[Federal Register Volume 61, Number 20 (Tuesday, January 30, 1996)]
[Notices]
[Pages 3043-3045]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 96-1579]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES
[Docket No. 93D-0398]


Microbiological Testing for Antimicrobial Food-Animal Drugs; 
Final Guidance; Availability

AGENCY: Food and Drug Administration, HHS.

ACTION: Notice.

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SUMMARY: The Food and Drug Administration (FDA) is announcing the 
availability of a guidance document entitled ``Microbiological Testing 
of Antimicrobial Drug Residues in Food.'' The availability of the draft 
guideline was announced on January 6, 1994; this final guidance 
document addresses the comments submitted on the draft guideline. The 
final guidance document, which was prepared by the Center for 
Veterinary Medicine (CVM), addresses human food safety issues that may 
be associated with food-animal antimicrobial drug products. This 
guidance document also provides points to consider when determining 
which antimicrobials may require supplemental testing and recommends 
test procedures for establishing that antimicrobial drug residues will 
not cause intestinal microflora perturbations in the consumer.

DATES: Written comments on the guidance document may be submitted at 
any time.

ADDRESSES: Submit written requests for single copies of the final 
guidance document ``Microbiological Testing of Antimicrobial Drug 
Residues in Food,'' to the Communications and Education Branch (HFV-
12), Center for Veterinary Medicine, Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1755. Send two self-
addressed adhesive labels to assist that office in processing your 
requests. Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, 12420 Parklawn Dr., rm. 1-23, 
Rockville, MD 20857. Requests and comments should be identified with 
the docket number found in brackets in the heading of this document. A 
copy of the guidance document and received comments may be seen at the 
Dockets Management Branch between 9 a.m. and 4 p.m., Monday through 
Friday.

FOR FURTHER INFORMATION CONTACT: Haydee Fernandez, Center for 
Veterinary Medicine (HFV-154), Food and Drug Administration, 7500 
Standish Pl., Rockville, MD 20855, 301-594-1684.

SUPPLEMENTARY INFORMATION:  FDA is announcing the availability of the 
final guidance document entitled ``Microbiological Testing of 
Antimicrobial Drug Residues in Food.'' In evaluating the safety of new 
animal drugs, the agency must determine, among other things, their 
cumulative effect in man or other animal as required by section 
512(d)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the act) (21 
U.S.C. 360b(d)(2)(B)). The guidance document describes the testing that 
may be necessary to establish that antimicrobial drug residues in food 
will be safe and will not cause intestinal microflora perturbations in 
the consumer.
    In the Federal Register of January 6, 1994 (59 FR 754), FDA issued 
a notice of availability of the draft guideline entitled 
``Microbiological Testing of 

[[Page 3044]]
Antimicrobial Drug Residues in Food.'' The draft guideline was made 
available for public comment to provide the agency with views to be 
considered in the development of the guideline. Comments were requested 
specifically on: (1) Recommendations for additional microbiological 
testing for antimicrobial drug residues that seek a safe concentration 
higher than 1 part per million (ppm) of microbiologically active 
residues in the total diet; (2) how the proposed guideline should 
relate the effect of low doses of antibiotics observed in model systems 
to potential adverse biological effects in humans; and (3) appropriate 
endpoints for monitoring the effects of the different classes of 
antibiotics. Interested persons were given until April 6, 1994, to 
comment on the draft guideline.
    The agency received comments from university faculty members and 
the animal drug industry. FDA has revised the draft guideline as a 
result of these comments. In addition, FDA is reviewing its approach to 
the development of guidance documents. In order to eliminate confusion 
caused by use of different nomenclature for guidance documents (e.g., 
``guidelines,'' ``points to consider'') and to make it clear that this 
document is not being issued under current Sec. 10.90(b) (21 CFR 
10.90(b)). FDA is issuing this document as ``guidance,'' not as a 
``guideline.''

I. General Comments on the Draft Guideline

    1. There was general consensus among the comments that 
microbiologically inactive metabolites and rapidly absorbed 
antimicrobials would not produce any adverse effect on the intestinal 
microflora of humans.
    CVM agrees that the compounds that are most likely to raise human 
food safety concerns are those that are microbiologically active. 
Microbiologically inactive metabolites and rapidly absorbed 
antimicrobials are not the focus of this guidance document.
    2. Industry commented that the sponsor of a compound should 
identify the active residues and conduct the appropriate 
microbiological endpoints in consultation with the agency.
    FDA agrees that, under the act, it is the sponsor's responsibility 
to identify the microbiological activity of its product and to monitor 
the appropriate microbiological endpoint(s) to establish the 
antimicrobial no observed effect level (NOEL). As with all studies with 
animal drugs, the sponsor is encouraged to discuss the protocol with 
CVM representatives prior to initiating the study.

II. Comments Regarding Model Systems

    3. The agency received several comments on the use of model systems 
to evaluate the effect of active residues on the human intestinal 
microflora. The model systems proposed in the comments were mainly in 
vitro systems using continuous flow. According to the comments, 
continuous flow systems allow the study of the effect of ``low levels'' 
of antimicrobials on human intestinal microflora by studying the 
selection for antibiotic resistance, the change in colonization 
resistance, the determination of anaerobic population counts, and the 
detection of virulence enhancement.
    The agency agrees that in vitro models may offer a valid test 
system for assessing the effect of ``low levels'' of antimicrobials on 
the human intestinal microflora.
    4. A trade association stated that it would be very difficult for 
the sponsors to undertake de novo development and validation of test 
procedures. The comment suggested that before requiring testing, CVM 
should have some experience with the model systems that could be used 
to study the microbiological endpoints. This could be done by funding 
research studies to develop and, if possible, validate the test 
procedures.
    CVM is not aware of any validated model system for the testing of 
all antimicrobial agents. CVM does intend to initiate research which 
will lead to the development of validated model systems for evaluating 
the effect of low levels of antimicrobials on the human intestinal 
microflora.

III. Comments Regarding the Proposed Upper Limit of 1 ppm 
Antimicrobial Activity

    5. Most comments agreed with FDA that 1 ppm was a level of 
microbiologically active residues that would be unlikely to produce any 
adverse effect on the human intestinal microflora and would, therefore, 
be safe. Because there was some confusion about how 1 ppm in the total 
diet should be interpreted in practice, the guidance document states 
CVM's belief, based on available data, that for antimicrobial drug 
residues in edible tissues from food-producing animals the acceptable 
daily intake (ADI) should be 1.5 milligrams per person per day (mg/
person/day). Sponsors may demonstrate through additional specific 
testing that an ADI for drug residues in excess of 1.5 mg/person/day is 
safe.
    6. One comment expressed concern that 1 ppm might not be a ``very 
low level'' for all antibiotics, mainly for new and more active 
molecules (per unit of weight) than current antimicrobials.
    CVM disagrees based on the majority of scientific opinion. CVM has 
concluded that 1 ppm (or 1.5 mg/person/day) is a conservative level for 
determining whether or not antibiotic residues will produce an adverse 
effect on the human intestinal microflora. However, as the guidance 
makes clear, CVM may request information on microbiological activity of 
any new animal drug.
    7. One comment from industry agreed that studies should be 
conducted by sponsors to establish microbiological activity, but 
disagreed with CVM's proposed use of microbiological activity as a 
valid endpoint for establishing tolerances for antimicrobial drugs. The 
comment argued that the predictive value of microbiological activity in 
determining the no effect level for the health and safety of 
individuals and the public has not been established. Therefore, 
according to the comment, microbiological activity should not be used 
to set the safe concentration but should only help to evaluate a NOEL 
established by classic toxicology. Instead, the comment stated that 
``if there is a microbiological effect at a safe concentration higher 
than 1 ppm microbiologically active residue, then the regulated 
toxicological no adverse effect level for total residue will need to be 
adjusted downward accordingly, taking into account the percentage of 
microbiologically active residue in the total residue and the nature of 
the observed microbiological effect.''
    CVM disagrees. It is well documented that high levels of 
antibiotics produce deleterious effects on intestinal microflora (see 
``Symposium on Microbiological Significance of Drug Residues in Food,'' 
Veterinary and Human Toxicology, 35 (supplement 1), 1993). Therefore, 
CVM has concluded that microbiological activity is a valid endpoint for 
establishing the safe concentration for antimicrobial drugs. Thus, when 
scientifically appropriate, CVM will determine the no effect level and 
calculate the safe concentration based on the results of 
microbiological testing.

IV. Comments Regarding the Proposed Classification of Intestinal 
Microflora Changes

    8. One comment suggested that FDA should classify the changes in 
the intestinal microflora as follows: (1) Changes in the number of 
microorganisms and composition of intestinal microflora; (2) changes in 
metabolic activity of the flora related to metabolism of exogenous and 

[[Page 3045]]
endogenous compounds; and (3) changes in antimicrobial resistance 
patterns and resistant genetic elements within the microflora.
    CVM generally agrees. CVM has identified the following areas for 
which microbiological residues represent a potential public health 
concern: (1) -Changes in the metabolic activity of the intestinal 
microflora; (2) changes in antimicrobial resistance patterns of the 
intestinal microflora; (3) changes in the colonization resistance 
properties (barrier effect) of the microflora; and (4) changes in the 
number of microorganisms and composition of the intestinal microflora.

V. Conclusion

    The Center specifically invites comments on how to relate the 
effect produced in the model systems to the identified public health 
concerns. In addition, information on the appropriate endpoints for 
monitoring the effects of the different classes of antibiotics is 
requested. The public has the opportunity to comment on this guidance 
document at any time. CVM will consider all comments for future 
modifications of this guidance document.
    Guidelines are generally issued under Secs. 10.85(a) (21 CFR 
10.85(a)) and 10.90(b). The agency is now in the process of revising 
Secs. 10.85(a) and 10.90(b). This guidance document does not bind the 
agency, and it does not create or confer any rights, privileges, or 
benefits for or on any person; however, it represents the agency's 
current thinking on microbiological testing of antimicrobial drug 
residues in food. A person may follow the guidance document or may 
choose to follow alternate procedures or practices. If a person chooses 
to use alternate procedures or practices, that person may wish to 
discuss the matter further with the agency to prevent an expenditure of 
money and effort on activities that may later be determined to be 
unacceptable to FDA.
    Interested persons may, at any time, submit to the Dockets 
Management Branch (address above) written comments on the guidance 
document. 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. The 
guidance document and received comments are available for public 
examination in the Dockets Management Branch between 9 a.m. and 4 p.m., 
Monday through Friday.
    Received comments will be considered to determine if further 
revision of the guidance document is necessary.

    Dated: January 22, 1996.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 96-1579 Filed 1-29-96; 8:45 am]
BILLING CODE 4160-01-F