[Federal Register Volume 65, Number 239 (Tuesday, December 12, 2000)]
[Proposed Rules]
[Pages 77532-77534]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-31587]
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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; Companion to Direct Final Rule
AGENCY: Food and Drug Administration, HHS.
ACTION: Proposed rule.
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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend
the biologics regulations applicable to microbiological controls for
licensed Anti-Human Globulin (AHG) and Blood Grouping Reagents (BGR).
FDA is proposing to remove the requirements that the products be
sterile. FDA is taking this action because the requirement that these
products be sterile is not necessary for the products to be safe, pure,
and potent. This proposed rule is a companion document to the direct
final rule published elsewhere in this issue of the Federal Register.
FDA is taking this action final because the proposed changes are
noncontroversial and FDA anticipates that it will receive no
significant adverse comment.
DATES: Submit written comments on or before February 26, 2001.
ADDRESSES: Submit written comments on the proposed 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
This proposed rule is a companion to the direct final rule
published in the final rules section of this issue of the Federal
Register. This companion proposed rule provides the procedural
framework to finalize the rule in the event that the direct final rule
receives any adverse comment and is withdrawn. The comment period for
this companion proposed rule runs concurrently with the comment period
for the direct final rule. Any comments received under this companion
rule will also be considered as comments regarding the direct final
rule. FDA is publishing the direct final rule because the rule contains
noncontroversial changes, and FDA anticipates that it will receive no
significant adverse comment.
An 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 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 significant adverse
comments.
If no significant adverse comment is received in response to the
direct final rule, no further action will be taken related to this
proposed rule. Instead, FDA will publish a confirmation document,
before the effective date of the direct final rule, confirming that the
direct final rule will go into effect on
[[Page 77533]]
June 11, 2001. Additional information about FDA's direct rulemaking
procedures is set forth in a guidance published in the Federal Register
of November 21,1997 (62 FR 62466).
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 (42 U.S.C 262) (the PHS
Act). 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 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 ensure 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 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 ``[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 in vitro diagnostics
(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 proposed revision
of the regulations would in no way undermine the safety, potency, or
purity of the products. The proposed 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 proposing to
revise the standards for AHG and BGR to remove the requirement that
these products be sterile.
II. Highlights of the Proposed Rule
FDA is proposing to amend 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 proposing to amend the regulations by deleting all
references to sterile processing techniques such as sterile filtration
and sterile container and closure systems. FDA is proposing to amend
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,
Secs. 660.21(a)(1) and 660.51(a)(1) include requirements regarding the
adequacy of the processing method. FDA is proposing to amend
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 proposing to
amend 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 proposed 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 proposed 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 proposed rule would 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 would still be required
to submit this information in the license application. See Sec. 601.2
regarding
[[Page 77534]]
requirements for the submission of samples and protocols to FDA.
III. 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 proposed rule under Executive
Order 12866 and 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 proposed rule is consistent with the regulatory philosophy and
principles identified in the Executive Order. This proposed 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 proposed rule amendments have
no compliance costs and do not result in any new requirements, the
agency certifies that the proposed 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 proposed 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.
IV. The Paperwork Reduction Act of 1995
FDA tentatively concludes that this proposed 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.
V. Request for Comments
Interested persons may submit to the Dockets Management Branch
(address above) written comments regarding this proposal 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, it is proposed that 21 CFR part 660 be
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 place 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. 00-31587 Filed 12-11-00; 8:45 am]
BILLING CODE 4160-01-F