[Federal Register Volume 71, Number 147 (Tuesday, August 1, 2006)]
[Proposed Rules]
[Pages 43392-43398]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: E6-12268]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 106 and 107

[Docket No. 1995N-0309] (formerly 95N-0309)
RIN 0910-AA04


Current Good Manufacturing Practice, Quality Control Procedures, 
Quality Factors, Notification Requirements, and Records and Reports for 
the Production of Infant Formula; Reopening of the Comment Period

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule; reopening of the comment period.

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SUMMARY: The Food and Drug Administration (FDA) is reopening until 
September 15, 2006 the comment period for the proposed rule published 
in the Federal Register of July 9, 1996 (the 1996 proposed rule) (61 FR 
36154). The 1996 proposed rule would revise FDA's infant formula 
regulations in 21 CFR parts 106 and 107, and FDA is reopening the 
comment period to receive comment only with respect to specific issues 
identified in this proposed rule.

DATES: Submit written or electronic comments by September 15, 2006.

ADDRESSES: You may submit comments, identified by Docket No. 1995N-0309 
and RIN 0910-AA04, by any of the following methods:
Electronic Submissions
    Submit electronic comments in the following ways:
     Federal eRulemaking Portal: http://www.regulations.gov. 
Follow the instructions for submitting comments.
     Agency Web site: http://www.fda.gov/dockets/ecomments. 
Follow the instructions for submitting comments on the agency Web site.
Written Submissions
    Submit written submissions in the following ways:
     FAX: 301-827-6870.
     Mail/Hand delivery/Courier [For paper, disk, or CD-ROM 
submissions]: Division of Dockets Management (HFA-305), Food and Drug 
Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852.
    To ensure more timely processing of comments, FDA is no longer 
accepting comments submitted to the agency by e-mail. FDA encourages 
you to continue to submit electronic comments by using the Federal 
eRulemaking Portal or the agency Web site, as described in the

[[Page 43393]]

Electronic Submissions portion of this paragraph.
    Instructions: All submissions received must include the agency name 
and Docket No. and Regulatory Information Number (RIN) for this 
rulemaking. All comments received may be posted without change to 
http://www.fda.gov/ohrms/dockets/default.htm, including any personal 
information provided. For additional information on submitting 
comments, see the ``How to Submit Comments'' heading of the 
SUPPLEMENTARY INFORMATION section of this document.
    Docket: For access to the docket to read background documents or 
comments received, go to http://www.fda.gov/ohrms/dockets/default.htm 
and insert the docket number(s), found in brackets in the heading of 
this document, into the ``Search'' box and follow the prompts and/or go 
to the Division of Dockets Management, 5630 Fishers Lane, rm. 1061, 
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Benson M. Silverman, Center for Food 
Safety and Applied Nutrition (HFS-850), Food and Drug Administration, 
5100 Paint Branch Pkwy., College Park, MD 20740, 301-436-1459, e-mail: 
[email protected].

SUPPLEMENTARY INFORMATION:

I. Background

    In the 1996 proposed rule, FDA proposed regulations to revise its 
infant formula regulations to establish requirements for quality 
factors and current good manufacturing practices (CGMPs), to amend the 
agency's quality control procedure, notification, and records and 
report requirements for infant formulas, to require that infant 
formulas contain, and be tested for, required nutrients and for any 
nutrient added by the manufacturer, throughout the formula's shelf 
life, to require that infant formulas be produced under strict 
microbiological controls, and to require that infant formula 
manufacturers implement the CGMP and quality control procedure 
requirements by establishing a production and in-process control system 
of their own design. The agency proposed these requirements to 
implement provisions of the Drug Enforcement, Education, and Control 
Act of 1986 (Public Law 99-570) that amended section 412 of the Federal 
Food, Drug, and Cosmetic Act (the act) (21 U.S.C. 350a).
    In the Federal Register of April 28, 2003 (the 2003 proposed rule) 
(68 FR 22341), FDA reopened the comment period for the proposed rule to 
update comments generally, and to receive new information based on 
three meetings of FDA's Food Advisory Committee that were held in 2002 
and 2003. Among other issues, the agency specifically requested comment 
on the following items: (1) Whether there is a need to include a 
microbiological requirement for Enterobacter sakazakii and, if so, what 
requirement the agency should consider to ensure the safety of powdered 
infant formulas and prevent future outbreaks; (2) what other changes in 
the proposed microbiological requirements would be appropriate to 
ensure the safety of powdered infant formula and to prevent outbreaks 
of illness; and (3) several questions related to quality factors, 
including the appropriate age for infant enrollment into clinical 
studies and the appropriate duration of these studies.
    Significant expert consultations held since the publication of the 
2003 proposed rule have provided information relevant to this 
rulemaking. First, a series of expert consultations has occurred 
related to providing scientific advice concerning E. sakazakii, 
Salmonella, and other microorganisms in powdered infant formula, as 
part of the Codex Alimentarius Commission Committee on Food Hygiene's 
(CCFH's) efforts to update the 1979 Recommended International Code of 
Hygienic Practice for Foods for Infants and Children (the 1979 Code). 
These consultations have resulted in two new reports, which we are 
adding to the record. The new reports are entitled ``The Food and 
Agriculture Organization of the United Nations and the World Health 
Organization. Enterobacter sakazakii and Other Microorganisms in 
Powdered Infant Formula: Joint FAO/WHO Meeting 2-4 February 2004'' 
(Ref. 1) and ``The Food and Agriculture Organization of the United 
Nations and the World Health Organization. Enterobacter sakazakii and 
Salmonella in Powdered Infant Formula: Meeting Report, FAO 
Headquarters, Rome, Italy, 16-20 January 2006'' (Ref. 2). We believe 
that the latter report is the most significant for purposes of 
informing this rulemaking with respect to E. sakazakii, and it is 
described more fully in section II.A of this document.
    In addition, new information has been provided by the Committee on 
the Evaluation of the Addition of Ingredients New to Infant Formula, 
which the Institute of Medicine (IOM) convened at the request of FDA 
and Health Canada, in part, to ``identify tools to evaluate the safety 
of ingredients new to infant formulas under intended conditions of use 
in term infants'' (Ref. 3 at 2). This consultation resulted in a March 
2004 report entitled ``Infant Formula: Evaluating the Safety of New 
Ingredients'' (the IOM report) (Ref. 3). This report is described more 
fully in section II.C of this document.

II. Request for Comments

    In the limited reopening of the comment period announced in this 
proposed rule, FDA is seeking comment only with respect to the 
following issues: (1) Whether FDA should require a microbiological 
standard for E. sakazakii for powdered infant formula of negative in 30 
x 10 gram (g) samples; (2) whether FDA should not require 
microbiological standards for aerobic plate count, coliforms, fecal 
coliforms, Listeria monocytogenes, Bacillus cereus, and Staphylococcus 
aureus; (3) whether FDA should require measurements of healthy growth 
beyond the two proposed quality factors of normal physical growth (as 
measured by body weight, recumbent length, head circumference, and 
average daily weight increment) and protein quality; (4) whether FDA 
should require a measure for body composition as an indicator of normal 
physical growth, and if so, what measure; and (5) whether FDA should 
require that the duration for a clinical study, if required, be no less 
than 15 weeks, and commence when infants are no older than 2 weeks of 
age. FDA will not consider comments outside the scope of these issues, 
which are discussed in more detail in the following sections of this 
document.

A. Microbiological Standard for E. sakazakii

    In the 2003 proposed rule, we asked for comment on whether there is 
a need to include a microbiological requirement for E. sakazakii, and 
if so, what requirement the agency should consider to ensure the safety 
of powdered infant formula and to prevent outbreaks of illness (68 FR 
22341 at 22342).
    Some comments identified a need to include a microbiological 
requirement for E. sakazakii, but did not suggest a specific standard. 
Other comments stated that there is no need to establish a specific 
standard for E. sakazakii. Some of these comments asserted that the 
evidence does not support the conclusion that the levels of E. 
sakazakii found in unopened infant formula present a risk of harm to 
infants, particularly healthy, term infants. Other comments asserted 
that there is no need to establish a standard because the safety of 
infant formula would be better assured by hazard analysis critical 
control plans and

[[Page 43394]]

environmental monitoring, including employing stricter criteria for the 
testing of indicator organisms, such as Enterobacteriaceae. One comment 
suggested that if FDA determines that microbiological specifications 
for future pathogens of concern are needed, it should use a mechanism 
for establishing these requirements, such as a guidance, that is less 
burdensome to publish or change than a regulation. Other comments 
suggested that point-of-use contamination from poor preparation 
practices represent the most significant risk of E. sakazakii infection 
for infants consuming formula. These comments suggested that education 
concerning formula preparation and handling, or additional labeling, is 
more likely to reduce the risk of infection than finished product 
testing. Some comments requested that FDA provide an explanation of the 
number and sample sizes required to test finished formula product for 
contamination. Other comments suggest that the addition of E. sakazakii 
inhibitors to formula, such as antimicrobials inhibitory to E. 
sakazakii that are presently approved for use in foods, provide a more 
effective means of preventing the growth of E. sakazakii.
    In the 2003 proposed rule, we also asked for comments on whether 
powdered infant formula to be consumed by premature and newborn infants 
should meet stricter microbiological requirements than formula intended 
for older infants (68 FR 22341 at 22342). With respect specifically to 
E. sakazakii, some comments said there should be a heightened standard 
for formulas intended for certain subpopulations of infants, including, 
variously, infants who are premature, of low birth weight, ill, or 
among a group described as vulnerable hospitalized infants. These 
comments argued that there should either be no standard or a lower 
standard for formulas intended for other infants. Other comments urged 
FDA to adopt the same standard for formulas intended for term infants 
as those formulas intended for premature infants because a risk of E. 
sakazakii infection exists in both populations. Some comments stated 
that FDA's request for comments on this issue is based on the incorrect 
premise that healthy newborns should be grouped with premature infants 
for purposes of risk assessment. The comments stated that the correct 
question is whether there should be separate standards for formulas for 
premature infants and formulas for healthy term infants. The comments 
stated that due to FDA's statutory authority under section 412(h)(2) of 
the act to establish terms and conditions for the exemption of formulas 
intended for infants who are low birth weight or who have unusual 
medical problems, any effort to establish stricter microbiological 
requirements for these formulas should be done with a separate notice 
and comment rulemaking.
1. What Were the ``Enterobacter sakazakii and Salmonella in Powdered 
Milk Formula'' Meeting's (the Rome Meeting's) Conclusions Regarding a 
Microbiological Standard for E. sakazakii?
    During January 16 to 20, 2006, in Rome, Italy, the Food and 
Agriculture Organization of the United Nations (FAO) and World Health 
Organization (WHO) convened the Rome meeting, a technical meeting on E. 
sakazakii and Salmonella in powdered infant formula (Ref. 2). The 
purposes of the Rome meeting were to consider scientific data newly 
available since the previous FAO/WHO technical meeting in February 
2004, to evaluate a quantitative risk assessment model using these data 
for E. sakazakii in powdered infant formula, to apply this model to 
various risk reduction scenarios, and to provide input to CCFH for the 
revision of the 1979 Code. A total of 16 experts from 11 countries 
participated in the Rome meeting in their individual capacities, 
including a senior FDA scientist with expertise in microbiological 
contamination (Ref. 2 at vii, 1).
    Recent data reviewed in the report of the Rome meeting include data 
concerning an E. sakazakii outbreak in France involving nine infants, 
two of which died, as well as evidence of a number of recalls of 
powdered infant formula contaminated with E. sakazakii (Ref. 2 at 8-9). 
These and other data reviewed in the report indicate that prevention 
efforts must target infants within and beyond the neonatal period 
(i.e., beyond the infant's first 28 days) and must target all infants, 
regardless of immune status (Ref. 2 at xiv). As stated in the report of 
the Rome meeting, based on a review of E. sakazakii infections 
worldwide, ``E. sakazakii meningitis tends to develop in infants during 
the neonatal period . . . E. sakazakii bacteraemia tends to develop in 
premature infants outside of the neonatal period with most cases 
occurring in infants less than 2 months of age. However, infants with 
immunocompromising conditions have developed bloodstream infections as 
late as age 10 months and previously healthy infants have also 
developed invasive disease outside the neonatal period'' (Ref. 2 at 8). 
The data indicate that premature infants and those with low birth 
weight are at highest risk for severe infection, that infants who 
contract bacteremia (infection of the blood stream) have a 10 percent 
mortality rate, that infants with meningitis have a 44 percent 
mortality rate, and most infants who survive meningitis experience 
long-term neurological consequences (Id. at 7-8). The data also support 
the conclusion that there is clear evidence of causality between E. 
sakazakii in powdered infant formula and illness in infants (Ref. 2 at 
5).
    The experts at the Rome meeting evaluated and reviewed a risk 
assessment model developed to describe the factors leading to E. 
sakazakii infection in infants and to identify potential risk 
mitigation strategies (Ref. 2). As described in the report, among other 
things, the risk assessment model ``provides the means to evaluate 
microbiological criteria and sampling plans in terms of the risk 
reductions achieved and the percentage of product lot rejected'' (Id. 
at xii). In the report, the experts did not select a specific risk 
management approach, recommending instead that the risk assessment 
model be applied by risk managers within CCFH and in member countries 
(Id. at xiv-xv).
    The model incorporates published research and extensive unpublished 
industry data on the prevalence of E. sakazakii in powdered infant 
formula (Ref. 2 at 44), as well as new data on consumer and hospital 
practices related to the use of powdered infant formula. The model 
estimates the risk to infants of illness from E. sakazakii from 
contaminated powdered infant formula.\1\ Using the model, relative risk 
reductions and lot rejection rates were projected for a total of 162 
scenarios, each incorporating the following: One of nine different 
sampling plans, one of three mean log concentrations of E. sakazakii, 
one of two between-lot standard deviations, and one of three within-lot 
standard deviations. The values for the mean log concentrations and the 
standard deviations were based on the published and unpublished data 
described previously in this document. For example, the model used mean 
log concentration of -5, -4, and -3 mean log10 colony-
forming units/g (CFU/g) (Ref. 2 at 46-47), while the estimated mean log 
concentrations in the data

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ranged from -2.79 to -5.24 CFU/g, with a mean of -3.84 CFU/g and 
between-lot standard deviation of 0.696 (Id. at 43).
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    \1\No dose-response for E. sakazakii has been established. The 
risk assessment model assumes that illness results from one colony 
forming unit (CFU) of E. sakazakii in dry powdered infant formula at 
the time of preparation and calculates an exponential dose-response 
parameter (Ref. 2 at 16).
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    As explained in the report of the Rome meeting, ``the risk 
associated with any specific [powdered infant formula] lot is a 
function of the number of contaminated servings it will yield, and the 
ability of a microbiological criterion to reduce that risk in an 
effective manner is based on correctly identifying those lots with the 
highest level of contamination'' (Id. at 50). For example, one scenario 
presented is for applying a sampling plan of negative in 30 x 10 g 
samples (n=30, s=10). In other words, under this sampling plan 30 10 g 
samples from various random parts of a lot of powdered infant formula, 
or a total of 300 g, must be negative for E. sakazakii. If this 
sampling plan is used for a lot of powdered infant formula with a mean 
log10 concentration of -5 CFU/g, a between-lot standard 
deviation of 0.8, and a within-lot standard deviation of 0.5, 1.4 
percent of tested lots can be expected to be found positive for E. 
sakazakii and would be rejected, and the relative risk reduction of E. 
sakazakii would be 1.21 (i.e., there would be roughly 20 percent fewer 
cases of E. sakazakii infection per year than would be the case if 
there were no powdered infant formula sampling plan in place). When 
this same sampling approach is applied to a lot of powdered infant 
formula with a mean log10 of -3 CFU/g (a substantially 
higher contamination level), allowing for the same standard deviations, 
the result is a probability that 37 percent of tested lots will be 
found positive and rejected and a relative risk reduction of 5.71. 
Thus, the more contaminated the powdered infant formula, the more the 
sampling can effectively reduce the risk of illness, because as the 
level of contamination increases, the lot rejection rate and the 
relative risk reduction increase. Similarly, the greater the 
variability in the concentration of the pathogen between lots, the 
greater the rejection rate within each sampling plan. Thus, if 
manufacturers focus on ensuring that the overall mean log concentration 
of the pathogen is low and that variation between lots is controlled, 
then the potential for rejection of the lot, and the risk of illness, 
are both lowered. (The model found that changing the variability within 
lots did not affect the projected outcomes (Id. at 49).)
2. Should FDA Require a Standard for E. sakazakii?
    We have considered the comments received in response to the 2003 
proposed rule and the information submitted in support of them, and 
have tentatively concluded that we disagree with those comments that 
oppose setting a standard for E. sakazakii. Some of the reasons given 
in the comments opposing such a standard (e.g., no evidence that levels 
of E. sakazakii in unopened powdered formula present a risk of harm to 
infants) no longer appear to be relevant, given the more recent data 
evaluated by the experts at the Rome meeting related to the health risk 
posed by contamination of powdered formula (Ref. 2). In addition, the 
comments asserting that alternatives to finished product testing (e.g., 
hazard analysis critical control plans and environmental monitoring, 
education on formula preparation and handling, or use of inhibitors in 
formula) provide sufficient assurance of safety did not provide support 
for such assertions with respect to E. sakazakii. Further, newly 
available data, particularly the data analyzed during the Rome meeting, 
make it clear that E. sakazakii poses a significant health risk that 
has been linked to powdered infant formula. FDA has tentatively 
concluded that, rather than recommending a standard in a guidance 
document, as suggested by one comment, these data support establishing 
a requirement for a standard for E. sakazakii in powdered infant 
formula.
    We have also reached a tentative conclusion, based on the 
scientific information currently available, about the level at which 
that standard should be set. Based on the data analyzed at the Rome 
meeting, FDA tentatively concludes that the establishment of a 
microbiological standard for E. sakazakii of negative in 30 x 10 g 
samples is appropriate to ensure the safety of powdered infant formula 
and prevent outbreaks. As described previously, FDA tentatively 
concludes that the standard FDA is considering in this proposed rule 
will prevent contamination at levels that have been shown to lead to 
outbreaks of E. sakazakii, based on the data evaluated by experts at 
the Rome meeting. Manufacturers would have the flexibility to decide 
what in-process controls, which may include environmental monitoring, 
are necessary to ensure compliance with the microbiological standard of 
negative in 30 x 10 g samples. FDA has tentatively concluded that end-
product testing would provide the manufacturer with the ability to 
verify the effectiveness of in-process controls and would provide FDA 
with the ability to determine compliance with the proposed performance 
standard for E. sakazakii. Such a standard also provides reasonable 
incentives for plants that need to better control E. sakazakii, while 
plants with effective control programs in place face only a minimal 
risk that positive sampling will necessitate lot rejection. Thus, FDA 
is considering a modification to part 106 (21 CFR part 106), in 
proposed Sec.  106.55, that would include a requirement that 
manufacturers test representative samples of each lot of powdered 
infant formula at the final product stage, before distribution, to 
ensure that each lot meets the microbiological quality standard of 
negative in 30 x 10 g samples. FDA is also considering a modification 
to proposed Sec.  106.3(g) to define ``lot'' as follows: ``Lot means a 
quantity of product, having a uniform character or quality, within 
specified limits, or, in the case of an infant formula produced by 
continuous process, it is a specific identified amount produced in a 
unit of time or quantity in a manner that assures its having uniform 
character and quality within specified limits.''
    FDA requests comment on the appropriateness of this standard and of 
the definition of the word ``lot.'' FDA is requesting interested 
persons to submit, as part of their comments, any available scientific 
information and data on both the incidence of, and sampling and testing 
for, E. sakazakii in powdered infant formula. In addition to seeking 
comments on these tentative conclusions in response to this proposed 
rule, we plan to consider and address in the final rule comments 
already submitted concerning these matters.
3. Should the Same E. sakazakii Standard Apply to All Infant Formulas 
Covered by This Rulemaking?
    We have tentatively concluded that it is not appropriate or 
feasible to establish a more stringent E. sakazakii standard for 
powdered infant formula that is to be consumed by premature or newborn 
infants. The population of infants, who may at some point in their 
infancy consume infant formula that is subject to the 1996 proposed 
rule, includes most infants who are fed infant formula, such as healthy 
term infants, preterm infants, low birth weight infants, ill, or 
hospitalized infants. The epidemiologic data, some of which is 
described previously in our summary of the Rome meeting, do not support 
the assumption that term, normal birth weight, and healthy infants--
including infants who are no longer newborns--are not also at risk of 
adverse health consequences associated with E. sakazakii contamination 
of infant formula (Ref. 2

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at 8). Furthermore, we are unaware of data that support the assumption 
that all preterm, low birth weight, ill, or hospitalized infants are 
exclusively fed formula specifically manufactured for their 
consumption. As a practical matter it would be difficult, except when 
the child is under supervised medical care, to limit the consumption by 
certain subgroups of infants only to a special category of formula. 
While it may become appropriate at some future date to propose a 
separate standard for formulas that are to be consumed by certain 
subpopulations of infants, we decline to do so at this time. Thus, we 
have tentatively concluded that it is appropriate to set a standard for 
E. sakazakii for infant formulas in proposed Sec.  106.55. In addition 
to seeking comments on these tentative conclusions in response to this 
proposed rule, we plan to consider and address in the final rule 
comments already submitted concerning these matters.

B. Elimination of Microbiological Standards for Aerobic Plate Count, 
Coliforms, Fecal Coliforms, Listeria monocytogenes, Staphylococcus 
aureus, and Bacillus cereus

    In the 1996 proposed rule, we proposed microbiological standards 
for aerobic plate count, coliforms, fecal coliforms, Salmonella spp., 
Listeria monocytogenes, Staphylococcus aureus, and Bacillus cereus. In 
the 2003 proposed rule, we asked for comment on what changes, if any, 
in the proposed microbiological requirements, other than for E. 
sakazakii, would be appropriate to provide for powdered infant formula 
and to ensure its safety if microorganisms are intentionally added to 
infant formulas (68 FR 22341 at 22342).
    Several comments took issue with the proposed requirement to test 
each batch of formula at the final product stage for the microorganisms 
listed in proposed Sec.  106.55. Other comments argued that testing for 
Listeria monocytogenes was unnecessary because this organism does not 
pose a significant health concern in infant formula. Several comments 
requested that FDA change the M value for Bacillus cereus to 1,000 most 
probable number/g (MPN/g) because there is no health concern associated 
with the proposed level of 100 MPN/g.
    With regard to coliforms and fecal coliforms, one comment requested 
that FDA replace these standards with one for E. coli due to the 
possibility of improper interpretation of coliform and fecal coliform 
tests.
    Regarding intentionally added microorganisms, one comment suggested 
that FDA exempt formulas containing these organisms from the aerobic 
plate count limit as long as the manufacturer employed sanitation 
indicative testing, such as testing for Enterobacteriaceae. One comment 
recommended an Enterobacteriaceae standard of 3.0 MPN/g but did not 
provide reasoning for this standard. Other than the comment disputing 
the overall need for testing each batch of formula for microorganisms, 
no comments argued that the proposed microbiological standard for 
Salmonella spp. is unwarranted.
1. What Were the Conclusions of the Rome Meeting Regarding 
Microbiological Standards for Organisms Other than E. sakazakii?
    The experts at the Rome meeting found that only E. sakazakii and 
Salmonella spp. in powdered infant formula had been clearly linked to 
illness in infants (Ref. 2 at 5). Because of this finding, they 
recommended standards only for E. sakazakii (discussed previously) and 
Salmonella spp.
    With respect to the existing microbiological standard for 
Salmonella spp. in the 1979 Code of negative in 60 x 25 g samples, the 
experts at the Rome meeting determined that this standard is effective 
for protecting public health.
2. Should FDA Set Standards for Microorganisms Other than E. sakazakii?
    FDA has considered comments submitted in response to the 1996 
proposed rule and the 2003 proposed rule, as well as the report of the 
Rome meeting. The comments submitted on microbiological testing no 
longer appear to be relevant, in part, due to the changes FDA is 
considering to the proposed microbiological testing requirements in the 
1996 proposed rule (discussed in the following paragraphs) in response 
to the data available from the Rome meeting. Further, FDA is aware of 
no marketed infant formula that contains intentionally added 
microorganisms and tentatively has decided not to consider requirements 
related to such formula, since it is not clear whether any such formula 
may be marketed at this time.
    FDA has tentatively concluded that there is no need to require 
routine batch testing for microorganisms other than E. sakazakii and 
Salmonella spp. We base this tentative conclusion on the following 
findings: (1) The data indicating both that E. sakazakii and Salmonella 
spp. in powdered infant formula are the microorganisms of public health 
concern associated with such formula, (2) the data that directly link 
the presence of these microorganisms to outbreaks of illness, and (3) 
the evidence that controls to address these pathogens in powdered 
infant formula will reduce the potential for infant illness. Based on 
this tentative conclusion, current proposed Sec.  106.55(b) and (c) 
would not be finalized and proposed Sec.  106.55(b) would be replaced 
with a provision that would require manufacturers to test 
representative samples of each lot of powdered infant formula at the 
final product stage, before distribution, to ensure that each lot meets 
the microbiological quality standard of negative in 30 x 10 g samples 
for E. sakazakii and negative in 60 x 25 g sub-samples for Salmonella 
spp.\2\
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    \2\Although the proposed standard for Salmonella in proposed 
Sec.  106.55 is listed as an M value of 0, proposed Sec.  106.55(c) 
states that ``FDA will determine compliance with the M values listed 
below using the Bacteriological Analytical Manual (BAM)'' (61 FR 
36154 at 36213). Chapter 1 of the BAM states that a sampling plan of 
60 x 25 g samples for Salmonella is appropriate for Category I 
foods, i.e., foods that ``would not normally be subjected to a 
process lethal to Salmonella between the time of sampling and 
consumption and are intended for consumption by the aged, the 
infirm, and infants'' (Andrews, W., et al., Bacteriological 
Analytical Manual Online, Chapter 1, available at http://
www.cfsan.fda.gov/~ebam/bam-1.html, April 2003).
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    Although FDA believes that testing for aerobic plate count and 
Enterobacteriaceae can be beneficial to manufacturers in monitoring 
their process and production sanitation, these tests do not distinguish 
between pathogenic and non-pathogenic bacteria. FDA is currently 
proposing standards for the two pathogenic bacteria in the family 
Enterobacteriaceae, i.e., E. sakazakii and Salmonella spp., whose 
presence in infant formula has been linked to outbreaks of illness. 
Therefore, FDA has tentatively concluded, based on recent data from the 
Rome report, that additional batch testing, beyond the proposed E. 
sakazakii and Salmonella spp. standards, is not warranted at this time 
to ensure the microbiological safety of powdered infant formula. 
Therefore, FDA has tentatively decided not to include requirements for 
testing microorganisms, other than Salmonella spp. and E. sakazakii, in 
the final rule.
    Under the testing regimen set forth in this proposed rule, the 
proposed testing standards in Sec.  106.55(c) would not be finalized. 
Thus, there would be no standards in a final rule for an aerobic plate 
count, coliform, fecal coliform test, Listeria monocytogenes, 
Staphylococcus aureus, or Bacillus cereus. Nor would there be a 
standard for Enterobacteriaceae in a final rule. However, even though 
batch testing

[[Page 43397]]

would not be required for these microorganisms, the presence of these 
microorganisms in an infant formula reflects that the formula was 
prepared, packed, or held under insanitary conditions whereby it may 
have been rendered injurious to health and therefore is adulterated 
under section 402(a)(4) of the act (21 U.S.C. 342(a)(4)). FDA is 
interested in receiving comments, based on the FAO/WHO meetings or 
other scientific information, concerning its current thinking regarding 
the establishment of microbiological standards only for E. sakazakii 
and Salmonella spp. In addition to seeking comments on these tentative 
conclusions in response to this proposed rule, we plan to consider and 
address in the final rule comments already submitted concerning these 
matters.

C. Assessing Normal Physical Growth in Infants

    In the 1996 proposed rule, FDA proposed a quality factor of normal 
physical growth (61 FR 36154 at 36215). Some comments to the 2003 
proposed rule questioned FDA's authority to establish such a quality 
factor and to require a clinical study to measure physical growth. The 
agency is considering those comments and will respond to them in the 
final rule. For purposes of this proposed rule, the agency is seeking 
comment on certain IOM recommendations for evaluating the safety of new 
ingredients in infant formula because these recommendations differed 
from what the agency proposed as quality factor requirements.
1. Clinical Studies to Measure Normal Physical Growth
    The IOM report considered a spectrum of tools that can be used for 
assessment of ingredient safety, including preclinical in vivo (animal) 
and in vitro toxicity studies and clinical human studies. The committee 
recognized the importance of conducting a clinical study of a new 
ingredient under the intended conditions of use, i.e., in the context 
of human consumption of an infant formula product. Such a study also 
allows for the evaluation of the entire formula matrix, including 
interactions among formula components. IOM recommended that 
``bioavailability be specifically addressed in any evaluation of the 
safety of infant formulas'' (Ref. 3 at 5). Thus, IOM's recommendations 
included the importance of assessing the bioavailability of an infant 
formula and its nutrients.
    The IOM report states that ``growth studies should remain the 
centerpiece of clinical testing of ingredients new to infant formulas'' 
(Id. at 113). The IOM report concludes that ``the inability of a 
formula to support growth represents a significant harm to infants and 
therefore growth is an essential endpoint for all safety assessments of 
an ingredient new to infant formulas'' (Id. at 105). The IOM report 
recommends, however, that growth studies are not sufficient on their 
own to assess ingredients new to infant formulas. IOM provides a 
hierarchical study of major organ systems and developmental-behavioral 
outcomes (Id. at 98). The IOM report states that ``growth deficits are 
likely to appear only secondary to effects on specific organs or 
tissues and may not appear for some time after nutritional insult'' 
(Id. at 113).
    While clinical studies that measure other aspects of the 
bioavailability of nutrients in an infant formula may prove valuable at 
a future time, FDA's current thinking is that it will not consider 
requiring additional measurements, under section 412 of the act, for 
the purpose of assessing the bioavailability of the formula and its 
nutrients, beyond those measures identified in the 1996 proposed rule. 
Certain measurements that IOM recommends, other than growth studies, 
involve invasive procedures and may raise ethical concerns.
    FDA is interested in receiving comments, based on the IOM report or 
other scientific information, concerning its current thinking that 
protein and physical growth are sufficient at this time for assessing 
the bioavailability of nutrients in an infant formula.
2. Body Composition as Measure of Normal Physical Growth
    FDA proposed growth measurements that include body weight, 
recumbent length, head circumference, and average daily weight 
increment (proposed Sec.  106.97(a)(1)(i)(B)). The IOM report 
recommends that growth measurements include weight, recumbent length, 
head circumference, weight and length velocity, and body composition 
(Id. at 107). Thus, FDA did not include a measure of body composition 
that IOM recommended.
    FDA tentatively concludes that a measure of body composition is not 
necessary to include as a measure of physical growth when a clinical 
study is used to evaluate the quality factor of physical growth. The 
IOM report recommends that measurement of normal physical growth 
include body composition and lists anthropometry (e.g., skinfold 
measurements), dual x-ray absorptiometry, and isotope dilution as the 
most feasible methods (Id. at 107). IOM states that body composition is 
a ``more sensitive indicator of infant nutritional status than measures 
of size,'' although body composition measurement methods can be 
expensive and frequently inaccurate (Id. at 108). FDA believes that, 
due to the expense and frequent inaccuracy of body composition 
measurement methods, and the adequacy of measures of body weight, 
recumbent length, head circumference, and data to calculate average 
daily weight increment for assessing an infant's growth when fed an 
infant formula, measurement of body composition is not warranted at 
this time. FDA is interested in receiving comments, based on the IOM 
report or other scientific information, concerning its current thinking 
that measures of body weight, recumbent length, head circumference, and 
data to calculate average daily weight increment are adequate for 
assessing the quality factor of normal physical growth.
3. Duration of Clinical Studies and Enrollment Age of Infants
    The IOM report recommends that, ideally, growth studies should be 
conducted over the entire period for which infant formula is intended 
to be fed as the sole source of nutrition, i.e., up to 6 months (180 
days), which is consistent with breastfeeding guidelines (Ref. 2 at 10 
and 112-113). IOM further states that a 120-day growth study, proposed 
by FDA, does not allow for the determination of delayed effects or for 
understanding longer-term effects of early perturbations in growth. 
This recommendation is based on breastfeeding guidelines that recommend 
exclusive breastfeeding for infants for at least the first 4 months of 
age and preferably for the first 6 months of age (Id. at 112). However, 
the IOM report acknowledges that ``there is no reason to think that an 
adverse effect of an ingredient new to formulas would be detected only 
between 4 and 6 months of age''\3\ and notes that many infants begin 
consuming foods other than formula between 4 and 6 months of age (Id. 
at 112). Consumption of foods other than infant formula has the 
potential to confound a growth study evaluating an infant formula.
---------------------------------------------------------------------------

    \3\IOM seems to inadvertently alternate between discussion of 
the study length in terms of duration (i.e., a 180-day study), 
versus the length in terms of the infant's age (i.e., the study 
should continue until the infant is 6 months of age). Because most 
studies will not commence on the day of the infant's birth, it is 
important to distinguish between the two. FDA has attempted to do so 
in its explanation of its current thinking on this issue.
---------------------------------------------------------------------------

    Although FDA agrees that the first 6 months of age is the optimal 
time to

[[Page 43398]]

measure infant growth, and would not discourage clinical studies for 
this time period, FDA believes it is not necessary to conduct a 
clinical study, for the purpose of evaluating physical growth as a 
quality factor, for the infants' entire first 6 months of age.
    FDA proposed that a clinical study be no less than 4 months in 
duration, enrolling infants no more than 1 month old at the time of 
entry into the study. FDA received several comments on this issue, both 
in response to the 1996 proposed rule and in response to the 2003 
proposed rule. None of the comments were in favor of a study duration 
requirement of 6 months. The comments FDA received favored a duration 
requirement ranging between 112 and 120 days, and recommended an 
enrollment requirement of between the age of 8 days and 1 month.
    To better capture the maximum amount of time during the most rapid 
growth period for infants, FDA is considering whether to require a time 
period for clinical studies of a period of no less than 15 weeks that 
would commence at no more than 2 weeks of age. FDA believes 15 weeks 
provides a sufficient amount of time for assessing the physical growth 
of infants. Given this relatively short time period and the importance 
of a sufficient length of time for determining growth outcomes, FDA 
believes it is important to require that the study commence no later 
than 2 weeks of age. These changes would result in a clinical study 
extending through approximately the infant's first 4 months of age. A 
required study duration of no less than 15 weeks corresponds to the 
Iowa reference data recommendations regarding the duration of a 
clinical study. FDA requests comments on whether, in light of the IOM 
report's 180-day recommendation, FDA should consider requiring a study 
period of no less than the infant's first 180 days (6 months). Comments 
should include any available supporting data and information.

III. What Comments Will Be Considered?

    Comments submitted in response to this proposed rule should focus 
solely on one or more of the following issues: (1) Whether FDA should 
require a microbiological standard for E. sakazakii for powdered infant 
formula of negative in 30 x 10 g samples; (2) whether FDA should not 
require microbiological standards for aerobic plate count, coliforms, 
fecal coliforms, Listeria monocytogenes, Staphylococcus aureus, and 
Bacillus cereus; (3) whether FDA should require measurements of healthy 
growth beyond the two proposed quality factors of normal physical 
growth (as measured by body weight, recumbent length, head 
circumference, and average daily weight increment) and protein quality; 
(4) whether FDA should require a measure for body composition as an 
indicator of normal physical growth, and if so, what measure, and (5) 
whether FDA should require the duration for a clinical study, if 
required, be no less than 15 weeks, and commence when infants are no 
older than 2 weeks of age. FDA requests comments on how, if we make the 
changes to the proposed rule outlined in this document, the costs and 
benefits would either be greater or less than estimated in the 1996 
proposed rule (61 FR 36154 at 36202). We also request comment on the 
extent to which the description of industry practices in the Rome 
meeting report (Ref. 2) accurately describes the activities of all 
firms supplying infant formula in the United States. Data supplied in 
response to these questions will be used to inform any rulemaking. FDA 
will not consider comments outside the scope of these issues.
    Comments previously submitted to the Division of Dockets Management 
do not need to be resubmitted, because all comments submitted to the 
docket number, found in brackets in the heading of this document, will 
be considered in development of the final rule.

IV. How to Submit Comments

    Interested persons may submit to the Division of Dockets Management 
(see ADDRESSES) written or electronic comments regarding this document. 
Submit a single copy of electronic comments or two paper copies of any 
mailed comments, except that individuals may submit one paper copy. 
Comments are to be identified with the docket number found in brackets 
in the heading of this document. Received comments may be seen in the 
Division of Docket Management between 9 a.m. and 4 p.m., Monday through 
Friday.

V. References

    The following references have been placed on display in the 
Division of Dockets Management (see ADDRESSES) and may be seen by 
interested persons between 9 a.m. and 4 p.m., Monday through Friday. 
(FDA has verified the Web site addresses, but we are not responsible 
for subsequent changes to the Web sites after this document publishes 
in the Federal Register.)
    1. The Food and Agriculture Organization of the United Nations 
and the World Health Organization, ``Enterobacter sakazakii and 
Other Microorganisms in Powdered Infant Formula: Joint FAO/WHO 
Meeting 2-4 February 2004,'' available at http://www.fao.org/documents/show_cdr.asp?url_file=/docrep/007/y5502e/y5502e00.htm 
(last visited May 10, 2006).
    2. The Food and Agriculture Organization of the United Nations 
and the World Health Organization, ``Enterobacter sakazakii and 
Salmonella in Powdered Infant Formula: Meeting Report, FAO 
Headquarters, Rome, Italy, 16-20 January 2006,'' available at ftp://ftp.fao.org/ag/agn/jemra/e_sakakazii_salmonella.pdf (last visited 
May 10, 2006).
    3. Committee on the Evaluation of Ingredients New to Infant 
Formula, ``Infant Formula: Evaluating the Safety of New 
Ingredients,'' National Institute of Medicine, March 1, 2004.

    Dated: July 24, 2006.
Jeffrey Shuren,
Assistant Commissioner for Policy.
[FR Doc. E6-12268 Filed 7-31-06; 8:45 am]
BILLING CODE 4160-01-S