[Federal Register Volume 65, Number 239 (Tuesday, December 12, 2000)]
[Rules and Regulations]
[Pages 77497-77499]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-31586]
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DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
21 CFR Part 660
[Docket No. 00N-1586]
Revision to Requirements for Licensed Anti-Human Globulin and
Blood Grouping Reagents
AGENCY: Food and Drug Administration, HHS.
ACTION: Direct final rule.
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SUMMARY: The Food and Drug Administration (FDA) is amending the
biologics regulations applicable to microbiological controls for
licensed Anti-Human Globulin (AHG) and Blood Grouping Reagents (BGR).
FDA is amending the regulations to remove the requirements that the
products be sterile. FDA is publishing this direct final rule because
the requirement that these products be sterile is not necessary for the
products to be safe, pure, and potent. FDA is issuing these amendments
directly as a final rule because they are noncontroversial and there is
little likelihood that FDA will receive any significant comments
opposing the rule. Elsewhere in this issue of the Federal Register, FDA
is publishing a proposed rule under FDA's usual procedures for notice
and comment in the event the agency receives any significant adverse
comments. If FDA receives any significant adverse comment that warrants
terminating the direct final rule, FDA will consider such comments on
the proposed rule in developing the final rule.
DATES: This rule is effective June 11, 2001. Submit written comments on
or before February 26, 2001. If FDA receives no significant adverse
comments during the specified comment period, the agency intends to
publish a confirmation document on or before the effective date of this
direct final rule confirming that the direct final rule will go into
effect on June 11, 2001. If the agency receives any significant adverse
comment during the comment period, FDA intends to withdraw this direct
final rule by publication in the Federal Register before the effective
date of this direct final rule.
ADDRESSES: Submit written comments on the direct final rule to the
Dockets Management Branch (HFA-305), Food and Drug Administration, 5630
Fishers Lane, rm. 1061, Rockville, MD 20852.
FOR FURTHER INFORMATION CONTACT: Stephen M. Ripley, Center for
Biologics Evaluation and Research (HFM-17), Food and Drug
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-
6210.
SUPPLEMENTARY INFORMATION:
I. Background
AHG and BGR are used primarily for testing human blood for the
detection of red cell antigens and antibodies. As defined in 21 CFR
660.20, BGR is a product that comes from blood, plasma, serum, or
protein-rich fluids and consists of an antibody-containing fluid
containing one or more of the blood grouping antibodies listed in 21
CFR 660.28(d).
Under 21 CFR 660.50, AHG is a serum or protein-rich fluid that
consists of one or more antiglobulin antibodies identified in 21 CFR
660.55(d). AHG and BGR are biological products as defined in section
351 of the Public Health Service Act (PHS ACT) (42 U.S.C 262). These
products are also devices, as defined in section 201 of the Federal
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 321), and fall within
the definition of in vitro diagnostic (IVD's) products in Sec. 809.3(a)
(21 CFR 809.3(a)).
AHG and BGR must meet the licensing requirements of section 351 of
the PHS Act and the regulations in parts 600 through 660 (21 CFR parts
600 through 660). Section 351 of the PHS Act, requires that a license
applicant demonstrate that the biological product that is the subject
of the application is safe, pure, and potent, and that the
manufacturing facilities are designed to assure that the biological
product continues to be safe, pure, and potent.
AHG and BGR are also medical devices and in vitro diagnostic
products as defined in Sec. 809.3(a) and therefore are subject under
the act and 21 CFR 809.20(b) to the requirements in the quality system
regulation (QSR) in part
[[Page 77498]]
820 (21 CFR part 820). The QSR requires that a manufacturer establish
appropriate manufacturing controls. A manufacturer must validate the
manufacturing process in accordance with Sec. 820.75 and establish
production and process controls (Sec. 820.70). See also the ``Guideline
for the Manufacture of In Vitro Diagnostic Products'' published in the
Federal Register of January 10, 1994 (59 FR 1402).
The standards for AHG and BGR were established by final rules
published in the Federal Register of February 11, 1985, and April 19,
1988, respectively (50 FR 5574 and 53 FR 12760). The standards in
Secs. 660.20(a) and 660.50(a) require BGR and AHG to be manufactured by
a ``method demonstrated to consistently yield a sterile product.'' In
addition, the requirements for processing methods of BGR and AHG under
Secs. 660.21(a)(2) and 660.51(a)(3) state that ``[o]nly that material
that has been fully processed, thoroughly mixed in a single vessel, and
sterile filtered shall constitute a lot,'' and under Secs. 660.21(a)(3)
and 660.51(a)(4) that ``[a] lot may be subdivided into clean sterile
vessels''.
When the regulations were codified, the agency expected that AHG
and BGR would be manufactured as sterile under the conditions
understood at that time. The agency also considered that the process of
sterile filtration and a sterile container and closure system, e.g.,
vessels, would be sufficient to yield consistently a sterile product
(50 FR 5574 at 5575; 53 FR 12760 at 12761). However, current good
manufacturing practices require aseptic processing controls to be in
place in order to ensure a sterile product. The agency considers AHG
and BGR to be microbiologically controlled IVD's, which are IVD's that
are capable of supporting microorganism life and growth and may contain
certain levels of microorganisms. Microbiologically controlled IVD's do
not need to be manufactured under aseptic conditions; however, they
should be manufactured under conditions such that the microbial level
will not adversely impact product performance. Manufacturers must
establish specifications for these products through testing and
validation. FDA's revision of the regulations would in no way undermine
the safety, potency, or purity of the products. The revisions would
also not prevent a manufacturer from implementing aseptic processing
controls for manufacturing AHG and BGR, if the manufacturer determines
such controls are appropriate for its product. Therefore, the agency is
revising the standards for AHG and BGR to remove the requirement that
these products be sterile.
II. Highlights of the Direct Final Rule
FDA is amending the biologics regulations by revising Secs. 660.20,
660.21, 660.50, and 660.51 to clarify the agency's requirements with
regard to microbiological control in manufacturing AHG and BGR. FDA is
amending the regulations by deleting all references to sterile
processing techniques such as sterile filtration and sterile container
and closure systems. FDA is amending Secs. 660.20(a) and 660.50(a) by
deleting the phrase regarding preparation ``by a method demonstrated to
yield consistently a sterile product'' because FDA recognizes that
controls to ensure a sterile product, i.e., aseptic processing
controls, are not necessary to ensure that AHG and BGR meet their
performance specifications. In addition, Sec. 660.21(a)(1) and
660.51(a)(1) include requirements regarding the adequacy of the
processing method. FDA is amending Secs. 660.21(a)(2) and 660.51(a)(3)
by deleting the term ``sterile'' because the manufacturer must
establish those controls appropriate for its product, and it may not be
necessary for microbiologically controlled IVD's to undergo sterile
filtration. FDA is amending Secs. 660.21(a)(3) and 660.51(a)(4) by
deleting the reference to ``clean, sterile vessels'' because FDA
believes that manufacturers are in the best position to determine the
appropriate level of microbial control for container and closure
systems. Appropriate process specifications must be established by the
manufacturer to ensure that microbiologically controlled IVD's are
manufactured under appropriate conditions and controls resulting in a
product that consistently meets all of its specifications. The
manufacturer must demonstrate in the license application that the
appropriate level of control of microbial contamination ensures that
the biological product continues to meet the licensing requirements.
The change to the regulation in no way affects the testing and
validation a manufacturer must perform in order to establish that the
manufacturing specifications are appropriate to ensure the product will
perform as intended. In addition, under the current good manufacturing
practice regulations for blood and blood components, end users of AHG
and BGR, such as blood banks, are required under Sec. 606.65(c) to
perform daily checks for potency and specificity of supplies and
reagents used in the collection and testing of blood and blood
components.
The agency also believes the change is consistent with other
requirements in the biologics regulations, such as the sterility
testing requirements set forth in Sec. 610.12. This section requires
sterility testing for most biological products; however, BGR and AHG
are specifically exempted from the sterility testing requirements for
bulk and final container material (Sec. 610.12(g)(4)).
The direct final rule will also remove the requirement in
Sec. 660.51(a)(4) that a manufacturer who subdivides a lot shall
include this information on the protocol. FDA is making this change to
reflect current agency practice. Manufacturers will still be required
to submit this information in the license application. See Sec. 601.2
regarding requirements for the submission of samples and protocols to
FDA.
III. Rulemaking Action
In the Federal Register of November 21, 1997 (62 FR 62466), FDA
described its procedures on when and how FDA will employ direct final
rulemaking. FDA has determined that this rule is appropriate for direct
final rulemaking because FDA views this rule as including only
noncontroversial amendments and anticipates no significant adverse
comments. Consistent with FDA's procedures on direct final rulemaking,
FDA is publishing elsewhere in this issue of the Federal Register, a
companion proposed rule to amend the biologics regulations by amending
the existing regulations to be more consistent with current accepted
practices. The companion proposed rule provides a procedural framework
within which the rule may be finalized in the event the direct final
rule is withdrawn because of any significant adverse comment. The
comment period for the direct final rule runs concurrently with the
companion proposed rule. Any comment received under the companion
proposed rule will be considered as comments regarding the direct final
rule.
FDA has provided a comment period on the direct final rule of 75
days after December 12, 2000. If the agency receives any significant
adverse comment, FDA intends to withdraw this direct final rule action
by publication of a document in the Federal Register before the
effective date of the direct final rule. A significant adverse comment
is defined as a comment that explains why the rule would be
inappropriate, including challenges to the rule's underlying premise or
approach, or would be ineffective or unacceptable without a change. In
determining whether an adverse comment is significant and warrants
[[Page 77499]]
terminating a direct final rulemaking, FDA will consider whether the
comment raises an issue serious enough to warrant a substantive
response in a notice and comment process. Comments that are frivolous,
insubstantial, or outside the scope of the rule will not be considered
significant or adverse under this procedure. A comment recommending a
rule change in addition to the rule would not be considered a
significant adverse comment, unless the comment states why the rule
would be ineffective without additional change. In addition, if a
significant adverse comment applies to an amendment, paragraph, or
section of this rule and that provision can be severed from the
remainder of the rule, FDA may adopt as final those provisions of the
rule that are not subjects of a significant adverse comment.
If any significant adverse comment is received during the comment
period, FDA will publish, before the effective date of this direct
final rule, a document withdrawing the direct final rule. If FDA
withdraws the direct final rule, any comments received will be applied
to the proposed rule and will be considered in developing a final rule
using the usual Administrative Procedure Act notice-and-comment
procedures.
If FDA receives no significant adverse comments during the
specified comment period, FDA intends to publish a confirmation
document, before the effective date of the direct final rule,
confirming the effective date.
IV. Analysis of Impacts
A. Review Under Executive Order 12866 and the Regulatory Flexibility
Act and the Unfunded Mandates Act of 1995
FDA has examined the impact of the direct final rule under
Executive Order 12866, the Regulatory Flexibility Act (5 U.S.C. 601-
612), and the Unfunded Mandates Reform Act of 1995 (Public Law 104-4).
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; distribute impact; and equity). The agency believes that
this direct final rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. This direct final rule is
not a significant regulatory action as defined by the Executive Order
and therefore is not subject to review under the Executive Order.
The Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize any significant impact of a rule
on small business entities. Because the direct final rule amendments
have no compliance costs and do not result in any new requirements, the
agency certifies that the direct 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. This direct final rule also does not trigger the requirement
for a written statement under section 202(a) of the Unfunded Mandates
Reform Act of 1995 because it does not impose a mandate that results in
an expenditure of $100 million or more by State, local, and tribal
governments in the aggregate, or by the private sector in any one year.
B. Environmental Impact
The agency has determined under 21 CFR 25.31(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.
C. Federalism
FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have substantial direct effects on the
States, on the relationship between the National Government and the
States, or on the distribution of power and responsibilities among the
various levels of government. Accordingly, the agency has concluded
that the rule does not contain policies that have federalism
implications as defined in the order and, consequently, a federalism
summary impact statement is not required.
V. The Paperwork Reduction Act of 1995
This direct final rule contains no collections of information.
Therefore, clearance by the Office of Management and Budget under the
Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520) is not required.
VI. Request for Comments
Interested persons may submit to the Dockets Management Branch
(address above) written comments regarding this direct final rule by
February 26, 2001. Two copies of any comments are to be submitted,
except that individuals may submit one copy. Comments are to be
identified with the docket number found in brackets in the heading of
this document. Received comments may be seen in the office above
between 9 a.m. and 4 p.m., Monday through Friday.
List of Subjects in 21 CFR Part 660
Biologics, Labeling, Reporting and recordkeeping requirements.
Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR part 660 is amended as follows:
PART 660--ADDITIONAL STANDARDS FOR DIAGNOSTIC SUBSTANCES FOR
LABORATORY TESTS
1. The authority citation for 21 CFR part 660 is revised to read as
follows:
Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 360, 360c,
360d, 360h, 360i, 371, 372; 42 U.S.C. 216, 262, 263, 263a, 264.
Sec. 660.20 [Amended]
2. Section 660.20 Blood Grouping Reagent is amended in paragraph
(a) by removing the words ``prepared by a method demonstrated to yield
consistently a sterile product and''.
Sec. 660.21 [Amended]
3. Section 660.21 Processing is amended in paragraph (a)(2) by
removing the word ``sterile''; and in paragraph (a)(3) by removing the
words ``clean, sterile vessels. Each subdivision shall constitute a
sublot.'' and adding in its place the word ``sublots.''
Sec. 660.50 [Amended]
4. Section 660.50 Anti-Human Globulin is amended in paragraph (a)
by removing the words ``and be prepared by a method demonstrated to
yield consistently a sterile product''.
Sec. 660.51 [Amended]
5. Section 660.51 Processing is amended in the first sentence of
paragraph (a)(3) by removing the word ``sterile'', and in paragraph
(a)(4) by removing the words ``clean, sterile vessels. Each subdivision
shall constitute a sublot'' and adding in its the word ``sublots'', and
in the third sentence by removing the words ``and on the protocol''.
Dated: December 3, 2000.
Margaret M. Dotzel,
Associate Commissioner for Policy.
[FR Doc. 00-31586 Filed 12-11-00; 8:45 am]
BILLING CODE 4160-01-F