[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
