b) * * *
(2) * * * Such evidence may be submitted by either the licensed
manufacturer of the Source Plasma Liquid or the manufacturer of the
final blood derivative product who has requested the Source Plasma
Liquid.
* * * * *
PART 660--ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR
LABORATORY TESTS
62. The authority citation for 21 CFR part 660 continues to read as
follows:
Authority: 21 U.S.C. 321, 351, 352, 353, 355, 360, 371; 42
U.S.C. 216, 262, 263, 263a, 264.
63. Section 660.21 is amended by revising paragraphs (a)(3) and (d)
to read as follows:
Sec. 660.21 Processing.
(a) * * *
(3) A lot may be subdivided into clean, sterile vessels. Each
subdivision shall constitute a sublot. If lots are to be subdivided,
the manufacturer shall include this information in the biologics
license application. The manufacturer shall describe the test
specifications to verify that each sublot is identical to other sublots
of the lot.
* * * * *
(d) Volume of final product. Each manufacturer shall identify the
possible final container volumes in the biologics license application.
* * * * *
64. Section 660.30 is amended by revising paragraph (b) to read as
follows:
Sec. 660.30 Reagent Red Blood Cells.
* * * * *
(b) Source. Reagent Red Blood Cells shall be prepared from human
peripheral blood meeting the criteria of Secs. 660.31 and 660.32 of
this chapter, or from umbilical cord cells which shall be collected and
prepared according to the manufacturer's biologics license application.
65. Section 660.33 is amended by revising the fifth sentence to
read as follows:
Sec. 660.33 Testing of source material.
* * * Where fewer than three donor sources of an antibody
specificity are available, test discrepancies shall be resolved in
accordance with the manufacturer's biologics license application. * * *
Dated: August 30, 1999.
Jane E. Henney,
Commissioner of Food and Drugs.
Donna E. Shalala,
Secretary of Health and Human Services.
[FR Doc. 99-27159 Filed 10-19-99; 8:45 am]
BILLING CODE 4160-01-F
