[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]


=======================================================================
-----------------------------------------------------------------------

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.

-----------------------------------------------------------------------

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