[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]



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.


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.

Biologics Evaluation and Research (HFM-17), Food and Drug 
Administration, 1401 Rockville Pike, Rockville, MD 20852-1448, 301-827-


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receives any adverse comment and is withdrawn.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 
    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 
    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 

[[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:


    1. The authority citation for 21 CFR part 660 is revised to read as 

    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]