Protein Efficiency Ratio Rat Bioassay Studies To Demonstrate That a New Infant Formula Supports the Quality Factor of Sufficient Biological Quality of Protein; Draft Guidance for Industry; Availability; Agency Information Collection Activities; Proposed Collection; Comment Request, 8868-8872 [2023-02836]
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Federal Register / Vol. 88, No. 28 / Friday, February 10, 2023 / Notices
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2022–D–2424]
Protein Efficiency Ratio Rat Bioassay
Studies To Demonstrate That a New
Infant Formula Supports the Quality
Factor of Sufficient Biological Quality
of Protein; Draft Guidance for Industry;
Availability; Agency Information
Collection Activities; Proposed
Collection; Comment Request
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice of availability.
The Food and Drug
Administration (FDA or we) is
announcing the availability of a draft
guidance entitled ‘‘Protein Efficiency
Ratio (PER) Rat Bioassay Studies To
Demonstrate That a New Infant Formula
Supports the Quality Factor of
Sufficient Biological Quality of
Protein.’’ The draft guidance, when
finalized, will provide information for
manufacturers and contract laboratories
that perform PER studies to assist in
designing, conducting, evaluating, and
reporting PER studies. The draft
guidance, when finalized, will explain
‘‘appropriate modifications’’ of AOAC
Official Method 960.48 (the AOAC
Method) with the aim of supporting
industry in successfully conducting PER
studies that demonstrate that a new
infant formula meets the quality factor
of sufficient biological quality of protein
when fed as the sole source of nutrition.
DATES: Submit either electronic or
written comments on the draft guidance
by May 11, 2023 to ensure that we
consider your comment on the draft
guidance before we begin work on the
final version of the guidance. Submit
electronic or written comments on the
proposed collection of information in
the draft guidance by May 11, 2023.
ADDRESSES: You may submit comments
on any guidance at any time as follows:
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SUMMARY:
Electronic Submissions
Submit electronic comments in the
following way:
• Federal eRulemaking Portal:
https://www.regulations.gov. Follow the
instructions for submitting comments.
Comments submitted electronically,
including attachments, to https://
www.regulations.gov will be posted to
the docket unchanged. Because your
comment will be made public, you are
solely responsible for ensuring that your
comment does not include any
confidential information that you or a
third party may not wish to be posted,
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such as medical information, your or
anyone else’s Social Security number, or
confidential business information, such
as a manufacturing process. Please note
that if you include your name, contact
information, or other information that
identifies you in the body of your
comments, that information will be
posted on https://www.regulations.gov.
• If you want to submit a comment
with confidential information that you
do not wish to be made available to the
public, submit the comment as a
written/paper submission and in the
manner detailed (see ‘‘Written/Paper
Submissions’’ and ‘‘Instructions’’).
Written/Paper Submissions
Submit written/paper submissions as
follows:
• Mail/Hand Delivery/Courier (for
written/paper submissions): Dockets
Management Staff (HFA–305), Food and
Drug Administration, 5630 Fishers
Lane, Rm. 1061, Rockville, MD 20852.
• For written/paper comments
submitted to the Dockets Management
Staff, FDA will post your comment, as
well as any attachments, except for
information submitted, marked and
identified, as confidential, if submitted
as detailed in ‘‘Instructions.’’
Instructions: All submissions received
must include the Docket No. FDA–
2022–D–2424 for ‘‘Protein Efficiency
Ratio (PER) Rat Bioassay Studies To
Demonstrate That a New Infant Formula
Supports the Quality Factor of
Sufficient Biological Quality of
Protein.’’ Received comments will be
placed in the docket and, except for
those submitted as ‘‘Confidential
Submissions,’’ publicly viewable at
https://www.regulations.gov or at the
Dockets Management Staff between 9
a.m. and 4 p.m., Monday through
Friday, 240–402–7500.
• Confidential Submissions—To
submit a comment with confidential
information that you do not wish to be
made publicly available, submit your
comments only as a written/paper
submission. You should submit two
copies total. One copy will include the
information you claim to be confidential
with a heading or cover note that states
‘‘THIS DOCUMENT CONTAINS
CONFIDENTIAL INFORMATION.’’ We
will review this copy, including the
claimed confidential information, in our
consideration of comments. The second
copy, which will have the claimed
confidential information redacted/
blacked out, will be available for public
viewing and posted on https://
www.regulations.gov. Submit both
copies to the Dockets Management Staff.
If you do not wish your name and
contact information to be made publicly
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available, you can provide this
information on the cover sheet and not
in the body of your comments and you
must identify this information as
‘‘confidential.’’ Any information marked
as ‘‘confidential’’ will not be disclosed
except in accordance with 21 CFR 10.20
and other applicable disclosure law. For
more information about FDA’s posting
of comments to public dockets, see 80
FR 56469, September 18, 2015, or access
the information at: https://
www.govinfo.gov/content/pkg/FR-201509-18/pdf/2015-23389.pdf.
Docket: For access to the docket to
read background documents or the
electronic and written/paper comments
received, go to https://
www.regulations.gov and insert the
docket number, found in brackets in the
heading of this document, into the
‘‘Search’’ box and follow the prompts
and/or go to the Dockets Management
Staff, 5630 Fishers Lane, Rm. 1061,
Rockville, MD 20852, 240–402–7500.
You may submit comments on any
guidance at any time (see 21 CFR
10.115(g)(5)).
Submit written requests for single
copies of the draft guidance to Office of
Nutrition and Food Labeling (HFS–800),
Center for Food Safety and Applied
Nutrition, Food and Drug
Administration, 5001 Campus Dr.,
College Park, MD 20740. Send one selfaddressed adhesive label to assist that
office in processing your request or
include a Fax number to which the draft
guidance may be sent. See the
SUPPLEMENTARY INFORMATION section for
information on electronic access to the
draft guidance.
FOR FURTHER INFORMATION CONTACT:
With regard to the draft guidance:
Andrea Lotze, Center for Food Safety
and Applied Nutrition, Office of
Nutrition and Food Labeling (HFS–800),
Food and Drug Administration, 5001
Campus Dr., College Park, MD 20740,
240–402–1450, email: Andrea.Lotze@
fda.hhs.gov; or Keronica Richardson,
Center for Food Safety and Applied
Nutrition, Office of Regulations and
Policy (HFS–024), Food and Drug
Administration, 5001 Campus Dr.,
College Park, MD 20740, 240–402–2378.
With regard to the proposed collection
of information: Rachel Showalter, Office
of Operations, Food and Drug
Administration, Three White Flint
North, 10A–12M, 11601 Landsdown St.,
North Bethesda, MD 20852, 240–994–
7399, PRAStaff@fda.hhs.gov.
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of
a draft guidance for industry entitled
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‘‘Protein Efficiency Ratio (PER) Rat
Bioassay Studies To Demonstrate That a
New Infant Formula Supports the
Quality Factor of Sufficient Biological
Quality of Protein.’’ Our regulations, at
21 CFR 106.96, establish requirements
for quality factors for infant formulas,
including the quality factor of sufficient
biological quality of protein. Subject to
a limited exception (see § 106.96(g)),
each manufacturer of an infant formula
that is not an eligible infant formula
must demonstrate that the formula
meets the quality factor of sufficient
biological quality of protein by
establishing the biological quality of the
protein in the infant formula when fed
as the sole source of nutrition using an
appropriate modification of the AOAC
Official Method 960.48 (the AOAC
Method) Protein Efficiency Ratio (PER)
Rat Bioassay (§ 106.96(f)).1
The AOAC Method provides a
procedure by which the quality of a
protein in food can be evaluated and
compared with those of other proteins.
Protein ‘‘quality’’ can be defined as the
ability of a protein to meet the essential
amino acid needs of an animal. The
AOAC Method is a standardized
bioassay with published collaborative
study data. The AOAC Method permits
the calculation of a PER as the ratio of
the average animal body weight gain per
gram of protein consumed of a test
protein versus casein after a 28-day
feeding period. Typically, the protein
concentration of both the test and casein
reference diet is set at about 10 percent,
a level that is below the estimated
requirement for growth of rats of 15
percent, to improve the sensitivity of the
method. While growth is slower at 10
percent protein than at 15 percent
protein, the lower protein level assures
that available protein is efficiently
utilized.
In the PER study described in the
AOAC Method, a protein ingredient was
assayed at 10 percent and other
potential variables were standardized so
that their numbers and potential effects
were minimized. Vitamin composition,
moisture, ash, carbohydrates, fat, and
fiber were adjusted between the casein
reference diet and the test diet. Use of
1 We support the principles of the ‘‘3Rs’’ to
reduce, refine, and replace animal use in testing
when feasible. We encourage sponsors to consult
with us if they wish to use a non-animal testing
method they believe is suitable, adequate, and
validated to demonstrate that the formula supports
the quality factor for the biological quality of the
protein as described in 21 CFR 106.96(g)(3). We
support alternative methods by exemption in 21
CFR 106.96(f) which allows the manufacturer to
request an exemption and provide certain required
assurances described in 21 CFR 106.96(g). The
applicability of this exemption is not the subject of
this guidance.
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a test diet that contains an infant
formula in its entirety introduces
matrices of high fat content and
additional vitamins, minerals, and other
ingredients, as well as the low protein
source. A major challenge in analyzing
infant formulas by the AOAC Method is
matching the casein reference diet and
test diet to achieve dietary groups with
as few confounding variables as
possible.
Since we promulgated § 106.96, we
have found that industry is experiencing
difficulties in consistently meeting its
requirements. Therefore, we are
announcing the availability of a draft
guidance for industry entitled ‘‘Protein
Efficiency Ratio (PER) Rat Bioassay
Studies To Demonstrate That a New
Infant Formula Supports the Quality
Factor of Sufficient Biological Quality of
Protein.’’ This draft guidance, when
finalized, will help infant formula
manufacturers and contract laboratories
that perform PER studies in designing,
conducting, evaluating, and reporting
PER studies. The draft guidance, when
finalized, will explain ‘‘appropriate
modifications’’ of the AOAC Method to
help manufacturers and contract
laboratories conduct PER studies that
demonstrate to FDA that a new infant
formula meets the quality factor of
sufficient biological quality of protein.
FDA’s work on this draft guidance
document began prior to significant
infant formula supply chain concerns
that arose in early 2022. Although this
guidance was not prepared specifically
to alleviate supply chain concerns, this
guidance will help ensure that infant
formula products meet FDA’s regulatory
requirements and will contribute to
ensuring a more resilient infant formula
supply. We are issuing the draft
guidance consistent with our good
guidance practices regulation (21 CFR
10.115). The draft guidance, when
finalized, will represent the current
thinking of FDA on this topic. It does
not establish any rights for any person
and is not binding on FDA or the public.
You can use an alternate approach to
make ‘‘appropriate modifications’’ if it
satisfies the requirements of the
applicable statutes and regulations.
Topics discussed in the draft guidance
include:
• Purpose of the AOAC Method;
• Overview of the AOAC Method as
originally described;
• Need for ‘‘appropriate
modifications’’ to update the AOAC
Method and for use of infant formulas
in PER bioassays;
• Conduct and analysis of a PER
study with ‘‘appropriate modifications’’
(matching the reference and test diets);
• Protocols and reports;
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• Reference guidelines; and
• Appendices: AOAC Official Method
960.48, composition of vitamin and
mineral mixtures, compositions of diets,
and examples of an approach for
matching vitamin, mineral, and
(methionine + cystine) compositions of
PER study diets.
II. Paperwork Reduction Act of 1995
Under the Paperwork Reduction Act
of 1995 (PRA) (44 U.S.C. 3501–3521),
Federal Agencies must obtain approval
from the Office of Management and
Budget (OMB) for each collection of
information they conduct or sponsor.
‘‘Collection of information’’ is defined
in 44 U.S.C. 3502(3) and 5 CFR
1320.3(c) and includes Agency requests
or requirements that members of the
public submit reports, keep records, or
provide information to a third party.
Section 3506(c)(2)(A) of the PRA (44
U.S.C. 3506(c)(2)(A)) requires Federal
Agencies to provide a 60-day notice in
the Federal Register concerning each
proposed collection of information
before submitting the collection to OMB
for approval. To comply with this
requirement, FDA is publishing notice
of the proposed collection of
information set forth in this document.
With respect to the following
collection of information, FDA invites
comments on these topics: (1) whether
the proposed collection of information
is necessary for the proper performance
of FDA’s functions, including whether
the information will have practical
utility; (2) the accuracy of FDA’s
estimate of the burden of the proposed
collection of information, including the
validity of the methodology and
assumptions used; (3) ways to enhance
the quality, utility, and clarity of the
information to be collected; and (4)
ways to minimize the burden of the
collection of information on
respondents, including through the use
of automated collection techniques,
when appropriate, and other forms of
information technology.
Protein Efficiency Ratio (PER) Rat
Bioassay Studies To Demonstrate That
a New Infant Formula Supports the
Quality Factor of Sufficient Biological
Quality of Protein
OMB Control Number 0910–0256—
Revision
Under § 106.96(e), an infant formula
must meet the quality factor of sufficient
biological quality of protein, and
§ 106.96(f) provides how an infant
formula manufacturer must demonstrate
that a formula meets this quality factor.
PER studies are used to demonstrate to
FDA that a new infant formula meets
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recordkeeping and reporting of
protocols and PER studies related to the
composition of test and control diets, as
well as conditions, adverse effects, and
attrition in rats. The draft guidance,
when finalized, also will explain
‘‘appropriate modifications’’ of the
AOAC Method to help manufacturers
and contract laboratories conduct PER
studies that demonstrate to FDA that a
the quality factor of sufficient biological
quality of protein when fed as the sole
source of nutrition. This draft guidance,
when finalized, would help
manufacturers and laboratories
performing PER studies in the design,
conduct, evaluation, and reporting of
such studies. When finalized, the draft
guidance would provide
recommendations for additional
new infant formula meets the quality
factor of sufficient biological quality of
protein.
Description of Respondents:
Respondents to the information
collection are manufacturers of infant
formula. Respondents are from the
private sector (for-profit businesses).
We estimate the burden of this
collection of information as follows:
TABLE 1—ESTIMATED ANNUAL RECORDKEEPING BURDEN 1
Number of
records per
recordkeeper
Number of
recordkeepers
Activity; guidance document section
Average burden
per
recordkeeping
Total annual
records
Records for composition of the test and
control diets during PER studies; Section IV.
Records for conditions, adverse effects,
and attrition in rats during PER studies;
Section IV.
15
2
30
15
140
2,100
Total ...................................................
..............................
..............................
..............................
1 There
Total hours
1 .......................
30
0.083 (5 minutes).
174
...........................
204
are no capital costs or operating and maintenance costs associated with this collection of information.
The estimates in tables 1 and 2 are
based on experience with our infant
formula safety and nutrition programs.
We estimate that fifteen manufacturers
annually will each create and maintain
two records for the composition of test
and control diets of PER studies. We
estimate the recordkeeping burden to be
1 hour per record for an annual burden
of 30 hours (15 manufacturers × 2
records). These estimates are based on
numerous PER study protocols, reports,
and laboratory experiences.
We estimate that fifteen
manufacturers annually will each create
and maintain 140 records to account for
conditions, adverse effects, and attrition
in rats during PER studies. We estimate
these records will take 5 minutes per
record for an annual burden of 174.3
hours, rounded to 174 (15
manufacturers × 140 records × 0.083/
hours). We calculate the total
recordkeeping burden will be 204 hours
annually.
TABLE 2—ESTIMATED ANNUAL REPORTING BURDEN 1
Number of
respondents
Activity; guidance document section
Total annual
responses
Average
burden per
response
Total hours
Development and submission of a PER study protocol;
Section V ..........................................................................
Development and submission of a PER study final report;
Section V ..........................................................................
15
1
15
70
1,050
15
1
15
40
600
Total ..............................................................................
........................
........................
........................
........................
1,650
1 There
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Number of
responses per
respondent
are no capital costs or operating and maintenance costs associated with this collection of information.
We estimate that fifteen
manufacturers will prepare and submit
to FDA a protocol to ensure that the
specifications of the AOAC Method and
FDA’s ‘‘appropriate modifications’’ are
met. A protocol is a detailed plan for the
conduct of the PER study that helps the
manufacturer meet the requirements of
§ 106.96. In Table 1 in Appendix 6 of
the draft guidance, we offer an
illustration of how the values can be
recorded as part of a protocol. An
interested manufacturer will call FDA to
discuss the manner in which a protocol
will be submitted. We estimate each
protocol will take 70 hours for an
annual burden of 1,050 hours (15
protocols × 70 hours).
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In addition, we estimate that fifteen
manufacturers will submit a final report
on all aspects of the PER study,
including Certificates of Analyses (i.e., a
full specification of results) for relevant
ingredients to FDA. A final report is
submitted in the same manner as a
protocol. We estimate each final report
will take 40 hours for an annual burden
of 600 hours (15 final reports × 40
hours). We calculate the total reporting
burden will be 1,650 hours annually.
This draft guidance also refers to
previously approved FDA collections of
information. The collections of
information in 21 CFR part 106 have
been approved under OMB control
number 0910–0256.
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III. Electronic Access
Persons with access to the internet
may obtain an electronic version of the
draft guidance at https://www.fda.gov/
RegulatoryInformation/Guidances/
default.html, https://www.fda.gov/
regulatory-information/search-fdaguidance-documents, or https://
www.regulations.gov.
IV. Other Issues for Consideration
Although FDA welcomes comments
on any aspect of the draft guidance, we
particularly invite comments on the
following sections, issues, and questions
related to the compositions of PER study
test (infant formula) and reference
(casein control) diets. We ask that your
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comments explain how suggestions will
meet the overall requirement of
demonstrating that the quality factor has
been met using an ‘‘appropriate
modification.’’ When commenting on a
particular question, please use the
question numbers below as this will
make it easier for us to determine how
a specific comment relates to a
particular question or topic.
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A. Questions for Section IV.B.1.c. Fats
and Carbohydrates
1. Fats
Question 1. Companies have
expressed difficulties in qualitative
matching of fat in test and reference
diets (e.g., problems with physical
consistency of reference diets when
qualitative matching is attempted) and
difficulties in quantitative matching
because of the much lower fat
requirement of rats. We invite
comments on whether the fat
compositions of the test and reference
diets should be matched: (a) on a
quantitative basis only; or (b) on both a
quantitative and qualitative basis. Please
explain your reasoning. If your answer
is (b), please describe what additional
flexibilities might be needed to reduce
problems with formulation and
palatability of the reference diets (e.g.,
use of more saturated fat in place of the
unsaturated (liquid) fats in infant
formulas; partial substitution of the
unsaturated fat in the infant formula
with saturated fat in the reference diet).
Please describe your experience with
use of fat compositions in the reference
diets that differ from that of the infant
formula.
Question 2. Would reducing the fat
content of the reference diet to about 80
percent that of the infant formula test
diet (e.g., to about 17–20 percent fat in
the reference diet versus about 22–25
percent fat in the test diet) help to avoid
issues (e.g., problems with physical
consistency of reference diets when
qualitative matching is attempted)
reported with high-fat reference diets? If
your answer is ‘‘yes,’’ please describe
other compositional changes that might
be needed to keep the test and reference
diets isocaloric. If your answer is ‘‘no,’’
please explain your reasoning.
Question 3. The need for vitamin E
increases with an increase in dietary
polyunsaturated fatty acids (PUFA) and
with the degree of unsaturation of
PUFA. We are proposing the use of a
minimum ratio value for vitamin
E:PUFA of 0.48 ± 0.28 milligrams (mg)
of d-a-tocopherol to grams (g) of PUFAs
in the PER study diets. We suggest that
the total PUFA content of the test and
reference diets be estimated from the
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Certificates of Analysis or other
information and used with dietary
concentrations of vitamin E to calculate
the ratio of vitamin E:PUFA for both
diets. The minimum ratio value of 0.48
can be used as a guideline for adjusting
the concentration of vitamin E in the
reference diet. Is this adjustment for
using vitamin E needed? If you think the
adjustment for vitamin E is needed,
please explain your reasoning. If your
answer is ‘‘no,’’ please explain why not.
Is the mean ratio of 0.48 mg d-atocopherol per gram of PUFA reasonable
or is there a more appropriate value?
Please explain your reasoning.
difficult to accurately record food
consumption. We invite comments on
specific problems that have arisen when
attempting to match dietary contents of
fat and water, as well as solutions that
have been identified to help limit the
occurrence of such problems. Should
flexibility be provided in matching the
water and fat contents of the diets? If
your answer is ‘‘yes,’’ please describe an
approach (i.e., explain the types of
flexibilities) that might be needed to
reduce problems with the physical
consistencies of the reference diets. If
your answer is ‘‘no,’’ please explain
your reasoning.
2. Carbohydrates
Question 4. In explaining appropriate
modifications to the AOAC Method, the
IFR states that, among other things, if an
infant formula contains a carbohydrate
source other than lactose, the source(s)
of carbohydrate in the formula should
be added in the reference diet as well
(see FDA’s interim final rule, Current
Good Manufacturing Practices, Quality
Control Procedures, Quality Factors,
Notification Requirements, and Records
and Reports, for Infant Formula, 79 FR
7933 at 8024, Feb. 10, 2014)).
The simultaneous qualitative
matching of fat and carbohydrate
composition has proven difficult during
formulation of PER study reference diets
(e.g., problems from adding sugars such
as sucrose; hardening of mixture and
compromised oil absorption when water
is added to liquid oils). Our current
thinking is that use of the same oil
blend in the infant formula and
reference diet may be one approach if
there is not a need to qualitatively
match all the carbohydrates. We invite
comments on potential solutions to
these difficulties. For example, would
altering the type of fat used in the
reference diet while retaining
quantitative matching of the fat contents
of the test and reference diets be
sufficient to overcome these problems?
Would the use of corn starch as a
carbohydrate source in the reference
diet allow the reference diet to be
formulated with the same oil blends
used in the infant formula? Please
explain your reasoning.
C. Questions for Section IV.B.1.e.
Mineral Content
Question 6. FDA’s regulations require
that the infant formula be studied in a
PER assay (§ 106.96(f)). Further, the
AOAC Method specifies that both the
PER study test and reference diets
contain similar contents of minerals
based on matched ash contents. We
invite comments on how this matching
could be achieved while meeting the
requirement that the infant formula be
tested. Is ash content alone an adequate
surrogate when matching minerals in
test and reference diets? If your answer
is ‘‘no,’’ please described why not and
discuss another approach that might be
used to achieve the matching of
minerals in test and reference diets.
Question 7. Multielement analysis
(e.g., ICP–AES (inductively coupled
plasma-atomic emission spectroscopy),
ICP–MS (inductively coupled plasmamass spectrometry)) is currently used
for the simultaneous analysis of many
minerals. We invite comments on
whether use of multielement analysis
for the quantitation and subsequent
matching of all minerals would be
preferable to continued use of ash as a
surrogate for mineral content. If your
answer is ‘‘yes,’’ please describe
reasonable expectations regarding how
such analyses can be used.
Question 8. In Appendix 6 of the draft
guidance, FDA has suggested a process
by which mineral compositions of the
test and reference diets can be matched
to within ±20 percent. We invite
comments on whether this is a
reasonable approach. If your answer is
‘‘no,’’ please explain your reasoning and
suggest an alternate approach.
B. Questions for Section IV.B.1.d.
Removal of Water From Liquid Infant
Formulas and Determination of
Moisture in PER Study Diets
Question 5. The AOAC Method
specifies a moisture content of 5 percent
in the PER study test and reference
diets. Some laboratories have had
difficulty preparing diets to match fat
and water contents, leading to physical
consistencies in diets that makes it
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D. Questions for Section IV.B.1.f.
Vitamin Content
Question 9. The AOAC Method
specifies that both the PER study test
and reference diets contain the same
vitamin composition. For the purpose of
studying infant formula, we understand
this to mean that the vitamin
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composition of the test and reference
diets in a PER study should be
comparable. We invite comments on
how such comparability should be
defined and how it might be achieved.
Question 10. In Appendix 6 of the
draft guidance, FDA has suggested a
process by which vitamin compositions
of the test and reference diets can be
matched to within ±20 percent. We
invite comments on whether this
approach is reasonable and ask you to
explain your thinking. If you do not
believe the approach is reasonable,
please explain your reasoning and
suggest an alternative approach.
Question 11. We invite comments on
whether the matching of the vitamin
compositions between the test and
reference diets should be eliminated
because, for example, vitamins such as
vitamin K and vitamin B12, among
others, do not impact the growth of rats
during the 28-day PER study. If your
answer is ‘‘yes, the matching of vitamin
compositions between test and reference
diets should be eliminated,’’ what do
you propose as the vitamin composition
for the reference diet? Please explain
your reasoning. If your answer is ‘‘no,’’
please explain your reasoning.
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E. Question for Section IV.B.1.g. Fiber
Question 12. We invite comment on
whether fiber should be added to the
PER study test and matched casein
reference diets under all conditions,
under specified conditions, or not
added at all. If your answer is ‘‘yes,
under all conditions,’’ what is your
proposed level of addition (e.g., to
match the concentrations of nondigestible fiber in the infant formula at
its rate of addition)? If your answer is
‘‘yes, under specified conditions,’’ what
are the specific conditions under which
fiber should be added and at what
concentration? If your answer is ‘‘no,
fiber should not be added,’’ please
explain your reasoning.
F. Question for Section IV.B.1.h. Sulfur
Amino Acids (Methionine, Cystine)
Question 13. In the draft guidance, we
recommend that the concentration of
inorganic sulfur (e.g., as sulfate salts) in
the PER study casein reference control
diet be adjusted to 0.964 g/kilograms
diet, the content calculated from the
mineral composition set forth in the
AOAC Method as originally described.
We also provide a procedure for
matching the (methionine + cystine)
concentrations in the casein reference
control and test diets, and for use of this
sulfur amino acid-matched group as a
second casein reference control group in
PER studies. This approach will reduce
the risk of a failure of the PER study
VerDate Sep<11>2014
17:41 Feb 09, 2023
Jkt 259001
control group. If you think the approach
is needed, please explain your
reasoning. If you think that such an
approach is not necessary, please
explain why not. If you think that other
approaches might be more helpful in
reducing the risk of a failure of the
reference control group, please describe
such approaches and explain their
advantages.
Dated: February 6, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023–02836 Filed 2–9–23; 8:45 am]
BILLING CODE 4164–01–P
DEPARTMENT OF HEALTH AND
HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA–2020–D–1136]
Temporary Policy on Repackaging or
Combining Propofol Drug Products
During the COVID–19 Public Health
Emergency; Withdrawal of Guidance
AGENCY:
Food and Drug Administration,
HHS.
ACTION:
Notice; withdrawal.
The Food and Drug
Administration (FDA or Agency) is
announcing the withdrawal of the
guidance for industry entitled
‘‘Temporary Policy on Repackaging or
Combining Propofol Drug Products
During the COVID–19 Public Health
Emergency,’’ which was issued in April
2020 to communicate a temporary
policy regarding the repackaging or
combining of propofol drug products.
FDA is withdrawing this guidance
document because the conditions that
created the need for this policy
described in the document have evolved
and the policy is no longer needed.
DATES: The withdrawal date is March
13, 2023.
FOR FURTHER INFORMATION CONTACT:
Kimberly Thomas, Office of Regulatory
Policy, Center for Drug Evaluation and
Research, Food and Drug
Administration, 10903 New Hampshire
Ave., Silver Spring, MD 20993, 301–
796–2357.
SUPPLEMENTARY INFORMATION:
SUMMARY:
I. Background
As part of FDA’s commitment to
providing timely guidance to support
response efforts to the Coronavirus
Disease 2019 (COVID–19) 1 pandemic,
1 The virus has been named ‘‘SARS–CoV–2’’ and
the disease it causes has been named ‘‘Coronavirus
Disease 2019’’ (COVID–19).
PO 00000
Frm 00081
Fmt 4703
Sfmt 4703
in April 2020, the Agency published the
guidance for industry entitled
‘‘Temporary Policy on Repackaging or
Combining Propofol Drug Products
During the COVID–19 Public Health
Emergency.’’ This guidance
communicated the Agency’s temporary
policy regarding the repackaging or
combining of propofol drug products by
licensed pharmacists in State licensed
pharmacies, Federal facilities, and
outsourcing facilities registered
pursuant to section 503B of the Federal
Food, Drug, and Cosmetic Act (FD&C
Act) (21 U.S.C. 353b).2 FDA had
received reports from some hospitals
that they were having difficulty
obtaining adequate supplies of FDAapproved propofol injectable emulsion
(propofol) products, 10 milligrams (mg)
per milliliter (mL), in the presentations
used to support COVID–19 patients who
had been sedated and intubated, or for
other procedures involved in the care of
such patients. At the time the guidance
was published, propofol was on FDA’s
drug shortage list, with several
presentations on backorder or on
allocation. FDA recognized that
pharmacies and outsourcing facilities
that had access to certain presentations
of propofol drug products wanted to
repackage or combine units of a
finished, FDA-approved drug product to
provide hospitals with presentations
needed for patients with COVID–19.
The guidance stated that as a temporary
measure during the public health
emergency related to COVID–19, or for
such shorter time as FDA may announce
by updating or withdrawing the
guidance based on evolving needs and
circumstances, FDA intended to extend,
under certain circumstances described
in the guidance, its existing enforcement
discretion policy described in the
2 As explained in the guidance, provided that
circumstances described in the guidance were
present, FDA did not intend to take action for
violations of section 505 (concerning new drug
applications), section 502(f)(1) (concerning labeling
with adequate directions for use), and section 582
(concerning drug supply chain security) of the
FD&C Act (21 U.S.C. 355, 352(f)(1), and 360eee-1)
if a State-licensed pharmacy, a Federal facility, or
an outsourcing facility prepared drug products as
described in this guidance and met other applicable
requirements. Applicable requirements included,
for example, the requirement that manufacturers
not adulterate a drug product by preparing, packing,
or holding the drug product under insanitary
conditions. See section 501(a)(2)(A) of the FD&C
Act (21 U.S.C. 351(a)(2)(A)). In addition, FDA did
not intend to take action for violations of section
501(a)(2)(B) of the FD&C Act if the drug product
was repackaged by a State-licensed pharmacy or a
Federal facility in accordance with the conditions
described in the guidance, and any applicable
requirements. Finally, with respect to entities that
did not qualify for the exemptions from registration
under section 510 of the FD&C Act (21 U.S.C. 360),
FDA did not intend to take action for violations of
section 502(o) of the FD&C Act.
E:\FR\FM\10FEN1.SGM
10FEN1
]]>Agencies
[Federal Register Volume 88, Number 28 (Friday, February 10, 2023)]
[Notices]
[Pages 8868-8872]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 2023-02836]
[[Page 8868]]
-----------------------------------------------------------------------
DEPARTMENT OF HEALTH AND HUMAN SERVICES
Food and Drug Administration
[Docket No. FDA-2022-D-2424]
Protein Efficiency Ratio Rat Bioassay Studies To Demonstrate That
a New Infant Formula Supports the Quality Factor of Sufficient
Biological Quality of Protein; Draft Guidance for Industry;
Availability; Agency Information Collection Activities; Proposed
Collection; Comment Request
AGENCY: Food and Drug Administration, HHS.
ACTION: Notice of availability.
-----------------------------------------------------------------------
SUMMARY: The Food and Drug Administration (FDA or we) is announcing the
availability of a draft guidance entitled ``Protein Efficiency Ratio
(PER) Rat Bioassay Studies To Demonstrate That a New Infant Formula
Supports the Quality Factor of Sufficient Biological Quality of
Protein.'' The draft guidance, when finalized, will provide information
for manufacturers and contract laboratories that perform PER studies to
assist in designing, conducting, evaluating, and reporting PER studies.
The draft guidance, when finalized, will explain ``appropriate
modifications'' of AOAC Official Method 960.48 (the AOAC Method) with
the aim of supporting industry in successfully conducting PER studies
that demonstrate that a new infant formula meets the quality factor of
sufficient biological quality of protein when fed as the sole source of
nutrition.
DATES: Submit either electronic or written comments on the draft
guidance by May 11, 2023 to ensure that we consider your comment on the
draft guidance before we begin work on the final version of the
guidance. Submit electronic or written comments on the proposed
collection of information in the draft guidance by May 11, 2023.
ADDRESSES: You may submit comments on any guidance at any time as
follows:
Electronic Submissions
Submit electronic comments in the following way:
Federal eRulemaking Portal: https://www.regulations.gov.
Follow the instructions for submitting comments. Comments submitted
electronically, including attachments, to https://www.regulations.gov
will be posted to the docket unchanged. Because your comment will be
made public, you are solely responsible for ensuring that your comment
does not include any confidential information that you or a third party
may not wish to be posted, such as medical information, your or anyone
else's Social Security number, or confidential business information,
such as a manufacturing process. Please note that if you include your
name, contact information, or other information that identifies you in
the body of your comments, that information will be posted on https://www.regulations.gov.
If you want to submit a comment with confidential
information that you do not wish to be made available to the public,
submit the comment as a written/paper submission and in the manner
detailed (see ``Written/Paper Submissions'' and ``Instructions'').
Written/Paper Submissions
Submit written/paper submissions as follows:
Mail/Hand Delivery/Courier (for written/paper
submissions): Dockets Management Staff (HFA-305), Food and Drug
Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD 20852.
For written/paper comments submitted to the Dockets
Management Staff, FDA will post your comment, as well as any
attachments, except for information submitted, marked and identified,
as confidential, if submitted as detailed in ``Instructions.''
Instructions: All submissions received must include the Docket No.
FDA-2022-D-2424 for ``Protein Efficiency Ratio (PER) Rat Bioassay
Studies To Demonstrate That a New Infant Formula Supports the Quality
Factor of Sufficient Biological Quality of Protein.'' Received comments
will be placed in the docket and, except for those submitted as
``Confidential Submissions,'' publicly viewable at https://www.regulations.gov or at the Dockets Management Staff between 9 a.m.
and 4 p.m., Monday through Friday, 240-402-7500.
Confidential Submissions--To submit a comment with
confidential information that you do not wish to be made publicly
available, submit your comments only as a written/paper submission. You
should submit two copies total. One copy will include the information
you claim to be confidential with a heading or cover note that states
``THIS DOCUMENT CONTAINS CONFIDENTIAL INFORMATION.'' We will review
this copy, including the claimed confidential information, in our
consideration of comments. The second copy, which will have the claimed
confidential information redacted/blacked out, will be available for
public viewing and posted on https://www.regulations.gov. Submit both
copies to the Dockets Management Staff. If you do not wish your name
and contact information to be made publicly available, you can provide
this information on the cover sheet and not in the body of your
comments and you must identify this information as ``confidential.''
Any information marked as ``confidential'' will not be disclosed except
in accordance with 21 CFR 10.20 and other applicable disclosure law.
For more information about FDA's posting of comments to public dockets,
see 80 FR 56469, September 18, 2015, or access the information at:
https://www.govinfo.gov/content/pkg/FR-2015-09-18/pdf/2015-23389.pdf.
Docket: For access to the docket to read background documents or
the electronic and written/paper comments received, go to https://www.regulations.gov and insert the docket number, found in brackets in
the heading of this document, into the ``Search'' box and follow the
prompts and/or go to the Dockets Management Staff, 5630 Fishers Lane,
Rm. 1061, Rockville, MD 20852, 240-402-7500.
You may submit comments on any guidance at any time (see 21 CFR
10.115(g)(5)).
Submit written requests for single copies of the draft guidance to
Office of Nutrition and Food Labeling (HFS-800), Center for Food Safety
and Applied Nutrition, Food and Drug Administration, 5001 Campus Dr.,
College Park, MD 20740. Send one self-addressed adhesive label to
assist that office in processing your request or include a Fax number
to which the draft guidance may be sent. See the SUPPLEMENTARY
INFORMATION section for information on electronic access to the draft
guidance.
FOR FURTHER INFORMATION CONTACT:
With regard to the draft guidance: Andrea Lotze, Center for Food
Safety and Applied Nutrition, Office of Nutrition and Food Labeling
(HFS-800), Food and Drug Administration, 5001 Campus Dr., College Park,
MD 20740, 240-402-1450, email: [email protected]; or Keronica
Richardson, Center for Food Safety and Applied Nutrition, Office of
Regulations and Policy (HFS-024), Food and Drug Administration, 5001
Campus Dr., College Park, MD 20740, 240-402-2378.
With regard to the proposed collection of information: Rachel
Showalter, Office of Operations, Food and Drug Administration, Three
White Flint North, 10A-12M, 11601 Landsdown St., North Bethesda, MD
20852, 240-994-7399, [email protected].
SUPPLEMENTARY INFORMATION:
I. Background
FDA is announcing the availability of a draft guidance for industry
entitled
[[Page 8869]]
``Protein Efficiency Ratio (PER) Rat Bioassay Studies To Demonstrate
That a New Infant Formula Supports the Quality Factor of Sufficient
Biological Quality of Protein.'' Our regulations, at 21 CFR 106.96,
establish requirements for quality factors for infant formulas,
including the quality factor of sufficient biological quality of
protein. Subject to a limited exception (see Sec. 106.96(g)), each
manufacturer of an infant formula that is not an eligible infant
formula must demonstrate that the formula meets the quality factor of
sufficient biological quality of protein by establishing the biological
quality of the protein in the infant formula when fed as the sole
source of nutrition using an appropriate modification of the AOAC
Official Method 960.48 (the AOAC Method) Protein Efficiency Ratio (PER)
Rat Bioassay (Sec. 106.96(f)).\1\
---------------------------------------------------------------------------
\1\ We support the principles of the ``3Rs'' to reduce, refine,
and replace animal use in testing when feasible. We encourage
sponsors to consult with us if they wish to use a non-animal testing
method they believe is suitable, adequate, and validated to
demonstrate that the formula supports the quality factor for the
biological quality of the protein as described in 21 CFR
106.96(g)(3). We support alternative methods by exemption in 21 CFR
106.96(f) which allows the manufacturer to request an exemption and
provide certain required assurances described in 21 CFR 106.96(g).
The applicability of this exemption is not the subject of this
guidance.
---------------------------------------------------------------------------
The AOAC Method provides a procedure by which the quality of a
protein in food can be evaluated and compared with those of other
proteins. Protein ``quality'' can be defined as the ability of a
protein to meet the essential amino acid needs of an animal. The AOAC
Method is a standardized bioassay with published collaborative study
data. The AOAC Method permits the calculation of a PER as the ratio of
the average animal body weight gain per gram of protein consumed of a
test protein versus casein after a 28-day feeding period. Typically,
the protein concentration of both the test and casein reference diet is
set at about 10 percent, a level that is below the estimated
requirement for growth of rats of 15 percent, to improve the
sensitivity of the method. While growth is slower at 10 percent protein
than at 15 percent protein, the lower protein level assures that
available protein is efficiently utilized.
In the PER study described in the AOAC Method, a protein ingredient
was assayed at 10 percent and other potential variables were
standardized so that their numbers and potential effects were
minimized. Vitamin composition, moisture, ash, carbohydrates, fat, and
fiber were adjusted between the casein reference diet and the test
diet. Use of a test diet that contains an infant formula in its
entirety introduces matrices of high fat content and additional
vitamins, minerals, and other ingredients, as well as the low protein
source. A major challenge in analyzing infant formulas by the AOAC
Method is matching the casein reference diet and test diet to achieve
dietary groups with as few confounding variables as possible.
Since we promulgated Sec. 106.96, we have found that industry is
experiencing difficulties in consistently meeting its requirements.
Therefore, we are announcing the availability of a draft guidance for
industry entitled ``Protein Efficiency Ratio (PER) Rat Bioassay Studies
To Demonstrate That a New Infant Formula Supports the Quality Factor of
Sufficient Biological Quality of Protein.'' This draft guidance, when
finalized, will help infant formula manufacturers and contract
laboratories that perform PER studies in designing, conducting,
evaluating, and reporting PER studies. The draft guidance, when
finalized, will explain ``appropriate modifications'' of the AOAC
Method to help manufacturers and contract laboratories conduct PER
studies that demonstrate to FDA that a new infant formula meets the
quality factor of sufficient biological quality of protein.
FDA's work on this draft guidance document began prior to
significant infant formula supply chain concerns that arose in early
2022. Although this guidance was not prepared specifically to alleviate
supply chain concerns, this guidance will help ensure that infant
formula products meet FDA's regulatory requirements and will contribute
to ensuring a more resilient infant formula supply. We are issuing the
draft guidance consistent with our good guidance practices regulation
(21 CFR 10.115). The draft guidance, when finalized, will represent the
current thinking of FDA on this topic. It does not establish any rights
for any person and is not binding on FDA or the public. You can use an
alternate approach to make ``appropriate modifications'' if it
satisfies the requirements of the applicable statutes and regulations.
Topics discussed in the draft guidance include:
Purpose of the AOAC Method;
Overview of the AOAC Method as originally described;
Need for ``appropriate modifications'' to update the AOAC
Method and for use of infant formulas in PER bioassays;
Conduct and analysis of a PER study with ``appropriate
modifications'' (matching the reference and test diets);
Protocols and reports;
Reference guidelines; and
Appendices: AOAC Official Method 960.48, composition of
vitamin and mineral mixtures, compositions of diets, and examples of an
approach for matching vitamin, mineral, and (methionine + cystine)
compositions of PER study diets.
II. Paperwork Reduction Act of 1995
Under the Paperwork Reduction Act of 1995 (PRA) (44 U.S.C. 3501-
3521), Federal Agencies must obtain approval from the Office of
Management and Budget (OMB) for each collection of information they
conduct or sponsor. ``Collection of information'' is defined in 44
U.S.C. 3502(3) and 5 CFR 1320.3(c) and includes Agency requests or
requirements that members of the public submit reports, keep records,
or provide information to a third party. Section 3506(c)(2)(A) of the
PRA (44 U.S.C. 3506(c)(2)(A)) requires Federal Agencies to provide a
60-day notice in the Federal Register concerning each proposed
collection of information before submitting the collection to OMB for
approval. To comply with this requirement, FDA is publishing notice of
the proposed collection of information set forth in this document.
With respect to the following collection of information, FDA
invites comments on these topics: (1) whether the proposed collection
of information is necessary for the proper performance of FDA's
functions, including whether the information will have practical
utility; (2) the accuracy of FDA's estimate of the burden of the
proposed collection of information, including the validity of the
methodology and assumptions used; (3) ways to enhance the quality,
utility, and clarity of the information to be collected; and (4) ways
to minimize the burden of the collection of information on respondents,
including through the use of automated collection techniques, when
appropriate, and other forms of information technology.
Protein Efficiency Ratio (PER) Rat Bioassay Studies To Demonstrate That
a New Infant Formula Supports the Quality Factor of Sufficient
Biological Quality of Protein
OMB Control Number 0910-0256--Revision
Under Sec. 106.96(e), an infant formula must meet the quality
factor of sufficient biological quality of protein, and Sec. 106.96(f)
provides how an infant formula manufacturer must demonstrate that a
formula meets this quality factor. PER studies are used to demonstrate
to FDA that a new infant formula meets
[[Page 8870]]
the quality factor of sufficient biological quality of protein when fed
as the sole source of nutrition. This draft guidance, when finalized,
would help manufacturers and laboratories performing PER studies in the
design, conduct, evaluation, and reporting of such studies. When
finalized, the draft guidance would provide recommendations for
additional recordkeeping and reporting of protocols and PER studies
related to the composition of test and control diets, as well as
conditions, adverse effects, and attrition in rats. The draft guidance,
when finalized, also will explain ``appropriate modifications'' of the
AOAC Method to help manufacturers and contract laboratories conduct PER
studies that demonstrate to FDA that a new infant formula meets the
quality factor of sufficient biological quality of protein.
Description of Respondents: Respondents to the information
collection are manufacturers of infant formula. Respondents are from
the private sector (for-profit businesses).
We estimate the burden of this collection of information as
follows:
Table 1--Estimated Annual Recordkeeping Burden \1\
--------------------------------------------------------------------------------------------------------------------------------------------------------
Number of Number of records Total annual
Activity; guidance document section recordkeepers per recordkeeper records Average burden per recordkeeping Total hours
--------------------------------------------------------------------------------------------------------------------------------------------------------
Records for composition of the test and 15 2 30 1................................ 30
control diets during PER studies;
Section IV.
Records for conditions, adverse effects, 15 140 2,100 0.083 (5 minutes)................ 174
and attrition in rats during PER
studies; Section IV.
--------------------------------------------------------------------------------------------------------------
Total................................ ................. ................. ................. ................................. 204
--------------------------------------------------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of information.
The estimates in tables 1 and 2 are based on experience with our
infant formula safety and nutrition programs. We estimate that fifteen
manufacturers annually will each create and maintain two records for
the composition of test and control diets of PER studies. We estimate
the recordkeeping burden to be 1 hour per record for an annual burden
of 30 hours (15 manufacturers x 2 records). These estimates are based
on numerous PER study protocols, reports, and laboratory experiences.
We estimate that fifteen manufacturers annually will each create
and maintain 140 records to account for conditions, adverse effects,
and attrition in rats during PER studies. We estimate these records
will take 5 minutes per record for an annual burden of 174.3 hours,
rounded to 174 (15 manufacturers x 140 records x 0.083/hours). We
calculate the total recordkeeping burden will be 204 hours annually.
Table 2--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Number of Average
Activity; guidance document Number of responses per Total annual burden per Total hours
section respondents respondent responses response
----------------------------------------------------------------------------------------------------------------
Development and submission of a 15 1 15 70 1,050
PER study protocol; Section V..
Development and submission of a 15 1 15 40 600
PER study final report; Section
V..............................
-------------------------------------------------------------------------------
Total....................... .............. .............. .............. .............. 1,650
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.
We estimate that fifteen manufacturers will prepare and submit to
FDA a protocol to ensure that the specifications of the AOAC Method and
FDA's ``appropriate modifications'' are met. A protocol is a detailed
plan for the conduct of the PER study that helps the manufacturer meet
the requirements of Sec. 106.96. In Table 1 in Appendix 6 of the draft
guidance, we offer an illustration of how the values can be recorded as
part of a protocol. An interested manufacturer will call FDA to discuss
the manner in which a protocol will be submitted. We estimate each
protocol will take 70 hours for an annual burden of 1,050 hours (15
protocols x 70 hours).
In addition, we estimate that fifteen manufacturers will submit a
final report on all aspects of the PER study, including Certificates of
Analyses (i.e., a full specification of results) for relevant
ingredients to FDA. A final report is submitted in the same manner as a
protocol. We estimate each final report will take 40 hours for an
annual burden of 600 hours (15 final reports x 40 hours). We calculate
the total reporting burden will be 1,650 hours annually.
This draft guidance also refers to previously approved FDA
collections of information. The collections of information in 21 CFR
part 106 have been approved under OMB control number 0910-0256.
III. Electronic Access
Persons with access to the internet may obtain an electronic
version of the draft guidance at https://www.fda.gov/RegulatoryInformation/Guidances/default.html, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or https://www.regulations.gov.
IV. Other Issues for Consideration
Although FDA welcomes comments on any aspect of the draft guidance,
we particularly invite comments on the following sections, issues, and
questions related to the compositions of PER study test (infant
formula) and reference (casein control) diets. We ask that your
[[Page 8871]]
comments explain how suggestions will meet the overall requirement of
demonstrating that the quality factor has been met using an
``appropriate modification.'' When commenting on a particular question,
please use the question numbers below as this will make it easier for
us to determine how a specific comment relates to a particular question
or topic.
A. Questions for Section IV.B.1.c. Fats and Carbohydrates
1. Fats
Question 1. Companies have expressed difficulties in qualitative
matching of fat in test and reference diets (e.g., problems with
physical consistency of reference diets when qualitative matching is
attempted) and difficulties in quantitative matching because of the
much lower fat requirement of rats. We invite comments on whether the
fat compositions of the test and reference diets should be matched: (a)
on a quantitative basis only; or (b) on both a quantitative and
qualitative basis. Please explain your reasoning. If your answer is
(b), please describe what additional flexibilities might be needed to
reduce problems with formulation and palatability of the reference
diets (e.g., use of more saturated fat in place of the unsaturated
(liquid) fats in infant formulas; partial substitution of the
unsaturated fat in the infant formula with saturated fat in the
reference diet). Please describe your experience with use of fat
compositions in the reference diets that differ from that of the infant
formula.
Question 2. Would reducing the fat content of the reference diet to
about 80 percent that of the infant formula test diet (e.g., to about
17-20 percent fat in the reference diet versus about 22-25 percent fat
in the test diet) help to avoid issues (e.g., problems with physical
consistency of reference diets when qualitative matching is attempted)
reported with high-fat reference diets? If your answer is ``yes,''
please describe other compositional changes that might be needed to
keep the test and reference diets isocaloric. If your answer is ``no,''
please explain your reasoning.
Question 3. The need for vitamin E increases with an increase in
dietary polyunsaturated fatty acids (PUFA) and with the degree of
unsaturation of PUFA. We are proposing the use of a minimum ratio value
for vitamin E:PUFA of 0.48 0.28 milligrams (mg) of d-
[alpha]-tocopherol to grams (g) of PUFAs in the PER study diets. We
suggest that the total PUFA content of the test and reference diets be
estimated from the Certificates of Analysis or other information and
used with dietary concentrations of vitamin E to calculate the ratio of
vitamin E:PUFA for both diets. The minimum ratio value of 0.48 can be
used as a guideline for adjusting the concentration of vitamin E in the
reference diet. Is this adjustment for using vitamin E needed? If you
think the adjustment for vitamin E is needed, please explain your
reasoning. If your answer is ``no,'' please explain why not. Is the
mean ratio of 0.48 mg d-[alpha]-tocopherol per gram of PUFA reasonable
or is there a more appropriate value? Please explain your reasoning.
2. Carbohydrates
Question 4. In explaining appropriate modifications to the AOAC
Method, the IFR states that, among other things, if an infant formula
contains a carbohydrate source other than lactose, the source(s) of
carbohydrate in the formula should be added in the reference diet as
well (see FDA's interim final rule, Current Good Manufacturing
Practices, Quality Control Procedures, Quality Factors, Notification
Requirements, and Records and Reports, for Infant Formula, 79 FR 7933
at 8024, Feb. 10, 2014)).
The simultaneous qualitative matching of fat and carbohydrate
composition has proven difficult during formulation of PER study
reference diets (e.g., problems from adding sugars such as sucrose;
hardening of mixture and compromised oil absorption when water is added
to liquid oils). Our current thinking is that use of the same oil blend
in the infant formula and reference diet may be one approach if there
is not a need to qualitatively match all the carbohydrates. We invite
comments on potential solutions to these difficulties. For example,
would altering the type of fat used in the reference diet while
retaining quantitative matching of the fat contents of the test and
reference diets be sufficient to overcome these problems? Would the use
of corn starch as a carbohydrate source in the reference diet allow the
reference diet to be formulated with the same oil blends used in the
infant formula? Please explain your reasoning.
B. Questions for Section IV.B.1.d. Removal of Water From Liquid Infant
Formulas and Determination of Moisture in PER Study Diets
Question 5. The AOAC Method specifies a moisture content of 5
percent in the PER study test and reference diets. Some laboratories
have had difficulty preparing diets to match fat and water contents,
leading to physical consistencies in diets that makes it difficult to
accurately record food consumption. We invite comments on specific
problems that have arisen when attempting to match dietary contents of
fat and water, as well as solutions that have been identified to help
limit the occurrence of such problems. Should flexibility be provided
in matching the water and fat contents of the diets? If your answer is
``yes,'' please describe an approach (i.e., explain the types of
flexibilities) that might be needed to reduce problems with the
physical consistencies of the reference diets. If your answer is
``no,'' please explain your reasoning.
C. Questions for Section IV.B.1.e. Mineral Content
Question 6. FDA's regulations require that the infant formula be
studied in a PER assay (Sec. 106.96(f)). Further, the AOAC Method
specifies that both the PER study test and reference diets contain
similar contents of minerals based on matched ash contents. We invite
comments on how this matching could be achieved while meeting the
requirement that the infant formula be tested. Is ash content alone an
adequate surrogate when matching minerals in test and reference diets?
If your answer is ``no,'' please described why not and discuss another
approach that might be used to achieve the matching of minerals in test
and reference diets.
Question 7. Multielement analysis (e.g., ICP-AES (inductively
coupled plasma-atomic emission spectroscopy), ICP-MS (inductively
coupled plasma-mass spectrometry)) is currently used for the
simultaneous analysis of many minerals. We invite comments on whether
use of multielement analysis for the quantitation and subsequent
matching of all minerals would be preferable to continued use of ash as
a surrogate for mineral content. If your answer is ``yes,'' please
describe reasonable expectations regarding how such analyses can be
used.
Question 8. In Appendix 6 of the draft guidance, FDA has suggested
a process by which mineral compositions of the test and reference diets
can be matched to within 20 percent. We invite comments on
whether this is a reasonable approach. If your answer is ``no,'' please
explain your reasoning and suggest an alternate approach.
D. Questions for Section IV.B.1.f. Vitamin Content
Question 9. The AOAC Method specifies that both the PER study test
and reference diets contain the same vitamin composition. For the
purpose of studying infant formula, we understand this to mean that the
vitamin
[[Page 8872]]
composition of the test and reference diets in a PER study should be
comparable. We invite comments on how such comparability should be
defined and how it might be achieved.
Question 10. In Appendix 6 of the draft guidance, FDA has suggested
a process by which vitamin compositions of the test and reference diets
can be matched to within 20 percent. We invite comments on
whether this approach is reasonable and ask you to explain your
thinking. If you do not believe the approach is reasonable, please
explain your reasoning and suggest an alternative approach.
Question 11. We invite comments on whether the matching of the
vitamin compositions between the test and reference diets should be
eliminated because, for example, vitamins such as vitamin K and vitamin
B12, among others, do not impact the growth of rats during the 28-day
PER study. If your answer is ``yes, the matching of vitamin
compositions between test and reference diets should be eliminated,''
what do you propose as the vitamin composition for the reference diet?
Please explain your reasoning. If your answer is ``no,'' please explain
your reasoning.
E. Question for Section IV.B.1.g. Fiber
Question 12. We invite comment on whether fiber should be added to
the PER study test and matched casein reference diets under all
conditions, under specified conditions, or not added at all. If your
answer is ``yes, under all conditions,'' what is your proposed level of
addition (e.g., to match the concentrations of non-digestible fiber in
the infant formula at its rate of addition)? If your answer is ``yes,
under specified conditions,'' what are the specific conditions under
which fiber should be added and at what concentration? If your answer
is ``no, fiber should not be added,'' please explain your reasoning.
F. Question for Section IV.B.1.h. Sulfur Amino Acids (Methionine,
Cystine)
Question 13. In the draft guidance, we recommend that the
concentration of inorganic sulfur (e.g., as sulfate salts) in the PER
study casein reference control diet be adjusted to 0.964 g/kilograms
diet, the content calculated from the mineral composition set forth in
the AOAC Method as originally described. We also provide a procedure
for matching the (methionine + cystine) concentrations in the casein
reference control and test diets, and for use of this sulfur amino
acid-matched group as a second casein reference control group in PER
studies. This approach will reduce the risk of a failure of the PER
study control group. If you think the approach is needed, please
explain your reasoning. If you think that such an approach is not
necessary, please explain why not. If you think that other approaches
might be more helpful in reducing the risk of a failure of the
reference control group, please describe such approaches and explain
their advantages.
Dated: February 6, 2023.
Lauren K. Roth,
Associate Commissioner for Policy.
[FR Doc. 2023-02836 Filed 2-9-23; 8:45 am]
BILLING CODE 4164-01-P
