INTERNATIONAL FORMULA COUNCIL

Comments to FDA\'s Proposed Part 106

**INFANT FORMULA REQUIREMENTS PERTAINING TO CURRENT GOOD**

**MANUFACTURING PRACTICE, QUALITY CONTROL PROCEDURES, QUALITY**

**FACTORS, RECORDS AND REPORTS, AND NOTIFICATION**

**TABLE OF CONTENTS**

# **IFC\'s General Comments to FDA\'s Proposal**

> I. IFC's Appreciation of FDA's Efforts and the Importance of GMPs 4
>
> II\. Specific Objection to April 28, 2003 Notice 5
>
> III\. FDA\'s Request for Comments - Key Issues 6
>
> IV\. Impact Analysis and Effective Date of the Final Regulation 17
>
> V. Overly Prescriptive/Inflexible Provisions 18
>
> VI\. "Specifications" 18
>
> VII\. Validation: Over-reliance on a "Drug" GMP Model 20
>
> VIII\. Recordkeeping: The Regulation Should Focus on "Necessary"
> Documents. 23
>
> IX\. Proposed Definition of "Manufacturer." 23
>
> X. Notification of "Adulteration." 24

XI. Redundancy 24

XII. Infant Formula Submission Review by FDA 25

XIII. FDA\'s Means to Assure the Safety and Availability of New and
      Improved Infant

> Formulas \-- Premarket Notification Not Premarket Approval 25

# **IFC\'s Specific Comments to FDA\'s Proposal**

106.3 Definitions. 29

##  **Subpart B\--Current Good Manufacturing Practice** 

106.5 Current good manufacturing practice. 41

106.6 Production and in-process control system. 41

106.10 Controls to prevent adulteration by workers. 45

106.20 Controls to prevent adulteration caused by facilities. 48

106.30 Controls to prevent adulteration caused by equipment or utensils
55

106.35 Controls to prevent adulteration due to automatic

(mechanical or electronic)
equipment..............................................64

106.40 Controls to prevent adulteration caused by ingredients,

containers, and
closures............................................................\...71

106.50 Controls to prevent adulteration during manufacturing. 76

106.55 Controls to prevent adulteration from microorganisms. 80

106.60 Controls to prevent adulteration during packaging and

labeling of infant
formula............................................................83

106.70 Controls on the release of finished infant formula. 84

106.80 Traceability. 86

106.90 Audits of current good manufacturing practice. 86

##  **Subpart C\--Quality Control Procedures** 

106.91 General quality control. 88

106.92 Audits of quality control procedures. 95

**Subpart D\--Conduct of Audits.**

106.94 Audit plans and procedures. 96

##  Subpart E\--Quality Factors for Infant Formulas 

106.96 Quality factors in infant formulas. 99

106.97 Assurances for quality factors. ...... 101

# **FDA\'s Request for Comments on Additional Quality Factors** 

106.100 Records. 116

##  **Subpart G\--Registration, Submission, and Notification Requirements** 

106.110 New infant formula registration. 129

106.120 New infant formula submission. 130

106.121 Quality factor submission. 140

106.130 Verification submission. 146

106.140 Submission concerning a change in infant formula that may

adulterate the
product............................................................\...149

106.150 Notification of an adulterated or misbranded infant formula. 152

107.1 Status and applicability of the regulations in part 107. 155

107.10 Nutrient Information. 155

107.240 Notification Requirements. 155

107.250 Termination of an infant formula recall. 156

## 

## 

##  August 26, 2003

Dockets Management Branch, HFA-305

Food and Drug Administration

5630 Fishers Lane, Rm. 1061

Rockville, MD 20852

#######  RE: Docket 95N-0309

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

Dear Sir or Madam:

This letter is prompted by the April 28, 2003 reopening by the Food and
Drug Administration (FDA or \"Agency\") of the comment period for the
proposed rule published by the Agency entitled, \"Current Good
Manufacturing Practice, Quality Control Procedures, Quality Factors,
Notification Requirements, and Record and Reports, for the Production of
Infant Formula" (61 *Federal* *Register* 36153; July 9, 1996). These
comments are submitted on behalf of all the major U.S. infant formula
manufacturers by the International Formula Council (\"IFC\"), the
association representing manufacturers of infant formula in the United
States.[^1] These comments address the new issues raised by the agency
when reopening the comment period and reflect the IFC current position
on each provision of the proposed rule. These comments replace the
December 6, 1996 comments submitted by IFC in response to the original
proposed rule.

**Format of IFC's Comment to the Proposed Regulation**

These comments contain two major sections: General Comments and Specific
Comments. The **General Comments** include comments that apply to the
proposed regulations as a whole and to requests for comments by the
Agency to multiple sections. **Specific Comments** address individual
sections of the proposal. When, in a Specific Comment to a proposed
section, a General Comment applies, it will simply be referenced and not
repeated. In April of 2003, seven additional issues within the scope of
this proposal, which had come to the Agency\'s attention since the 1996
proposal was published, were set forth in the announcement of the
reopening of comments. Rather than address all of them separately at the
outset, we have chosen a few key issues to address in the General
Comments, and have woven the rest of our comments on those issues into
the Specific Comments wherever they are the most relevant.  

Each of the IFC\'s Specific Comments will be preceded by two columns.
The language proposed by FDA will be in the left hand column, and the
language that the IFC would suggest be substituted (or other action, if
any), will be described in the right hand column. In those instances
when changes are suggested, a "redlined" version will also be provided
immediately beneath the FDA-proposed and IFC-suggested language to
assist in the understanding of the desired change(s). When utilized,
this will show by strike-through words that IFC suggests deleting and by
shading the words that IFC suggests adding.

The entire text of the IFC\'s suggested language is included in these
comments (Attachment A), as is a redlined comparison of the IFC\'s
suggested language with language proposed by FDA. (Attachment B)

**IFC\'s General Comments to FDA\'s Proposal**

**I. IFC\'s Appreciation of FDA\'s Effort and the Importance of GMPs**

The 1996 proposal was the result of a significant effort by FDA. When
Congress enacted legislation that required FDA to promulgate Good
Manufacturing Practice ("GMP") Regulations specific to infant formula,
the Agency worked hard to familiarize itself with the manufacturing
methods of these important food products. As mentioned by FDA in the
preamble to the 1996 Proposed GMP Regulation, several people at FDA
responsible for the preparation and drafting of the proposal have
visited the manufacturing facilities of the IFC members for the purpose
of learning something about each manufacturer's unique manufacturing
systems and processes. The results of these efforts were evident from
the proposal. Generally, the 1996 proposed regulation was a good initial
effort at establishing a GMP regulation for infant formula that was
flexible enough both to accommodate each manufacturer's current
manufacturing methods, and to allow for incorporation of the inevitable
improvements in technology that the future holds. There were, however, a
number of very significant concerns with the proposal that the IFC
addressed in its comments to the 1996 proposal. As discussed below, had
FDA reviewed the IFC's and other comments to that initial proposal, and
reproposed a GMP regulation for infant formula incorporating the
Agency's conclusions based on those comments, the process would be
significantly more advanced than where it is now.

We would like to underscore that IFC's comments are not lightly made,
given the importance all industry members attach to GMPs. In the absence
to date of a thorough system of specific regulatory requirements
relating to GMP, the industry has developed a comprehensive course of
good manufacturing practice and developed a commensurate level of
internal expertise on manufacturing issues, all of which is well
illustrated by the industry's excellent record of manufacturing safe,
high-quality infant formula products over the more than 20 years since
the passage of the Infant Formula Act. In light of the importance that
the industry attaches to the manufacturing of the important product it
produces, the FDA must recognize that the industry's expertise on issues
affecting infant formula manufacturing is at least equal to if not
greater than the expertise that is resident within FDA. As we proceed
with our comments, it may be noted that a careful review of the
authorities cited in support of the 1996 proposed requirements calls
into question the existence of concrete bases for a number of the
proposed "requirements" and, thus, appears to reflect "administrative"
expertise and thinking as opposed to the practical hands-on experience
the industry possesses. We trust that our practical expertise will be
accorded the credence that it is due during the Agency's attempt to
resolve any remaining issues.

**II. Specific Objection to April 28, 2003 Notice**

Before getting to the substance of our comments, IFC would like to
express the surprise experienced by the infant formula industry at the
nature and timing of the Agency's re-proposal. For years we have been
told by Agency personnel, albeit informally, that the GMP regulations
were in the process of being finalized. Now, instead of offering a
meaningful FDA response to our past comments on the 1996 proposal or on
the major initiatives brought before the FAC, the Agency, without any
indication of where it may be headed, has merely asked for our
commentary again. We respectfully object to the process FDA has followed
as one that shields from industry comment the thinking and direction FDA
has on the critical issues at the heart of this initiative.

The Agency's April 28, 2003 "reproposal" of the GMP rule is particularly
frustrating because it raises new issues not previously covered by the
original proposed rule and fails to provide any guidance on how the
Agency proposes to address these new issues. For example, the reproposal
requests extensive information on whether there is a need to include a
microbiological requirement in the final regulation for *E. sakazakii*
and whether the microbiological requirements for powdered infant
formulas intended for premature and newborn infants should be higher
than those for older infants. The reproposal raises these and other
issues that are beyond the scope of the original proposal and fails to
offer proposed regulatory language that would provide insight on how the
Agency intends to address these new issues in a final regulation.

The Agency's initiative seems at odds with the fundamental obligation of
an agency under the Administrative Procedure Act ("APA") to make its
views known to the public in a concrete and focused forum so as to make
criticism or formulation of alternatives possible. *See Home Box Office
Inc. v. FCC*, 567 F.2d 9, 36 (D.C. Cir. 1977), *cert denied* 434 U.S.
829 (1977), and *rehearing denied*, 434 U.S. 988 (1977). The APA
requires that a notice of proposed rulemaking must include "either the
terms or substance of the proposed rule or a description of the subject
or issues involved." The notice's general format places the subjects and
issues into a historical but not analytical context. In the process, the
notice fails to describe the range of alternatives actually being
considered by the Agency and gives no indication where FDA is headed
either on a response to the extensive comments it received on the 1996
rule, or on how it is leaning toward resolving those issues. As a
result, we are forced to comment on rules we may not see until they are
purportedly "final".

A key hallmark of the administrative notice and comment rulemaking
process is providing fairness to interested parties. *See Small Refiner
Lead Phase-Down Task Force v. EPA*, 705 F.2d 506, 547 (D.C. Cir. 1983).
Fairness includes the opportunity to comment meaningfully on the
substantive regulations that will apply. A key prerequisite for
meaningful comment is the Agency's rationale connecting data and law to
the regulation being proposed. *See Florida Power and Light Company v.
United States*, 846 F.2d 765, 771 (D.C. Cir. 1988). As contemplated
under the APA, the rulemaking process is meant to be a shared enterprise
that empowers the public to question the proposed regulation and the
data and assumptions on which it is based before it becomes effective.
In issuing the "reproposal" of the GMP final rule, the Agency has failed
to meet the foregoing goals of rulemaking. Thus, the IFC strongly
believes that an additional round of notice and comments must follow
this "reproposal" especially to the extent that the Agency intends to
draft regulations addressing the new substantive issues not found in the
original proposed rule.

**III. FDA\'s Request for Comments - Key Issues**

FDA and IFC share the mutual goal of assuring that a final GMP
regulation emerges from the notice and comment process that achieves a
number of important public health objectives, including:

> Fostering innovation and quality in infant formulas; and

-   Establishing only provisions that avoid unnecessary costs and add
    value to the product, i.e., only provisions that increase assurance
    that infant formulas are safe, wholesome and fulfill their important
    function in infant nutrition.

To those ends, we have addressed several of FDA's seven questions
throughout our comments and would like separately to address three key
issues raised in the FDA's April 28 notice reopening the comment period.
Two of these issues -- the emergence of *Enterobacter sakazakii* (*E.
sakazakii*) and the assessment of normal growth -- also have been
addressed recently by FDA Food Advisory Committees.

**FIRST ISSUE: *ENTEROBACTER SAKAZAKII* (FDA's Issue 1)**

In light of the discussions held at the March 18-19, 2003 meeting of
FDA's Food Advisory Committee, Subcommittee on Contaminants and Natural
Toxicants (CNTS), IFC would like to emphasize that there is no need to
establish a specific microbiological requirement for *E. sakazakii*.
Infrequent but disturbing reports have been published during the course
of the last 20 years indicating that *E. sakazakii* is an opportunistic
microorganism capable of causing serious infections in low birth weight
and immunocompromised infants. (*E. sakazakii* is an opportunist in that
it may only be a significant threat to health in these abovementioned,
specific highly susceptible populations.) Suggestive evidence does
establish a possible association with powdered infant formula. However,
where there has been an association with powdered infant formula,
infections are almost exclusively associated with preparation and use of
reconstituted powdered infant formula in hospitals. Thus, reported
infections may be related to the vulnerability of the hospital
population and deviations from infant formula good hygienic handling
practices, as developed by the American Dietetic Association. Premature
infant infections associated with *E. sakazakii* are rare; and term
infant infections associated with *E. sakazakii* are rarer still. This
is consistent with a recent publication from Health Canada using a
suckling mouse model that found this organism has low infectivity, and
that large numbers of organisms are needed to cause infection, even with
the most virulent strains. The available evidence provides the Agency no
basis for regulatory concern even when measured by the Act's
conservative safety standards.

Although the available scientific evidence does not permit a
comprehensive risk assessment, the available evidence does permit the
rather straightforward conclusion, like that reached by the Food
Advisory Committee, that whatever risk to term infants that powdered
infant formula may pose by virtue of the presence of *E. sakazakii*,
that risk is not only lower than that which is associated with premature
infants but also is unquantifiable. Although the issue merits further
exploration like the Codex Alimentarius Commission's risk assessment
initiative, there is no basis upon which FDA can support any conclusion
that suggests that *E. sakazakii* presents an actionable risk of harm to
healthy term infants. For these reasons, IFC does not believe it is
necessary to establish a specific microbiological requirement for *E.
sakazakii* in infant formulas.

The April 28 Notice asked in particular whether powdered infant formula
to be consumed by premature and newborn infants should meet stricter
microbiological requirements than formula intended for older infants.

There is scientific and medical rationale, supported by both experience
and provisions in the Infant Formula Act, to set different standards for
formulas intended for premature (low birth weight) infants than those
for term infants. There is no apparent basis to set different standards
for healthy term newborn infants and older infants born at term, except
in the sense that older term infants who are weaned are subject to the
microbiological standards applicable to the general food supply.

The example of different standards for premature and term infants is
made by inspection of published information on infection by *E.
sakazakii*. The literature on *E. sakazakii*-associated illness cited by
FDA in its presentation to the March 18-19, 2003 CNTS of the FAC was
examined to assess what evidence may implicate formula as a possible
cause of *E. sakazakii*-related disease among healthy term infants.

In summary from the data reviewed,[^2] the total reported cases of *E.
sakazakii* infection in infants born at term and greater than 2500 grams
is four infants. In two cases (Block et al., Monroe and Tift) there is
only an association of *E. sakazakii* infection with formula feeding. In
one other case (Muytjens et al.), there was positive evidence of
contamination from hospital equipment where tests of powdered formula
itself were negative, and in the fourth report (Biering et al.) the
authors note mishandling of reconstituted formula by "extended periods
of time in bottle heaters." Handling practice is clearly important; the
data from CDC and others presented at the FAC meeting showed that there
was virtually no growth of *E. sakazakii* at 4 degrees C and that the
doubling time at room temperature is about 40 minutes.

The absence of reported cases does not mean that there have been no
occurrences among healthy term infants. But it does suggest that the
presence of extremely low levels of the organism as reported by the FDA,
Muytjens et al. 1988, and the recent Canadian survey, is not sufficient
by itself to pose a risk. The only reported occurrences of disease in
healthy term infants where the reconstituted formula was shown to be
contaminated also had evidence of external contamination or mishandling
of reconstituted product. Given the low risk of *E.
sakazakii*-associated illness in healthy term infants from properly
prepared formula, FDA's current *de facto* standard of zero tolerance of
*E. sakazakii* in formulas for term infants is not warranted.

Further rationale that supports a separate standard for low birth weight
(LBW) and at-risk infants is found in section 412(a)(1)(A) and (B) of
the FFDCA, which exempts formulas represented and labeled for use by
infants who are LBW or who have unusual medical problems (such as would
require hospitalization) from the good manufacturing practices
established under 412(b)(2)(A), that include microbiological
specifications.

The CNTS of the FAC met on March 18-19, 2003, and was in agreement that
there is a very small risk, though not quantifiable because of the
absence of data, that healthy term infants could develop illness because
of *E. sakazakii* contaminated formula. According to the minutes, "The
population at risk are preterm infants born at less than 36 weeks
gestational age up to a post term age of 4-6 weeks, immunocompromised
infants at any age, and term infants hospitalized in level 2 and level 3
neonatal intensive care units." Healthy term infants are not included
among those identified as "at risk" but were separated by FAC from
at-risk groups.

The FAC determined "There is probably a low but as yet unquantified risk
in healthy term infants, which cannot be described with data available
at this time." What does "probably a low but as yet unquantified risk"
mean? Most simply, it is the qualified language of an academic group
that knows to be careful to avoid absolutes. There is "probably a low
but as yet unquantified risk" of all kinds of maladies. The risk is so
remote that healthcare or behavioral decisions are not made on the basis
of that risk.

FDA should be reluctant to extrapolate an estimate of risk that is
developed primarily from data and information involving preterm infants
to a risk among healthy term infants. The FAC that met April 4-5, 2002
discouraged this type of extrapolation for other safety assessments,
such as growth (although FAC did express frustration that safety and
growth were used interchangeably by FDA). At the April 4-5, 2002 meeting
of the FAC, preterm infants were described as very different than term
infants with respect to medical needs, nutritional needs and
vulnerability to disease. While older preterm infants (e.g., 32-36
weeks) have digestive and absorptive capabilities sufficient to absorb
the nutrient levels found in preterm formula many young preterm infants
have not yet developed a mature intestinal barrier function. Other
preterm infants may have dysmotility or compromised GI function that
could result in greater vulnerability to potential pathogenic bacteria
in the intestine. Consequently, in the assessment of risk of disease
from GI pathogens, there is need to consider separately infants
according to post-conceptional age.

IFC believes that *E. sakazakii* can be more effectively controlled
through routine surveillance of indicator organisms, coupled with strong
Hazard Analysis Critical Control Point (HACCP) programs, labeling and
education. Although proactive measures may be taken to reduce the level,
frequency, and incidence of *E. sakazakii* in powdered infant formula,
total eradication of the microorganism from powdered infant formula is
not currently technologically possible given the nature of food powder
manufacturing. U.S. Infant Formula Manufacturers, in cooperation with
government and the healthcare community, have embarked on an aggressive
and ambitious program to further define and reduce, to the extent
possible, any potential risk posed from powdered infant formula. The
immediate focus and responsibility of the industry has been to identify
and implement labeling and education, and manufacturing measures and to
lay the groundwork for a series of steps to reduce the potential for the
microorganism to reach levels (in the powdered can, in the bottle, or in
the feeding tube) that would constitute a hazard to health.

IFC contributed several documents for the consideration of the FAC
Subcommittee on Contaminants and Natural Toxicants meeting to discuss
*E. sakazakii* in March 2003 and thereafter. The dialogue on this topic
between IFC and FDA is ongoing, and we believe it is premature to
comment further in this context. Since the Agency has specifically
requested comments on this topic for the docket on the proposed GMPs, we
have attached those documents we previously contributed as an appendix
to our comments. Those documents include:

-   IFC's June 20, 2003 letter to Dr. Christine Taylor re Industry
    Proposal on Infant Formula Powder Labeling (Attachment C)

-   IFC's June 27, 2003 letter to Dr. Christine Taylor re Proposed
    Discussion Points on Powdered Infant Formula Good Manufacturing
    Practices (Attachment D)

-   IFC's July 7, 2003 letter to Dr. Christine Taylor re Special
    Products (Attachment E)

-   Douglas L. Archer's July 7, 2003 letter to Robert C. Gelardi re
    Summary of Industry Data re Testing for *E. sakazakii* in Powdered
    Infant Formula -- Submitted to Dr. Christine Taylor on July, 7, 2003
    (Attachment F)

[**SECOND ISSUE: ASSESSMENT OF NORMAL GROWTH** (FDA's Issue
6)]{.underline}

In light of the discussions held at the two 2002 meetings of the FDA's
ad hoc Infant Formula Subcommittee of the Food Advisory Committee, IFC
has taken a new look at the basis for this proposed "quality factor". As
explained below, IFC believes that the Agency's effort to establish
"normal growth" as a required quality factor is flawed and should be
abandoned. The clearest definition of "quality factor" comes in one line
from the legislative history: "Quality factors pertain to the
bioavailability of a nutrient and the maintenance of level or potency of
nutrients through an expected shelf life of the product."[^3] FDA may
have based its concept of "healthy growth" on another line in the
legislative history to the effect that "the growth of infants during the
first few months of life often determines the pattern of development and
quality of health in adult life." This statement was apparently used to
emphasize the conclusion that appears at the end of the same paragraph:
"the availability of infant formula which is safe and nutritious is
critically important to the health of our nation."[^4]

As responsible manufacturers of infant formula, the industry absolutely
agrees with the critical importance assigned to ensuring the
bioavailability of infant formula, and agrees with Congress' obvious
concerns about bioavailability and nutrient potency throughout shelf
life. Growth is clearly an indicator of bioavailability and, as such,
can be an important point to consider when a question of bioavailability
is raised. But, few changes in an infant formula raise such questions,
and the routine demonstration of growth relative to most changes in an
infant formula cannot be considered a specific legal "requirement."
Thus, we object on legal, scientific, and policy reasons to the proposed
establishment of evidence of "normal growth" (or "healthy growth"
according to the April notice) as a quality factor to be looked for on
any regular basis.

**Legal Issues:** The Infant Formula Act states that the Secretary
"shall by regulation establish requirements for quality factors for
infant formulas to the extent possible consistent with current
scientific knowledge, including quality factor requirements for the
nutrients required by subsection (i). Federal Food, Drug, and Cosmetic
Act (FFDCA) § 412(b)(1). The Infant Formula Act makes no mention of
"normal growth," nor does it define "quality factors." The FFDCA makes
it clear that quality factors could be established for components in the
formula such as protein quality and the quality of other nutrients that
may be added to the infant formula. By defining "normal growth" as a
quality factor, the Agency essentially would be establishing a
requirement that applies to the entire infant formula matrix and not
merely a component found in the infant formula. There simply is no basis
in the plain language of the statute or the legislative history to
support such an interpretation of quality factor.

Indeed, a review of the legislative history establishes that both
Congress and FDA in comments to the bills under consideration,
considered quality factors to be limited to individual components in the
infant formula. In the Senate record pertaining to the 1986 amendments
Senator Metzenbaum described the 1986 amendments as providing testing
for "each essential nutrient" and further described "the quality factor
of nutrient content requirements of the law, as demonstrated by the
testing called for in the amendments." In its comments on the 1986
amendments, FDA informed the Senate that the state of knowledge and
science with respect to quality factors was still evolving, and that,
therefore, there was a basis for only one quality factor for a nutrient
\[referring to protein efficiency ratio\]. 132 [Cong. Rec.]{.smallcaps}
S14042, 14046 (daily ed. Sept. 27, 1986) (statement of Sen.
Metzenbaum)). These statements evidence a Congressional intent, and an
agency agreement with such intent, that quality factors would be
established for components in the formula. Moreover, the Agency remarks
indicate that at the time of passage of the Infant Formula Act
Amendments, FDA envisioned the establishment of only one quality factor,
namely for protein efficiency ratio. FDA could have identified growth as
a quality factor then but did not, so that such an interpretation was
not before the Congress when it considered and enacted the 1986
amendments. Moreover, in the legislative history of the 1980 Act,
statements by Senator Metzenbaum and Mr. Gore refer to testing in the
context of laboratory analysis of required nutrients, never in the
context of clinical studies.

The establishment of "normal growth" as a quality factor essentially
results in the imposition of mandatory clinical study requirements for
infant formulas, unless the manufacturer would qualify for one of the
narrow exemptions found in the FDA proposal. Under the Infant Formula
Act, a premarket notification must be submitted before a manufacturer
introduces into commerce a "new infant formula." The premarket
notification must contain numerous data and information, including data
demonstrating that the new infant formula meets the quality factor
requirements established by FDA. "New infant formula" is defined broadly
to include (1) infant formulas manufactured by a person which has not
previously manufactured an infant formula and (2) an infant formula
manufactured by a person which has previously manufactured infant
formula and in which there is a major change, in processing or
formulation, from a current or any previous formulation produced by such
manufacturer. FFDCA § 412(c)(2). The proposed rule contains a broad
definition of major change that would mandate the filing of a premarket
notification for numerous changes in processing and/or formulation.
While the industry recognizes that clinical studies may be needed to
assess some of these major changes (such as the use of a certain new
ingredients with no prior history of use in infant formulas), there is
no scientific basis to mandate clinical studies for other major changes
(such as the manufacture of an infant formula on a new processing line).

The Infant Formula Act does not provide FDA with the legal authority to
require infant formula manufacturers to conduct clinical studies for new
infant formulas. The statute does not impose a clinical testing
requirement and indeed, Congress specifically rejected an earlier
version of a bill that would have imposed clinical testing. In testimony
before the House of Representatives, then-Commissioner of Food and
Drugs, Jere Goyan, interpreted the proposed legislation as requiring
manufacturers of infant formula \"to conduct tests, including clinical
tests, where appropriate, to determine the safety of the formula and
complete reports on the tests.\" *Nutritional Quality of Infant Formula:
Hearings on H.R. 6590, H.R. 6608, H.R. 5836, and H.R. 5839 Before the
Subcomm. on Health and the Environment of the House Comm. on Interstate
and Foreign Commerce*, 96th Cong. 74 (1980) (Statement of Jere E. Goyan,
Commissioner, Food and Drug Administration). In response to Dr. Goyan\'s
testimony regarding clinical testing, Representative Mottl, co-sponsor
of the bill stated: "\[i\]t is important that we define what we mean
when we speak of testing. When I say testing, I am speaking of analysis
in the chemical and nutritional laboratories, and I am not referring to
clinical trials.\" *Id.* at 120 (Statement of Rep. Mottl, Member, House
Comm. on Interstate and Foreign Commerce).

In addition, the 1996 proposal to define the general quality factor as a
growth study is inconsistent with the "Guidelines Concerning
Notification and Testing of Infant Formulas" incorporated into section
412(c)(2) of the 1986 Amendments to the Infant Formula Act (hereinafter
"1986 Guidelines"; Attachment G). This section of the Infant Formula Act
provides that "for purposes of this paragraph, the term 'major change'
has the meaning given to such term in section 106.30(c)(2) of title 21,
Code of Federal Regulations (as in effect on August 1, 1986), *and*
*guidelines issued thereunder."* FFDCA § 412(c)(2) (*emphasis added)*.
The phrase "*guidelines issued thereunder*" is a direct reference to the
1986 Guidelines. These Guidelines state:

> "FDA has recognized that premarket clinical evaluation in humans may
> be appropriate whenever certain changes affecting the nutritional
> profile of an infant formula are made, particularly in the case of new
> or reformulated products. FDA has also recognized that the degree and
> complexity of the clinical testing needed, will vary according to the
> extent of the changes in the formula. Until guidelines are developed,
> it is therefore understood that the scope of the clinical testing
> necessary for new and reformulated infant formulas will be decided by
> the manufacturer on a case-by-case basis and that the chemical testing
> alone for major reformulation may not be sufficient to determine
> adequacy of the product."

Thus, the key points about clinical testing in the Guidelines were that:

-   FDA anticipated *guidelines* for clinical testing, not mandatory
    requirements (indeed, as FDA had contracted a review by the American
    Academy of Pediatrics, subsequently published in 1988, it is likely
    that the Agency was anticipating AAP's Guidelines);

-   There is acknowledgement that the *degree and complexity* of
    clinical testing would vary,

-   The scope of the testing was to be *decided by the manufacturer*,
    and

-   Testing was to be decided by the manufacturer on a *case-by-case
    basis*.

Importantly, in these Guidelines FDA acknowledges that there *may be* a
need to go beyond chemical and nutritional analyses, as was described in
the legislative history to the IFA, but does not suggest that the Agency
would require a growth study for every change. Unfortunately, there is
no discussion of this important document in the preamble to the 1996
proposed rule. Guidelines written under FDA contract by the American
Academy of Pediatrics (1988) were careful to note that there were many
situations in which a change in the composition of formula would not
generate the need for clinical study, and other situations where the
relevant clinical endpoints would not be growth, but biochemical
indicators of nutritional status. That case-by-case consideration by AAP
seems closer to the 1986 Guidelines than FDA's 1996 proposed rule.

In the 1996 proposal, FDA characterized the growth study recommendations
made in the AAP's guidelines as quality factors. The identification of
quality factors as a synonym for clinical studies seems to have
developed after AAP's Guidelines, because the term "quality factors"
never appears in the AAP document. Besides a routine growth study, FDA
did not propose to make other types of clinical studies that were
described by AAP (e.g., serum chemistries) into quality factors, and
certainly did not define the need for growth studies in the focused way
that AAP did. AAP was careful to limit the scope of testing of a formula
to which a new component is added, noting, "a formula modification does
not require testing of the formula components that are unchanged.\"

**Scientific Issues:** In addition to the absence of any legal basis,
there are meaningful scientific weaknesses to establishing growth as a
quality factor. FDA's proposal would require the manufacturer to conduct
an adequate and well-controlled clinical study to determine whether an
infant formula supports normal physical growth. This methodology is
scientifically ideal to answer the question of whether a new substance
added to an existing formula has an effect on the bioavailability of a
nutrient required for infant growth. However, not every change in an
infant formula raises questions as to infant growth that cannot be
answered adequately by other scientific supportive data. \[Russell J.
Merritt's November 2002 Slide Presentation to FAC (Attachment H); Jon A.
Vanderhoof's November 2002 Slide Presentation to FAC (Attachment I);
Jose M. Saavedra's November 2002 Slide Presentation to FAC (Attachment
J); IFC's "Decision Tree for Documentation of Nutritional Adequacy of a
New or Changed Infant Formula" submitted to the FAC in November 2002
(Attachment K); IFC's "Decision Tree Chart for Documentation of
Nutritional Adequacy of a New or Changed Infant Formula" submitted to
FAC in November 2002 (Attachment L).

FDA is correct to insist that new substances themselves that might be
added to formula be GRAS. The GRAS notification process provides FDA a
venue to raise any safety concerns, including concerns about matrix
issues, processing issues or nutrient interactions. It is at this point
that safety issues, including the potential for impact on growth, need
to be raised and resolved. In order to prevent unnecessary and invasive
clinical study, as much reliance as possible should be placed on animal
studies. Routine growth studies are not designed and generally not
powered to detect rarely occurring adverse events, so are not
comprehensive safety studies. Nor should they be. The law fixes the
composition of all essential nutrients in infant formula. New
ingredients are often substances identified in human milk as having a
nutritional function. A case-by-case review of available evidence can
identify when there is a need for safety endpoints in clinical studies.

**Policy Issues:** As was obvious during the FAC discussions, not enough
is known about what constitutes optimal growth to make it possible to
choose the one perfect standard against which "normal" or "healthy"
growth should be judged. Thus, as a matter of policy, it seems wasteful
and wrong for a science-based Agency to place needless dependence on
growth as an outcome. Focusing on a single outcome causes FDA problems
in being even handed: how can the Agency allow one manufacturer to bring
about an advancement and recover the cost of investment for a formula
innovation, while not allowing all other manufacturers to use the same
ingredient in their formulas. The only answer to FDA is to require each
company to conduct a growth study on the same new substance, justified
under the assertion that the "matrix" used by different manufacturers or
some peculiar nutrient-nutrient interaction could result in one
manufacturer's formula giving a lower growth response. This approach
levels the playing field some, but begs the questions about the ethics
of requiring redundant studies that do not improve public health and
about the Agency's commitment to the protection of human subjects of
scientific studies. Simply put, focusing on quality factors as what they
are meant to be -- indicators of bioavailability or potency -- is far
more sensible and far more consistent with the literal language of the
statute, and helps avoid unnecessary and ethically unjustified testing.

Thus, the Agency should abandon the attempt to define a general quality
factor as a growth study. Quality Factors should remain indicators of
the potency or biological quality of a nutrient as originally defined.
FDA should still have a provision for clinical studies but any
requirement should stem from the language in the 1986 Guidelines. To
this end, IFC proposes to add new regulatory provision in section
106.120 that would clarify the instances in which clinical studies would
be included in a premarket notification for a new infant formula. The
new section 106.120(b)(6) proposed by IFC is modeled after the language
found in the 1986 Guidelines and would incorporate into the regulations
the practices and procedures that have been in place for almost two
decades. As will be discussed in more detail below in our comments to
the new section 106.120(b)(6), a clinical study would be required to
support a premarket notification for a responsible party that has not
previously manufactured infant formula in the United States. The new
provision also would clarify that clinical studies may be necessary when
a current manufacturer or responsible party predicts, based on
experience or theory, that a major change could have a possible
significant adverse impact on bioavailability of nutrients and when
chemical testing or scientific information are unavailable to rule out
such an adverse impact.

In the April 28 Notice, the Agency requested comment on what
requirements the Agency should establish to determine when manufacturers
must conduct clinical growth studies for a new or reformulated infant
formula. (Issue 6a) The 1986 Guidelines provide the industry and the
Agency the instruction to determine on a case-by-case basis when a
clinical study is needed and what the nature of the study is. The new
section proposed by IFC would address the instances when a manufacturer
may conclude that a clinical study should be conducted to support a
major change in formulation. This proposed provision recognizes that a
clinical study is unnecessary when there are other available scientific
information that can predict the impact that the major change will have
on the bioavailability of the nutrients in the formula. \[IFC's "Sample
Clinical Growth Trial Protocol for Healthy Term Infants" submitted to
the FAC in November 2002 (Attachment M)\] This framework provides the
flexibility that is needed to devote clinical research towards its most
productive outcome.

**Summary and Recommendations:** For the legal, scientific and policy
reasons explained above, IFC believes that FDA should not define "normal
growth" as a quality factor. IFC also believes that FDA should delete
the clinical study requirements contained in proposed 106.97(a). IFC
recognizes that there are some instances in which it is appropriate to
include clinical studies in a premarket notification and has proposed a
new section 106.120(b)(6) to address this issue. IFC urges the Agency to
adopt the new 106.120(b)(6) proposed by IFC because this provision
mirrors the language found in the 1986 Guidelines, a guideline that has
been sanctioned by Congress through its incorporation into the Infant
Formula Act. IFC also believes that it would be appropriate for the
Agency to include a statement in the preamble to the final regulation
encouraging interested parties to meet with the Agency when exploring
formulation and other changes to infant formulas for the purpose of
deciding whether a clinical study would be needed and if so, to reach
agreement on the type of study needed. Study design should remain the
responsibility of the manufacturer, but should be mutually agreed to
prior to study initiation.

The Agency also requested comments whether additional quality factors,
specifically for fat, calcium, and phosphorus bioavailability, should be
established. The IFC has provided its comments on this request in its
specific comment to proposed 106.96(c).

##### THIRD ISSUE: CONTROL SYSTEMS AND STORAGE AREAS (FDA's Issue 3a)

A third key issue raised in the FDA's 2003 notice reopening the comment
period -- control systems for raw, in-process and finished materials --
was extensively addressed in our 1996 comments and will again be
addressed in these 2003 comments.

The proposal requires separate storage areas for raw materials,
in-process goods and finished product goods to achieve physical
differentiation for \"pending release,\" \"released\" and
\"quarantine.\" The IFC notes that this is impractical and unwarranted
for the infant formula industry. While the IFC agrees that each
manufacturer must establish an effective system to identify and to
control product during all stages of production, physical separation is
an extreme measure to require and is not justified. The raw materials
for infant formula involve truckloads of bagged ingredients and
packaging materials, as well as tank trucks or railcars of liquid
ingredients. The sheer magnitude of the physical volume of materials,
the monumental warehouse expansion needs and the significant headcount
increases to accommodate the constant movement of materials to areas
designated for the various control categories, would be enormous. In
addition to the resource concerns with this proposal, the constant
movement of such large quantities of materials would surely create
quality problems, including increased risk of contamination and
cross-contamination, spills, damage, etc. Infant formula manufacturers
design, maintain and run their operations to be compliant with food
current good manufacturing practices, 21 CFR 110.20(b)(1). This section
of the regulations states:

> \(b\) *Plant construction and design*. Plant buildings and structures
> shall be suitable in size, construction, and design to facilitate
> maintenance and sanitary operations for food-manufacturing purposes.
> The plant and facilities shall:

(1) Provide sufficient space for such placement of equipment and storage
    of materials as is necessary for the maintenance of sanitary
    operations and the production of safe food.

This current system is working, thus, there is no need to mandate
physical barriers because such barriers are not always necessary. The
manufacturer, when developing the design of the facility, is in the best
position to determine the controls that need to be in place and the
regulations need to maintain this flexibility.

Accordingly, the IFC proposes a quality-based alternative approach in
its specific comments below.

Moreover, in current infant formula manufacturing practice, and
throughout the food industry, systematic control of inventories (raw and
finished) is common and widely used. These systems utilize controls in
addition to or in lieu of strict physical segregation of un-approved and
approved for use materials, in-process substances and finished products.
The utilization of a computer based inventory status control, which
requires that a worker seek out the status of a material prior to use,
coupled with the required checks and verifications, should be sufficient
in controlling the use of an ingredient or raw material. In the
pharmaceutical industry, FDA has recognized this concept since the
1980s. What is important, and should be required, is that the status of
any ingredient or raw material can be easily determined and controlled
-- whether by physical location, status tagging, records, or a
combination thereof. Mandated physical segregation of materials based
(solely) on status would be an unnecessary and unjustified burden upon
the industry, as alternate means of material control have been and are
being successfully employed in other GMP situations.

Comments specific to the other issues raised in the Agency's 2003
reopening announcement, including air filtration systems, calibration
practices and microbiological controls, are included in the Specific
Comments section.

IFC agrees with FDA's decision to remove clinical study protocol
provisions from these proposed regulations (FDA's Issue 7). A number of
comments pertaining to the contemplated Guidance document on clinical
studies are included herein and more detailed comments will be provided
separately at a later date.

**IV. Impact Analysis and Effective Date of the Final Regulation**

The impact analysis included with FDA\'s proposal concludes that infant
formula manufacturers already comply with \"many\" of the requirements
of the proposed rule. FDA\'s assessment of the status of manufacturers\'
compliance with the proposal as of 1996 is relevant not only to the
financial impact of the final regulation, but also to the length of time
that it will take for current manufacturers to achieve compliance with
the final regulation. This premise forms the basis for FDA to adopt an
\"Option 2\" analysis, which incorporates the assumption that the
proposed regulation will be adopted as it was proposed (1996 Proposal at
p. 36202).

Contrary to FDA\'s assessment, the IFC\'s analysis of the proposal has
identified a number of significant proposed provisions with which
manufacturers may not currently be complying with the specifics of the
proposal. These provisions include, but are not limited to, proposed
requirements relating to cold storage, separate physical storage,
validation and setting specifications at the outer limits. Nevertheless,
the FDA concerns covered by the proposed provisions are already being
addressed by current industry practices.

IFC\'s comments include several suggested revisions that could allow
manufacturers to continue to address these concerns with minimal change
to current practice. This will avoid the unnecessary costs and potential
compromises of quality of changing to a different practice where the
desired end\--protection of the public health\-- is already being
achieved. FDA's April announcement of the reopening of the comment
period requested comments on the specific changes in current activities
that would be required for companies to comply with proposal. This is
difficult to summarize, although we have made reference to these
activities throughout our comments.

More importantly, it is unnecessary and unduly burdensome to ask
industry to spend the time necessary to itemize and estimate the cost of
every activity that would have to change, when we can otherwise
demonstrate that there is no need for a particular change. However, in
an effort to be responsive to FDA's request, we have attempted under the
relevant sections to qualitatively identify the relative cost impact of
implementing activities that would have to change. It is important to
recognize that safe high-quality formula is already being regularly
manufactured under current regulations and manufacturing practices.

IFC states once again its strong view that an additional round of notice
and comment is a necessary procedural step to effecting a defensible and
appropriate final regulation. (Refer to II. Specific Objection to April
28, 2003 Notice.) If an additional round of notice and comments is not
granted, the actual time needed to implement the provisions of the final
rule will depend on the number of the significant proposed provisions
which are adopted as final regulations. In some instances, from six
months to several years may be necessary.

Given the extent of the IFC\'s concerns over certain provisions, we are
also troubled that the relatively short time given for comment on this
complex regulation did not enable us to prepare comments that exhibit
the depth of understanding and convey with clarity the needed changes to
the proposal that the industry always strives to present in its comments
to the Agency. As FDA is aware, the infant formula GMP proposal involves
an extremely technical subject, impacts every facet of a complex
manufacturing operation and contains numerous provisions that are
interdependent. Because of the IFC\'s concern about the content and the
effective date of the final regulation, we invite FDA to contact the IFC
if any of the IFC\'s comments are unclear or not fully understood.

**V. Overly Prescriptive/Inflexible Provisions**

In our 1996 comments, we spoke of the Clinton Administration\'s
\"Reinventing Government\" initiative to reduce the economic and other
burdens of overly prescriptive or inflexible regulations. While that
initiative no longer exists, per se, its spirit remains in full force,
particularly with the current Administration's emphasis on
accountability. Application of the spirits of both "Accountability" and
"Reinventing Government" to good manufacturing practice regulations
should dictate that FDA establish the results to be achieved in the
infant formula manufacturing process, but not prescribe or limit the
ways in which the required results can be achieved. Many provisions in
the proposed regulation, unfortunately, are inflexible and overly
prescriptive. In many instances, and without scientific justification,
FDA's proposal mandates the use of only one method to prevent infant
formula adulteration; alternative, equally effective, methods are not
described, compared or permitted. Common sense, as well as
Administrative guidance requires the least burdensome means of
preventing adulteration, which would include allowing alternative
methods of preventing adulteration.

\[See: Robert C. Gelardi's Oral Testimony before the FAC, April 4, 2002
(Attachment N)\]

**VI. "Specifications"**

The effect of the proposed regulations is to require that the outer
limits of acceptability be defined for multiple quality parameters and
that specifications be set at those outer limits. They require in many
places that materials exceeding these limits must be rejected. While
this concept might initially appear to have merit to assure that infant
formula is not distributed unless it is \"within specifications,\" it
does not withstand close scrutiny. It differs significantly from
established control practices, and could lead to less tightly controlled
production practices.

IFC members establish tight internal specifications, much tighter than
the proposed outer acceptability limits. These tight specifications are
intended to and operate to force the manufacturer\'s production controls
to achieve a very consistent finished product. While the objective
during manufacturing is to produce a product that falls within these
tight internal specifications, the failure to do so does not necessarily
mean that the product is in any way adulterated or unfit. Any result
outside the tight, internal specifications triggers formal, documented
review for material disposition decisions. A result outside of these
tight specifications, however, does not trigger automatic rejection,
because these tight internal specifications are set far more narrowly
than the outer acceptability limits.

The IFC believes that setting specifications as defined in the proposed
regulation is ill advised for the following reasons:

a.  Setting specifications at the outer acceptability limits would
    result in the widest possible specification bands. These bands would
    have very little meaning for day-to-day operations, because a
    manufacturer should be encouraged to control its manufacturing
    process tightly. A manufacturer who controlled its process only
    within outer limits could be expected to produce formulas of
    disturbingly variable quality.

b.  Because infant formula manufacturers control processes and set
    specifications well within outer acceptability limits for most
    situations, they have not identified every outer limit for every
    process and product parameter that would result in rejection.
    Implementation of this outer acceptability limit approach with
    \"documentation of the scientific basis for each standard or
    specification,\" as mentioned in the preamble, would require an
    overwhelming amount of technical and administrative resources and
    would require years of effort to complete. Even if these limits were
    finally obtained, their application would be questionable in
    complex, multi-factorial situations. A combination of individual
    results within the outer limits could form the basis of a rejection
    decision if reviewed critically, even though no specific outer
    acceptability limit was exceeded. Under the proposal\'s concept of
    specifications, however, that critical review would not necessarily
    occur. Therefore, it is much more protective to have tighter
    specification limits set, with mandatory documented reviews if they
    are not met, as is the current practice.

c.  Setting tighter specifications than these outer acceptability limits
    is scientifically justified. Reviews for material acceptability
    beyond these tighter specification limits assure the proper
    assessment of each individual situation and serve to aid the
    manufacturer far better than having individual outer acceptability
    limits, which may not be useful in every case. In fact, IFC members
    establish even tighter \"target values\" within specifications where
    the operators will adjust the process if the range limit is
    exceeded. No documented review is necessary in situations where
    results are outside target values, as long as the measured
    parameters are still within current specifications. The approach of
    having target values within specifications, both of which are well
    within any outer acceptability limits, keeps the product and the
    process well centered, tightly controlled and consistent.

d.  If the proposal is enacted, it would represent a significant
    expenditure in time and resources to identify outer limits for
    multiple quality parameters. Such effort would produce no additional
    quality benefits or consumer protection. In fact, operating within
    the outer acceptability limits contemplated by the proposal would
    probably have the undesirable result of manufacture of infant
    formulas with more variable nutrient content and quality
    characteristics. This is a direct contradiction of what a GMP
    regulation should promote.

Therefore, the IFC strongly recommends that the final regulation
preserve the IFC members\' current practice of target values (tight
control ranges), coupled with a review and documentation requirement for
deviations. These practices better serve the interest of achieving
consistent high quality infant formulas. The comments throughout the
remainder of this document reflect this recommended approach.

If, despite the IFC\'s urging, the Agency opts to establish the
definition of \"specification\" at the outer acceptability limits, then
it is strongly recommended that the manufacturers be allowed the
alternative to retain the current tighter control range approach and to
determine whether or not outer acceptability limits need to be
established at each given step in the manufacturing process, as opposed
to making the establishment of outer limits an absolute requirement in
every case.

**VII. Validation: Over-reliance on a "Drug" GMP Model**

IFC previously commented in 1996 that FDA's proposal over-relied on
CDER's drug GMP model as the basis for its proposed infant formula GMP
regulation. Although the comment addressed many provisions in the drug
GMPs that were incorporated in the proposed infant formula GMPs, the
specific element focused upon in the 1996 IFC comments was validation.

It is significant in the context of CFSAN's 2003 reopening of the 1996
infant formula GMPs that seven years have passed and that CDER is in the
process of implementing a significant examination and revaluation of its
drug GMPs under an initiative known as \"Pharmaceutical Current Good
Manufacturing Practices (cGMPs) for the 21st Century: A Risk Based
Approach.\" FDA summarized the initiative as follows:

> On August 21, 2002, FDA announced a major new initiative on the
> regulation of drug product quality. The two-year program, which
> applies to human drugs and biologics and veterinary drugs, has several
> ambitious objectives. One is to ensure that regulatory review and
> inspection policies are based on state-of-the-art pharmaceutical
> science and to encourage the adoption of new technological advances by
> the pharmaceutical industry. FDA will determine the best pathway to
> better integrate advances in quality management techniques, including
> quality systems approaches, into the Agency\'s regulatory standards
> and systems for the review and inspection processes. Additionally,
> risk-based approaches, that focus both industry and Agency attention
> on critical areas, will be implemented. Finally, enhancements to the
> consistency and coordination of Agency drug quality regulatory
> programs will be made. FDA Press Release
> (http://www.fda.gov/cder/gmp/21stcenturysummary.htm)

The IFC submits that FDA's current risk based drug GMP initiative may be
a model from which infant formula GMPs may benefit. The IFC suggests
that the infant formula industry partner with CFSAN, in much the same
way that CDER, CBER and CVM are partnering with the industries they
regulate to arrive at risk-based GMPs that accomplish the objectives of
"Pharmaceutical Current Good Manufacturing Practices (cGMPs) for the
21st Century: A Risk Based Approach."

The balance of this general comment will, like the IFC's 1996 comment,
focus on the validation requirements of the reopened proposal. The IFC's
1996 comments stated that the validation section in proposed section
106.35 was so vague and the impact so enormous that implementing it,
without engaging the efforts of an extensive interactive task force
(composed of both industry and FDA personnel) would be unwise. In
proposed section  106.35(a)(4) the Agency proposed that, for purposes of
the section, "validation" means establishing documented evidence that
provides a high degree of assurance that a system will consistently
produce a product meeting its predetermined specifications and quality
characteristics. In proposed section 106.35(b)(1), FDA proposed that all
automatic systems be designed, installed, tested, and maintained in a
manner that will ensure that they are capable of performing their
intended function. While these provisions are capable of an
interpretation appropriate to infant formula, they are also capable of
an interpretation more appropriate to pharmaceutical manufacture. In the
absence of some assurance to the contrary, IFC was concerned that an
inappropriate drug-style interpretation might prevail.

It is imperative that drugs contain the precise amount of active
ingredient to achieve efficacy in treating illness. Moreover, most
\"drugs,\" even if manufactured properly, are potentially toxic.
Therefore, because their margin of safety can be so critical, their
manufacture requires far more critical tolerances than do infant
formulas. Accordingly, it is important not blindly to take the historic
\"drug\" approach in proposing regulations for infant formula. For
instance, requiring strict \"drug-like\" validation and revalidation of
systems used to manufacture infant formula would be extremely costly,
unnecessarily burdensome and a disincentive for process improvements
(i.e., improvements may not be implemented simply because of the burden
of complex re-validation).

One of the purposes of systems validation is to lessen the need to rely
on finished product testing to establish the acceptability of the
finished product as stated in the May, 1987 [Guideline on General
Principles of Process Validation]{.underline}: \"Successfully validating
a process may reduce the dependence upon intensive in process and
finished product testing.\" But, lessening of testing does not justify
validation of systems used to manufacture infant formulas, because
validation will not lessen the extensive, legally mandated testing
burden for infant formula. The nutrient content of infant formulas is
mandated by the Infant Formula Act, as is testing for each of those
mandated nutrients in each batch of infant formulas (by validated
methods if the IFC\'s comments to proposed 106.91(a)(4) are accepted).
Thus, compliance of infant formulas with the required nutrient levels is
currently achieved without the imposition of extensive drug-like
validation requirements, and extensive validation requirements will
provide no greater assurance of compliance.

The Agency has proposed an all-encompassing definition of
\"validation.\" As seen in the pharmaceutical industry, excessive
validation requirements forced manufacturers to minimize process
improvements and quality and product innovations. If applied to infant
formula manufacturers, it would result in substantial lost capacity and
may close the doors to many potential new manufacturers. This degree of
validation is well beyond the scope that has been applied even in the
drug industry. It would cost many millions of dollars to accomplish and
would require a time frame to achieve compliance measured in years.
Neither the industry nor consumers are ready for such an exhaustive and
unwarranted burden, which would entail significant additional costs to
infant formula manufacturing without any additional consumer protection.

Contrasted to the manufacture of drugs, which involves relatively simple
formulations and processes, infant formula manufacturing involves
several times the number of pieces of equipment and software to produce
the finished product. Thus, applying drug-type validation requirements
on the infant formula industry will have a very heavy cost impact. This
is contrary to one of the purposes of the regulations stated by the
Agency in the preamble \-- to allow potential new competition, without
huge, burdensome financial impact.

Having carefully considered the industry's experience over the last 7
years with validated processes and systems, IFC has refined its thinking
on the proposed requirements. The industry remains of the view that the
indiscriminate and across-the-board requirement of validation is
inappropriate. Nevertheless, IFC clearly recognizes that validation of
critical systems can be a valuable quality assurance tool for the infant
formula manufacturer. Infant formula manufacturers are already
validating systems and procedures based upon a risk-based criticality
assessment. IFC believes that the Agency should recognize and accept a
tiered approach to validation including such other concepts as
verification, qualification, capability studies, challenge testing, and
operational testing. For example, HACCP involves both risk-based
criticality assessment and other documented levels of control. Each
company should decide the levels of validation required, based upon the
degree of criticality of each system to assuring the safety and quality
of the infant formula produced. The Agency's April announcement of the
reopening of the comment period asked how often manufacturers validate
their systems. It is impossible to respond to this in any quantified
manner, but it can be said that systems that manufacturers deem critical
are revalidated whenever they undergo any significant change.

Manufacturers may use a variety of qualification and validation
processes prior to release of commercial product to assure that systems
and procedures can produce acceptable quality product on an ongoing
basis. ("Acceptable quality" product is that product that meets
manufacturer specifications and the requirements of the FFDCA). These
activities identify the systems involved in the manufacture of a given
infant formula product and characterize the criticality of each system
based on its potential for product impact. Using specifications and
quality characteristics, test plans based on the categorized systems are
developed, testing is completed, results are documented, and commercial
product release is based on compliance. Changes or modifications to the
existing qualified systems and validated processes occur following a
formal documented review of the proposed changes to establish potential
product impact and to respond with the appropriate validation activity.

The Agency also proposed in 1996 that systems be validated before their
first use to manufacture commercial product. IFC believes that this
aspect of the provision is overly stringent, since any product produced
during a validation run that met release criteria should be eligible for
commercial release. As proposed, the rule would arbitrarily and
capriciously require that whole batches of infant formula, worth up to
hundreds of thousands of dollars each, be produced solely for validation
purposes, only to be discarded. The cost impact across the industry of
this aspect of the rule would be huge. Even in the rigid world of drug
validation, "concurrent validation" is accepted by the Agency and would
allow for the release of validation batches that otherwise met release
criteria.

As we stated in our 1996 comments, the validation section is "so vague,
as presently proposed, and the impact is so enormous that implementing
106.35 would be counterproductive unless significant further dialogue
with the Agency to acquire a mutual understanding of this concept takes
place." Therefore, if the Agency persists in its belief that validation
should be employed by the infant formula industry, the IFC recommends
that the Agency and the industry form a working task force to define the
scope and content of risk-based systems validation for infant formula.
Such definitions would be limited to hardware and software for
applications that are critical to the manufacture of infant formula, and
would exclude non-critical systems. Through such a task force, the
Agency will be able to assess the cost impact and the degree of industry
resources and time necessary to attain compliance. This type of
cooperative approach involving a working team of FDA and industry
representatives has been previously employed for Low Acid Canned Food
matters and for the current 1986 Guidelines, and would be appropriate in
this subject area as well.

**VIII. Recordkeeping: The Regulation Should Focus on "Necessary"
Documents**

The proposed documentation requirements are very burdensome. They would
certainly necessitate additional staffing to implement, but it is
difficult to quantify this cost without further clarification.
Similarly, it is not possible to comment further on the estimated annual
recordkeeping burden until these regulations are finalized.

However, the IFC believes the required records should be limited overall
to focus on and incorporate the statutory reference to \"necessary\"
documents, rather than the broad \"including but not limited to\"
language of the proposal. The IFC\'s suggested revisions reflect this
approach. Also, the IFC recommends that the final regulation reflect the
acceptability of electronic recordkeeping.

**IX. Proposed Definition of "Manufacturer"**

The proposed definition of \"manufacturer\" will result in multiple and
overlapping responsibilities, recordkeeping, and notifications to FDA
whenever co-packers are involved in the manufacture of infant formula.
The IFC does not believe that duplicate responsibilities for the same
activity serve any purpose in the majority of proposed requirements, and
suggests that the concept of \"responsible party\" be introduced to
eliminate duplication. If the IFC's recommendations are accepted, for
certain requirements, the responsible party will replace the
manufacturer completely, in order to avoid duplication and to fix actual
responsibility appropriately. For other requirements, the responsible
party is suggested as a possible alternative to the manufacturer, so
that the parties involved may decide what is appropriate.

For the purpose of \"registration," alone, IFC believes that it will
serve FDA\'s purpose (e.g., inspections and counterfeit formula
surveillance) to require registration by all parties involved in any
aspect of infant formula manufacturing.

**X. Notification of "Adulteration" or "Misbranding"**

A violation of the final infant formula GMP, no matter how minor or
inconsequential, will constitute a \"technical adulteration or
misbranding\" of the product. In turn, adulteration and misbranding of
products potentially triggers FDA\'s full enforcement arsenal. While
FDA\'s enforcement discretion can temper the deployment of this arsenal,
unique provisions of the law applicable only to infant formula require
close examination. In the realm of food providers, infant formula
manufacturers alone are required to notify FDA when distributed products
are \"adulterated\" or \"misbranded.\" Thus, it is critical to weigh
each proposed regulation for the consequences of a finding of
\"adulteration\" or "misbranding" to ensure that they are appropriate.

Key to the appropriate application of infant formula GMPs is that only a
finding of the type of adulteration of significance to public health
should trigger a given consequence. Likewise, only significant or
actionable misbranding situations should trigger notification. Thus,
when the 1986 amendments were enacted, Senator Hatch stated that
\"technical violations\" should not trigger notification or recall:

\"We didn\'t feel that notification or recalls should be required in all
cases which might constitute a technical adulteration or misbranding,
but, rather, felt that an actual rather than theoretical risk to human
health must exist\....\" (Cong. Record \-- Senate, Sept. 27, 1986, p.
S14047)

Echoing Senator Hatch, Senator Metzenbaum said that it was not the
intention of Congress:

\"that formula be deemed adulterated or that the submission requirement
\... or the notification requirement \... be triggered by violations
such as clerical lapses, unless of course they are of such a nature as
may affect the quality or content of the formula.\" (Id. at S14046).

Senator Metzenbaum concluded by directing FDA to distinguish one variety
of violation from the other in regulations or guidelines. It is
important for the final GMP regulations to reflect this legislative
intent so that minor, technical violations do not trigger frequent
notifications when the quality or content of infant formula is not
conceivably compromised.

**XI. Redundancy**

Another objective of \"Reinventing Government\" that the current
Administration has apparently ratified is to reduce the number of
redundant and/or meaningless regulations. Numerous activities proscribed
or mandated by the proposed infant formula GMPs are already proscribed
or mandated by the current Food GMPs and/or other existing FDA
regulations. These include personnel requirements, and the permitted use
of food ingredients and food-contact materials. Such redundancies do not
provide the public with any greater protection. They serve only to
create unnecessary confusion in those plants manufacturing both infant
formulas and similar products not intended for use by infants, at the
same time that they contravene Administrative guidance.

FDA\'s specific stated intent in promulgating the Food GMPs was to have
those regulations function as \"umbrella\" regulations. Additional
regulations, targeted at specific industries, were contemplated under
the Food GMP umbrella. (See 51 F.R. 22459 (June 19, 1986), comment 3)
Consistent with this expressed intention, and to avoid duplication
consistent with President Clinton\'s mandate, we recommend that any
duplicate requirements be eliminated from the infant formula GMP
regulations. The public may rest assured that infant formula
manufacturers are already sufficiently guided by the presence of these
provisions under the Food GMP umbrella regulations.

**XII. Infant Formula Submission Review by FDA**

IFC also wishes to express the need for FDA to establish and make known
a well-defined, transparent and practical process for the receipt,
review and disposition of various submissions from industry. Such an
agency process needs to have clearly defined aspects, such as time
lines, how a submission is reviewed and by whom, and, importantly, a
response and dialogue process with the submitter in addressing Agency
interests. This process is necessary for ethical industry to be able to
plan and implement infant formula advancements in a reasonable and
mutually cooperative manner.

The Agency has made significant strides in providing acknowledgment
letters in a timely manner, in identifying an appropriate contact for
follow-up questions on a given submission, and in overcoming their
previous reluctance to discuss submissions while they are under review.
More progress is needed in most of these areas, however, and also in
providing greater clarification, as to which types of substantive
additions to a submission will cause the 90-day clock to start ticking
all over again, versus which will be considered helpful in completing
the initial review within the statutory time period.

**XIII. FDA\'s Means to Assure the Safety and Availability of New and
Improved Infant Formulas \-- Premarket Notification Not Premarket
Approval**

FDA and infant formula manufacturers share the responsibility of
carrying out the intention of Congress to assure that new and improved
infant formulas reach the public expeditiously. Congress was clear that
it envisioned premarket notifications to FDA, but not a premarket
approval process:

\"When Mr. Metzenbaum\'s earlier amendment was approved by the Senate,
it contained a provision which would have required a premarket approval
by the Secretary for new or altered formulas. The FDA has since made a
strong case that a premarket approval is not desirable in this instance.
FDA points out that the burden to produce a safe and effective formula
should remain squarely on the shoulders of the manufacturer.\"
(Congressional Record \-- Senate, September 27, 1986, p. S14046)

Consistently, Mr. Hatch stated the following on the record:

\"I also agree with the FDA that premarket approval is not desirable in
this instance and understand that the \[notification\] procedure is not
intended to become a precursor of such FDA action.\" (*Id.* at S14047)

Thus, the notification requirement was intended by Congress as a means
of assuring consumers a reasonable standard of safety while not
unreasonably burdening the industry through a potentially cumbersome
system of premarket clearance. \[See: Senate Committee on Labor and
Human Resources Report, No.96-916: The Infant Formula Act, p.6\]

There are several provisions in the GMP proposal that exceed the
premarket notification structure intended by Congress when it enacted
the 1986 Infant Formula Act Amendments.

The Framers of the Infant Formula Act intended the line between
premarket notification and premarket approval to be bright. To this end,
Congress took the extraordinary, in fact unique, step to develop and
codify nutrient specifications. For formulas, FDA's role in the
premarket notification process was perceived by Congress as comprising
the task of confirming that the required specifications are met for each
new or significantly modified formula.

To ensure that this important review function did not evolve into a
premarket approval evaluation, Congress channeled the Agency's
substantive authority under section 412 to apply only to those elements
necessary to ensure that a Syntex/NeoMulsoy nutrient deficiency scenario
never occurs again. Over the years, the practices and procedures FDA has
followed in reviewing section 412 notifications have consistently taken
on more and more of the trappings of premarket approval systems quite
different from the limited, precise review function contemplated in the
statutory scheme.

FDA has so proceeded even though, Congress, when it amended the Infant
Formula Act in 1986, rejected premarket approval for infant formulas.
Instead, in order to assure the nutritional integrity of infant formula,
Congress granted FDA express authority to enact GMPs, require record
development and maintenance, and impose in-process controls. All of
these requirements were designed to help ensure the nutritional quality
of formula and, thus, avoid the marketing of a nutrient-deficient
formula. Tellingly, the resulting statutory scheme carefully avoids any
form of preclearance or premarket approval role for FDA and, instead,
focuses on the role of 1) establishing standards and practices
manufacturers must follow and 2) documenting compliance. As FDA
approaches accomplishing the statutory goal of enacting workable GMP
requirements and, in the process, enhancing the nutritional quality of
formulas, it commensurately must turn its attention to revising its
practices to better achieve the statute's goal of premarket notification
bereft of unauthorized and unwarranted premarket approval attributes.

**IFC'S SPECIFIC COMMENTS TO FDA'S PROPOSAL**

  -----------------------------------------------------------------------
  FDA Proposed Regulation             IFC Suggested Language
  ----------------------------------- -----------------------------------
  **Part 106\--INFANT                 **Part 106\--INFANT
  FORMULA\--REQUIREMENTS PERTAINING   FORMULA\--REQUIREMENTS PERTAINING
  TO CURRENT GOOD MANUFACTURING       TO CURRENT GOOD MANUFACTURING
  PRACTICE, QUALITY CONTROL           PRACTICE, QUALITY CONTROL
  PROCEDURES, QUALITY FACTORS,        PROCEDURES, QUALITY FACTORS,
  RECORDS AND REPORTS, AND            RECORDS AND REPORTS, AND
  NOTIFICATION**                      NOTIFICATION**

  **106.1 Status and applicability of **106.1 Status and applicability of
  the regulations in part 106.**      the regulations in part 106.**

  106.1(a) The criteria set forth in  Acceptable as proposed.
  subparts B, C, and D of this part   
  prescribe the steps that            
  manufacturers must take under       
  section 412(b)(2) and (b)(3) of the 
  Federal Food, Drug, and Cosmetic    
  Act (the act) in processing infant  
  formula. If the processing of the   
  formula does not comply with any    
  regulation in subparts B, C, or D   
  of this part, the formula will be   
  deemed to be adulterated under      
  section 412(a)(3) of the act.       

  106.1(b) The criteria set forth in  Acceptable as proposed.
  subpart E of this part prescribe    
  the quality factor requirements     
  that infant formula must meet under 
  section 412(b)(1) of the act. If    
  the formula fails to comply with    
  any regulation in subpart E of this 
  part, it will be deemed to be       
  adulterated under section 412(a)(2) 
  of the act.                         

  106.1(c) The criteria set forth in  Acceptable as proposed.
  subpart F of this part implement    
  the record retention requirements   
  established in section 412(b)(4) of 
  the act. Failure to comply with any 
  regulation in subpart F of this     
  part is a violation of section      
  301(e) of the act.                  

  106.1(d) The criteria set forth in  Acceptable as proposed.
  subpart G of this part describe the 
  circumstances in which infant       
  formula manufacturers are required  
  to register with, submit to, or     
  notify the Food and Drug            
  Administration, and the content of  
  those registrations, submissions,   
  or notifications, under section     
  412(c), (d), and (e) of the act.    
  Failure to comply with any          
  regulation in subpart G of this     
  part is a violation of section      
  301(s) of the act.                  
  -----------------------------------------------------------------------

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **106.3 Definitions.**            | **106.3 Definitions.**            |
|                                   |                                   |
| 106.3(a) Batch means a specific   | 106.3(a) Batch means a specific   |
| quantity of an infant formula or  | quantity of an infant formula     |
| other material that is intended   | that is intended to have uniform  |
| to have uniform character and     | composition, character and        |
| quality, within specified limits, | quality, and is produced          |
| and is produced according to a    | according to a master             |
| single manufacturing order during | manufacturing order during the    |
| the same cycle of manufacture.    | same cycle of manufacture.        |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.3(a) Batch means a specific quantity of an infant formula ~~or other
material~~ that is intended to have uniform [composition]{.mark},
character and quality, ~~within specified limits~~, and is produced
according to a [master]{.mark} ~~single~~ manufacturing order during the
same cycle of manufacture.

IFC Comment

IFC is unsure what is meant by \"or other material\" in the context of
this proposal and has suggested striking it from the definition of
batch, but using it in the definition of \"lot\" in 106.3(g) and (h).
The word \"composition\" adds to the accepted concept of the
characteristics of a batch.

See the IFC\'s General Comment concerning Specifications for the
rationale to strike \"within specified limits.\" In addition to the
rationale in that General Comment, the phrase creates a substantive
requirement that could cause confusion if contained in a definition.
Whether a batch meets specified limits relates to the disposition of the
batch (as a substantive matter), not to whether it is a batch (a
definitional matter). Currently Specifications for products are set
based on research and clinical studies. Because infant formula
manufacturers control processes and set specifications well inside outer
acceptability limits for most situations, they have not identified every
outer limit for every process and product parameter that would result in
rejection. Implementation of this outer acceptability limit approach
with \"documentation of the scientific basis for each standard or
specification,\" as mentioned in the preamble, would require an
overwhelming amount of technical and administrative resources and would
require years of effort to complete. Extensive resources would be needed
for additional personnel for research, analytical testing and
manufacturing to evaluate each new product to the limits of
acceptability. This would have a large impact on resources and would not
provide any additional safety factor for the consumer. Additionally, if
each specification needs to be tested to failure, the cost would prevent
or severely limit new product development. Moreover, even if these
limits of acceptability were identified, their application would be
questionable in complex, multi-factorial situations. That such a
requirement is unnecessary can be seen by the fact that current
formulation policy and release procedures required by regulation ensure
the release of product that routinely meets infant formula standards.

Finally, the IFC has suggested changing \"single\" to \"master.\" The
definition should not suggest that a manufacturing order for in-process
adjustments, undertaken so that the batch meets nutritional
requirements, might contravene the definition.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+===================================+===================================+
| 106.3(b) Final‑product‑stage      | Acceptable as proposed.           |
| means the point in the            |                                   |
| manufacturing process, before     | Acceptable as proposed.           |
| distribution of an infant         |                                   |
| formula, at which the infant      | Acceptable as proposed.           |
| formula is homogeneous and is not |                                   |
| subject to further degradation    | Acceptable as proposed.           |
| due to processing                 |                                   |
|                                   |                                   |
| 106.3(c) Indicator nutrient means |                                   |
| a nutrient whose concentration is |                                   |
| measured during the manufacture   |                                   |
| of an infant formula to confirm   |                                   |
| complete addition and uniform     |                                   |
| distribution of a premix or other |                                   |
| substance of which the indicator  |                                   |
| nutrient is a part.               |                                   |
|                                   |                                   |
| 106.3(d) Infant means a person    |                                   |
| not more than 12 months of age.   |                                   |
|                                   |                                   |
| 106.3(e) Infant formula means a   |                                   |
| food which purports to be or is   |                                   |
| represented for special dietary   |                                   |
| use solely as a food for infants  |                                   |
| by reason of its simulation of    |                                   |
| human milk or its suitability as  |                                   |
| a complete or partial substitute  |                                   |
| for human milk.                   |                                   |
+-----------------------------------+-----------------------------------+
| 106.3(f) In‑process batch means a | Acceptable as proposed.           |
| combination of ingredients at any |                                   |
| point in the manufacturing        |                                   |
| process before packaging.         |                                   |
+-----------------------------------+-----------------------------------+
| 106.3(g) Lot means a batch, or a  | 106.3(g) Lot means a batch, a     |
| specifically identified portion   | specifically identified portion   |
| of a batch, having uniform        | of a batch, or other material     |
| character and quality within      | having uniform composition,       |
| specified limits; or, in the case | character and quality; or, in the |
| of an infant formula produced by  | case of an infant formula         |
| continuous process, it is a       | produced by continuous process,   |
| specific identified amount        | it is a specific identified       |
| produced in a unit of time or     | amount produced in a unit of time |
| quantity in a manner that assures | or quantity in a manner that      |
| its having uniform character and  | assures its having uniform        |
| quality within specified limits.  | composition, character and        |
|                                   | quality.                          |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.3(g) Lot means a batch, ~~or~~ a specifically identified portion of
a batch, [or other material]{.mark} having uniform [composition]{.mark},
character and 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 [composition]{.mark}, character and
quality ~~within specified limits~~.

IFC Comment

See the IFC\'s Specific Comment to proposed 106.3(a). The IFC believes
that the phrase \"or other material\" in this definition encompasses raw
material lots, etc. better than it does in the definition of \"batch.\"

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.3(h) Lot number, control      | Acceptable as proposed.           |
| number, or batch number means any |                                   |
| distinctive combination of        | Acceptable as proposed.           |
| letters, numbers, symbols, or any |                                   |
| combination of them, from which   |                                   |
| the complete history of the       |                                   |
| manufacture, processing, packing, |                                   |
| holding, and distribution of a    |                                   |
| batch or lot of infant formula or |                                   |
| other material can be determined. |                                   |
|                                   |                                   |
| 106.3(i) Major change in an       |                                   |
| infant formula means any new      |                                   |
| formulation, or any change of     |                                   |
| ingredients or processes where    |                                   |
| experience or theory would        |                                   |
| predict a possible significant    |                                   |
| adverse impact on levels of       |                                   |
| nutrients or bioavailability of   |                                   |
| nutrients, or any change that     |                                   |
| causes an infant formula to       |                                   |
| differ fundamentally in           |                                   |
| processing or in composition from |                                   |
| any previous formulation produced |                                   |
| by the manufacturer. Examples of  |                                   |
| infant formulas deemed to differ  |                                   |
| fundamentally in processing or in |                                   |
| composition include:              |                                   |
+-----------------------------------+-----------------------------------+
| 106.3(i)(1) Any infant formula    | Acceptable as proposed.           |
| produced by a manufacturer who is |                                   |
| entering the U.S. market;         |                                   |
+-----------------------------------+-----------------------------------+
| 106.3(i)(2) Any infant formula    | Acceptable as proposed.           |
| powder processed and introduced   |                                   |
| for commercial or charitable      |                                   |
| distribution by a manufacturer    |                                   |
| who previously only produced      |                                   |
| liquids (or vice versa);          |                                   |
+-----------------------------------+-----------------------------------+
| 106.3(i)(3) Any infant formula    | Acceptable as proposed.           |
| having a significant revision,    |                                   |
| addition, or substitution of a    |                                   |
| macronutrient (i.e., protein,     |                                   |
| fat, or carbohydrate), with which |                                   |
| the manufacturer has not had      |                                   |
| previous experience;              |                                   |
+-----------------------------------+-----------------------------------+
| 106.3(i)(4) Any infant formula    | Acceptable as proposed.           |
| manufactured on a new processing  |                                   |
| line or in a new plant;           |                                   |
+-----------------------------------+-----------------------------------+
| 106.3(i)(5) Any infant formula    | 106.3(i)(5) Any infant formula    |
| manufactured containing a new     | manufactured containing a new     |
| constituent not listed in section | nutrient not listed in section    |
| 412(i) of the act, such as        | 412(i) of the act, such as        |
| taurine or L-carnitine;           | taurine or L-carnitine;           |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.3(i)(5) Any infant formula manufactured containing a new
[nutrient]{.mark} ~~constituent~~ not listed in section 412(i) of the
act, such as taurine or L-carnitine;

IFC Comment

We believe that the use of the term "nutrient" is much more consistent
with the purpose of the Infant Formula Act: the assurance of proper
nutrition. The Agency's proposed language, "new constituent," opens the
scope of section 412. "New constituent" is clearly overbroad and could
render, as a major change, a wholly and harmless innocuous new
constituent at nominal levels and, furthermore, is beyond the basic
scope of Section 412: The Assurance of Nutritional Adequacy.

Additionally, FDA's April announcement of the reopening of the comment
period requested comments on the specific changes in current activities
that would be required for companies to comply with the proposal. Infant
formula manufacturers currently provide a submission when a new nutrient
is added to the product. If the new regulations require that any new
constituent renders a formulation a "new formula" or "major change",
this would significantly increase the number of filings that would need
to be developed -- each requiring a 90-day review period. This would
result in additional resources being expended at both the manufacturer
and within FDA with no added benefit to the consumer.

The term \"constituent\" alone is problematic, as it could make a
\"major change\" of what would truly be a \"minor change\" (e.g., a
change in emulsifier). The phrase suggested by the IFC eliminates this
potential result, while continuing to convey the examples listed by FDA
in the proposed language.

+---------------------------------+------------------------------------+
| FDA Proposed Regulation         | IFC Suggested Language             |
+---------------------------------+------------------------------------+
| 106.3(i)(6) Any infant formula  | Acceptable as proposed.            |
| processed by a manufacturer on  |                                    |
| new equipment that utilizes a   | Acceptable as proposed.            |
| new technology or principle     |                                    |
| (e.g., a change from terminal   |                                    |
| sterilization to aseptic        |                                    |
| processing); and                |                                    |
|                                 |                                    |
| 106.3(i)(7) An infant formula   |                                    |
| for which there has been a      |                                    |
| fundamental change in the type  |                                    |
| of packaging used (e.g.,        |                                    |
| changing from metal cans to     |                                    |
| plastic pouches).               |                                    |
+---------------------------------+------------------------------------+

  ---------------------------------- ------------------------------------
  FDA Proposed Regulation            IFC Suggested Language

  None.                              106.3(j) Minor change in an infant
                                     formula means any new formulation,
                                     or any change of ingredients or
                                     processes where experience or theory
                                     would not predict a possible
                                     significant adverse impact on
                                     nutrient levels or nutrient
                                     availability. Minor changes may or
                                     may not affect whether a formula is
                                     adulterated under section 412(a) of
                                     the Act; changes that affect whether
                                     a formula is adulterated under
                                     section 412(a) of the Act would
                                     require the manufacturer to notify
                                     FDA prior to first processing.

                                     106.3(j)(1) Examples of minor
                                     changes to infant formulas that
                                     require notification prior to first
                                     processing include:

                                     106.3(j)(1)(i) Reduction of a
                                     nutrient that results in a label
                                     change, change in a nutrient level
                                     which is within 10% of the nutrient
                                     levels, minimum or maximum required
                                     by Section 412(g) of the FFDCA and
                                     is at least 10% closer to the
                                     required level;

                                     106.3(j)(1)(ii) Any change in the
                                     identity of the ingredients
                                     providing nutrients required under
                                     section 412 (g) of the Act or trace
                                     nutrients added voluntarily
                                     consistent with 21 CFR 107.10(b)(5);

                                     106.3(j)(1)(iii) Any design change
                                     in the formulation or processing of
                                     an infant formula which the
                                     manufacturer determines calls for
                                     non-routine nutrient testing prior
                                     to release, for the purpose of
                                     determining whether a possible
                                     change has occurred in the levels of
                                     nutrients in meeting requirements of
                                     Section 412(g) of the Act.

                                     106.3(j)(2) Examples of minor
                                     changes to infant formulas that do
                                     not require notification prior to
                                     first processing include:

                                     106.3(j)(2)(i) Minor reduction of
                                     iron level;

                                     106.3(j)(2)(ii) Replacing certain
                                     nutrient forms with another form;

                                     106.3(j)(2)(iii) Adjustments in the
                                     quantity of a nutrient in a premix
                                     or individually added nutrient that
                                     results in a specification change
                                     for that nutrient in the finished
                                     product;

                                     106.3(j)(2)(iv) Changes in
                                     time-temperature conditions of
                                     preheating during handling of bulk
                                     product that cannot reasonably be
                                     expected to cause an adverse impact
                                     on nutrient levels or nutrient
                                     availability;

                                     106.3(j)(2)(v) Changes in oxygen
                                     content of a packaged product that
                                     might have minimal effect on the
                                     level of nutrients.
  ---------------------------------- ------------------------------------

IFC Redlined Version

[106.3(j) Minor change in an infant formula means any new formulation,
or any change of ingredients or processes where experience or theory
would not predict a possible significant adverse impact on nutrient
levels or nutrient availability. Minor changes may or may not affect
whether a formula is adulterated under section 412(a) of the Act;
changes that affect whether a formula is adulterated under section
412(a) of the Act would require the manufacturer to notify FDA prior to
first processing.]{.mark}

[106.3(j)(1) Examples of minor changes to infant formulas
include:]{.mark}

[]{.mark}

[106.3(j)(1)(i) Reduction of a nutrient that results in a label change,
change in a nutrient level which is within 10% of the nutrient levels,
minimum or maximum required by Section 412(g) of the FFDCA and is at
least 10% closer to the required level;]{.mark}

[106.3(j)(1)(ii) Any change in the identity of the ingredients providing
nutrients required under section 412 (g) of the Act or trace nutrients
added voluntarily consistent with 21 CFR 107.10(b)(5);]{.mark}

[]{.mark}

[106.3(j)(1)(iii) Any design change in the formulation or processing of
an infant formula which the manufacturer determines calls for
non-routine nutrient testing prior to release, for the purpose of
determining whether a possible change has occurred in the levels of
nutrients in meeting requirements of Section 412(g) of the Act.]{.mark}

[]{.mark}

[106.3(j)(2) Examples of minor changes to infant formulas that do not
require notification prior to first processing include:]{.mark}

[]{.mark}

[106.3(j)(2)(i) Minor reduction of iron level;]{.mark}

[]{.mark}

[106.3(j)(2)(ii) Replacing certain nutrient forms with another
form;]{.mark}

[]{.mark}

[106.3(j)(2)(iii) Adjustments in the quantity of a nutrient in a premix
or individually added nutrient that results in a specification change
for that nutrient in the finished product;]{.mark}

[]{.mark}

[106.3(j)(2)(iv) Changes in time-temperature conditions of preheating
during handling of bulk product that cannot reasonably be expected to
cause an adverse impact on nutrient levels or nutrient
availability;]{.mark}

[]{.mark}

[106.3(j)(2)(v) Changes in oxygen content of a packaged product that
might have a minimal effect on the level of nutrients.]{.mark}

IFC Comment

The 1996 Proposal omitted any mention of "minor change." The current
regulations, however, define "minor change" in 21 CFR 106.30(c)(1) as
follows:

> A minor change is a minor reduction in nutrient levels, a minor
> increase in levels of nutrients that are subject to maximum limits
> established under section 412(g) of the Act or in regulations
> established under section 413(a)2) of the Act, or any other change
> where experience or theory would not predict a possible significant
> adverse impact on nutrient levels or nutrient availability. After a
> minor change the manufacturer shall analyze representative samples for
> all nutrients so changed and those possibly affected by the change.

In addition to this definition, FDA years ago issued guidance (currently
available on the Agency's website) that the industry has routinely
followed in assessing whether a change is major or minor. By omitting
the minor change concept entirely, the 1996 proposal produced
unnecessary confusion on the part of industry and, we believe, has
resulted in inconsistent positions on the part of the Agency regarding
the factors and considerations that govern a determination of whether
and when a notification required under the Infant Formula Act must be
submitted. The definition of "minor change" suggested above incorporates
the concepts articulated by the FDA in its 1986 Guidelines. The
definition will provide needed clarification.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.3(j) Manufacturer means a       Acceptable; Renumbered as 106.3(k).
  person who prepares, reconstitutes, 
  or otherwise changes the physical   
  or chemical characteristics of an   
  infant formula or packages or       
  labels the product in a container   
  for distribution.                   

  106.3(k) Microorganisms means       Delete.
  yeasts, molds, bacteria, and        
  viruses and includes, but is not    
  limited to, species having public   
  health significance.                
  ----------------------------------- -----------------------------------

#########  IFC Redlined Version

106.3(~~j~~[k]{.mark}) Manufacturer means a person who prepares,
reconstitutes, or otherwise changes the physical or chemical
characteristics of an infant formula or packages or labels the product
in a container for distribution.

~~106.3(k) Microorganisms means yeasts, molds, bacteria, and viruses and
includes, but is not limited to, species having public health
significance.~~

IFC Comment

See the IFC\'s General Comment regarding Redundancy. This definition of
\"Microorganisms\" is identical to the definition in the Food GMPs
(110.3(i)), which are also applicable to the manufacture of infant
formulas.

**Rest of page intentionally left blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.3(l) New infant formula       | Acceptable as proposed.           |
| means:                            |                                   |
|                                   | Acceptable as proposed.           |
| \(1\) An infant formula           |                                   |
| manufactured by a person that has | Acceptable as proposed.           |
| not previously manufactured an    |                                   |
| infant formula for the U.S.       |                                   |
| market, and                       |                                   |
|                                   |                                   |
| \(2\) An infant formula           |                                   |
| manufactured by a person that has |                                   |
| previously manufactured infant    |                                   |
| formula and in which there is a   |                                   |
| major change in processing or     |                                   |
| formulation from a current or any |                                   |
| previous formulation produced by  |                                   |
| such manufacturer.                |                                   |
+-----------------------------------+-----------------------------------+
| 106.3(m) Nutrient means any       | 106.3(m) Required nutrient means  |
| vitamin, mineral, or other        | any vitamin, mineral, or other    |
| substance or ingredient that is   | substance or ingredient in infant |
| required in accordance with the   | formula that is required by the   |
| table set out in section          | act or by regulations issued      |
| 412(i)(1) of the act or by        | pursuant to the act.              |
| regulations issued under section  |                                   |
| 412(i)(2) or that is identified   |                                   |
| as essential for infants by the   |                                   |
| Food and Nutrition Board of the   |                                   |
| National Research Council through |                                   |
| its development of a Recommended  |                                   |
| Dietary Allowance or an Estimated |                                   |
| Safe and Adequate Daily Dietary   |                                   |
| Intake range, or that has been    |                                   |
| identified as essential for       |                                   |
| infants by the Food and Drug      |                                   |
| Administration through a Federal  |                                   |
| Register publication.             |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.3(m) [Required]{.mark} ~~N~~nutrient means any vitamin, mineral, or
other substance or ingredient [in infant formula]{.mark} that is
required ~~in accordance with the table set out in section 412(i)(1)
of~~ by the act or by regulations issued ~~under section 412(i)(2) or
that is identified as essential for infants by the Food and Nutrition
Board of the National Research Council through its development of a
Recommended Dietary Allowance or an Estimated Safe and Adequate Daily
Dietary Intake range, or that has been identified as essential for
infants by the Food and Drug Administration through a Federal Register
publication~~ [pursuant to the act]{.mark}.

IFC Comment

The IFC believes that the intention of the proposal is to describe the
ways in which new required nutrients can be added to the list of those
already required by the nutrient table. The changes suggested by the IFC
are intended to simplify the proposed language. For instance, the IFC
was confused by the third point of this definition ("identified \... in
a Federal Register publication") and if and how it related to the first
point (a regulation issued under 412(i)(2)). If this third point were
interpreted to cover Federal Register publications that did not
constitute rulemaking, the IFC feels that it would be confusingly vague.
To eliminate this interpretational confusion, the IFC suggests
broadening the first point so that it encompasses all FDA rulemaking
activities related to infant formula and eliminating the last clause of
the proposal. Finally, although the IFC has the utmost respect for the
NRC development of RDA\'s, the IFC does not believe that the Infant
Formula Act gives FDA the authority to sub-delegate its authority to
establish required infant formula nutrients and levels.

The IFC interprets both the proposed language and its suggested
revisions as applying to \"essential\" nutrients, and not to other
potential or current ingredients in infant formula. In other words, the
regulations will create no restrictions on the ability of a manufacturer
to include new ingredients (assuming compliance with other provisions in
the regulations), nor do they in any way affect substances that are
being added currently in compliance with existing regulations.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.3(n) Nutrient premix means a    Acceptable as proposed.
  combination of ingredients          
  containing two or more nutrients    
  received from a supplier or         
  prepared by an infant formula       
  manufacturer.                       

  106.3(o) Quality factors mean those 106.3(o) Quality factors mean those
  factors necessary to demonstrate    factors necessary to demonstrate
  that the infant formula, as         the bioavailability of a nutrient
  prepared for market, provides       and the maintenance of level or
  nutrients in a form that is         potency of nutrients through an
  bioavailable and safe as shown by   expected shelf life of the product.
  evidence that demonstrates that the 
  formula supports healthy growth     
  when fed as a sole source of        
  nutrition.                          
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.3(o) Quality factors mean those factors necessary to demonstrate
[the bioavailability of a nutrient and the maintenance of level or
potency of nutrients through an expected shelf life of the
product]{.mark} ~~that the infant formula, as prepared for market,
provides nutrients in a form that is bioavailable and safe as shown by
evidence that demonstrates that the formula supports healthy growth when
fed as a sole source of nutrition~~.

######### IFC Comment 

As discussed at length in our general comments, IFC is strongly of the
view that any effort to establish "healthy" or "normal" growth as a
quality factor is flawed and should be abandoned. We specifically
incorporate by reference those comments in support of the above noted
recommended deletions from this proposed section.

We would delete the gratuitous reference to safety in the proposed
definition to be consistent with the fact that, as discussed in our
General Comments, the Infant Formula Act does not deal with "safety" per
se, but rather with nutritional adequacy. This is also consistent with
the fact that the Food Drug and Cosmetic Act *does* ensure safety in
many ways. Consequently, the additional regulation dictated by the
Infant Formula Act was only needed to focus on the particular reliance
of infants on the nutritional aspects of a food that might substitute
for breast milk as their sole source of nutrition.

We would also separate out the reference to evidence of growth because
bioavailability might be established in many ways other than by a
clinical trial. As discussed in our General Comment section on
"Assessment of Normal Growth," such evidence should not be considered a
"Quality Factor" per se, nor should it be expected on a routine basis.
Moreover, as was clear from the 2002 Food Advisory Committee discussions
held to better understand how to assess growth, the task of defining
\"normal physical growth,\" which already appears in several of the
proposed regulations -- let alone \"healthy growth,\" which is used here
-- is an elusive one, given the wide range of acceptable growth patterns
exhibited by infants of different ages, genders, ethnic origins and
feeding practices. IFC believes that "expected physical growth" is a
more meaningful term and a more measurable criterion, since it may be
established by comparison to the ranges used in whichever of the
various, currently accepted, credible medical references may be most
appropriate. Consequently, we suggest that the term be changed wherever
it appears throughout the proposed GMPs.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.3(p) Representative sample      Acceptable as proposed.
  means a sample that consists of a   
  number of units that are drawn      
  based on rational criteria, such as 
  random sampling, and intended to    
  ensure that the sample accurately   
  portrays the material being         
  sampled.                            

  106.3(q) Shall is used to state     Acceptable as proposed.
  mandatory requirements.             

  106.3(r) Should is used to state    Acceptable as proposed.
  recommended or advisory procedures  
  or to identify recommended          
  equipment.                          

  None.                               106.3(s) Responsible party means
                                      the manufacturer of an infant
                                      formula when all manufacturing
                                      steps are performed by a single
                                      entity; however, when several
                                      entities are involved in the
                                      manufacture of a given formula, it
                                      means the manufacturer or other
                                      entity that has agreed to assume
                                      responsibility for ensuring that
                                      all requirements for notification
                                      and/or assurance under these
                                      regulations are satisfied.
  ----------------------------------- -----------------------------------

IFC Redlined Version

[106.3(s) Responsible party means the manufacturer of an infant formula
when all manufacturing steps are performed by a single entity; however,
when several entities are involved in the manufacture of a given
formula, it means the manufacturer or other entity that has agreed to
assume responsibility for ensuring that all requirements for
notification and/or assurance under these regulations are
satisfied.]{.mark}

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer. The
IFC does not believe that FDA needs or wants to receive multiple
notifications conveying identical information or to saddle multiple
manufacturers of the same formula with duplicative responsibilities for
the same task. Such duplication could be required under the proposed
regulations when two or more manufacturers are involved in the
manufacture of an infant formula. Therefore, introduction of the concept
of \"Responsible Party\" permits multiple manufacturers to agree in
advance who will bear the various responsibilities. It should be clear,
however, that all manufacturers must register, i.e., they cannot avoid
registration by virtue of the concept of Responsible Party.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| None.                             | 106.3(t) Specifications means     |
|                                   | quality control limits or         |
|                                   | standards for raw materials,      |
|                                   | in-process materials and finished |
|                                   | product, which are established by |
|                                   | the manufacturer for purposes of  |
|                                   | controlling quality and           |
|                                   | consistency for infant formula.   |
|                                   | Failure to meet an established    |
|                                   | specification requires a          |
|                                   | documented review and material    |
|                                   | disposition decision.             |
|                                   |                                   |
|                                   | 106.3(u) Target Value means       |
|                                   | quality control limits or         |
|                                   | standards for raw materials,      |
|                                   | in-process materials and finished |
|                                   | product which are established by  |
|                                   | the manufacturer for purposes of  |
|                                   | targeting the manufacturing       |
|                                   | process to a tight range within   |
|                                   | broader specifications. Failure   |
|                                   | to meet an established target     |
|                                   | value shall result in an          |
|                                   | immediate review and adjustment,  |
|                                   | if necessary, during the          |
|                                   | manufacturing process. No         |
|                                   | documented review and material    |
|                                   | disposition is needed when a      |
|                                   | target value is not met, as long  |
|                                   | as the established specification  |
|                                   | is met.                           |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

[106.3(t) Specifications means quality control limits or standards for
raw materials, in-process materials and finished product, which are
established by the manufacturer for purposes of controlling quality and
consistency for infant formula. Failure to meet an established
specification requires a documented review and material disposition
decision.]{.mark}

[106.3(u) Target Value means quality control limits or standards for raw
materials, in-process materials and finished product which are
established by the manufacturer for purposes of targeting the
manufacturing process to a tight range within broader specifications.
Failure to meet an established target value shall result in an immediate
review and adjustment, if necessary, during the manufacturing process.
No documented review and material disposition is needed when a target
value is not met, as long as the established specification is
met.]{.mark}

IFC Comment

See the IFC\'s General Comment concerning Specifications. In the drug
industry, there is common acceptance that the term \"specification\"
means a predetermined value or range for a given parameter. That
parameter must be met in order routinely to continue the manufacturing
process or to release the product for distribution. Failure to meet a
specification triggers special, non-routine, documented review, not
automatic rejection of the product. This is appropriate because the
specifications, like those in the manufacture of infant formula, are set
well within the outer limits that would cause adulteration. In view of
the IFC\'s definition of \"Specification,\" the IFC has suggested
deleting the word \"standard\" whenever it appears with the word
\"Specification\" in FDA\'s proposed language.

The term \"target value\" should also be defined, not for purposes of
requiring them, but instead to recognize that some infant formula
manufacturers use them for quality control purposes. When they are used,
it is important that they be distinguished from specifications, because
the failure to meet a target value should not trigger the kind of
detailed and documented review triggered by a failure to meet
specifications.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  None.                               106.3(v) Critical is used to
                                      describe systems or equipment that
                                      have been designated by the infant
                                      formula manufacturer as necessary
                                      to control in order to prevent
                                      adulteration.
  ----------------------------------- -----------------------------------

IFC Redlined Version

[106.3(v) Critical is used to describe systems or equipment that have
been designated by the infant formula manufacturer as necessary to
control in order to prevent adulteration.]{.mark}

IFC Comment

This suggested definition of \"critical\" is introduced to provide a
mechanism to reduce some of the unnecessary burden of this
\"validation\" concept by limiting its scope to those areas of
manufacture, which may truly have public health significance. It also
emphasizes the responsibility of the manufacturer to make a careful
determination of which areas may have this significance.

**Rest of page intentionally left blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **Subpart B\--Current Good        | **Subpart B\--Current Good        |
| Manufacturing Practice**          | Manufacturing Practice**          |
|                                   |                                   |
| **106.5 Current good              | **106.5 Current good              |
| manufacturing practice.**         | manufacturing practice.**         |
|                                   |                                   |
| 106.5(a) The regulations set      | Acceptable as proposed.           |
| forth in this subpart and, for    |                                   |
| liquid infant formulas, in part   | Acceptable as proposed, but note  |
| 113 of this chapter define the    | that \"act\" is already defined   |
| minimum current good              | in proposed 106.1(a).             |
| manufacturing practices that are  |                                   |
| to be used in, and the facilities |                                   |
| or controls that are to be used   |                                   |
| for, the manufacture, processing, |                                   |
| packing, or holding of an infant  |                                   |
| formula. Compliance with these    |                                   |
| provisions is necessary to ensure |                                   |
| that such infant formula provides |                                   |
| the nutrients required under Sec. |                                   |
| 107.100 of this chapter and is    |                                   |
| manufactured in a manner designed |                                   |
| to prevent its adulteration.      |                                   |
|                                   |                                   |
| 106.5(b) The failure to comply    |                                   |
| with any regulation set forth in  |                                   |
| this subpart or, for liquid       |                                   |
| infant formulas, in part 113 of   |                                   |
| this chapter in the manufacture,  |                                   |
| processing, packing, or holding   |                                   |
| of an infant formula shall render |                                   |
| such infant formula adulterated   |                                   |
| under section 412(a)(3) of the    |                                   |
| Federal Food, Drug, and Cosmetic  |                                   |
| Act (the act).                    |                                   |
+-----------------------------------+-----------------------------------+
| **106.6 Production and in-process | **106.6 Production and in-process |
| control system.**                 | control system.**                 |
|                                   |                                   |
| 106.6(a) Manufacturers shall      | 106.6(a) Manufacturers shall      |
| conform to the requirements of    | conform to the requirements of    |
| this subpart by implementing a    | this subpart by implementing a    |
| system of production and          | system of production and          |
| in-process controls. This         | in-process controls. This         |
| production and in-process control | production and in-process control |
| system shall cover all stages of  | system shall cover those stages   |
| processing, from the receipt and  | of processing, storage and        |
| acceptance of the raw materials,  | distribution that are under the   |
| ingredients, and components       | manufacturer\'s control, from the |
| through the storage and           | receipt and acceptance of the raw |
| distribution of the finished      | materials, ingredients, and       |
| product and shall be designed to  | components through the storage    |
| ensure that all the requirements  | and distribution of the finished  |
| of this subpart are met.          | product, and shall be designed to |
|                                   | ensure that all the requirements  |
|                                   | of this subpart are met.          |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.6(a) Manufacturers shall conform to the requirements of this subpart
by implementing a system of production and in‑process controls. This
production and in‑process control system shall cover ~~all~~
[those]{.mark} stages of processing, [storage and distribution that are
under the manufacturer\'s control]{.mark}, from the receipt and
acceptance of the raw materials, ingredients, and components through the
storage and distribution of the finished product[,]{.mark} and shall be
designed to ensure that all the requirements of this subpart are met.

IFC Comment

The requirement that the production and in-process control systems cover
everything, including the distribution of finished product, could appear
to extend beyond the time that the manufacturer has control of the
product. While a manufacturer should be required to maintain
responsibility for its product through those distribution channels that
are under its control, at the point that its control ends, the
manufacturer cannot be expected to be responsible to assure proper
distribution practices. That necessarily falls on another party. Also,
when co packers are involved, the scope of responsibility of that party
is necessarily limited to the specific aspect of manufacturing, storage
or distribution that the co packer has been contracted to handle. The
suggested wording change incorporates these concepts.

With respect to drugs, this concept is conveyed in 210.2(b).

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.6(b) The production and       | Acceptable as proposed.           |
| in-process control system shall   |                                   |
| be set out in a written plan, or  |                                   |
| set of procedures, that is        |                                   |
| designed to ensure that an infant |                                   |
| formula is manufactured in a      |                                   |
| manner that will prevent          |                                   |
| adulteration of the infant        |                                   |
| formula.                          |                                   |
+-----------------------------------+-----------------------------------+
| 106.6(c) At any point, step, or   | 106.6(c) The manufacturer shall   |
| stage in the production process   | identify the points, steps, or    |
| where control is necessary to     | stages in the production process  |
| prevent adulteration, the         | where control is critical to      |
| manufacturer shall:               | prevent adulteration. The         |
|                                   | manufacturer shall, with respect  |
| 106.6(c)(1) Establish standards   | to such points:                   |
| or specifications to be met;      |                                   |
|                                   | 106.6(c)(1) Establish             |
|                                   | specifications and, where         |
|                                   | appropriate, target values;       |
+-----------------------------------+-----------------------------------+

#  IFC Redlined Version

106.6(c) ~~At any point, step, or stage~~ [The manufacturer shall
identify the points, steps, or stages]{.mark} in the production process
where control is ~~necessary~~ [critical]{.mark} to prevent
adulteration~~, the~~[. The]{.mark} manufacturer shall[, with respect to
such points]{.mark}:

106.6(c)(1) Establish ~~standards or~~ specifications [and, where
appropriate, target values]{.mark} ~~to be met~~;

######### IFC Comment 

See the IFC's General Comment entitled Specifications and its proposed
addition of the term definition above. As proposed, the language \"any
point, step, or stage\...\" refers, literally, to every conceivable
manufacturing activity, for under the new legal standard that will begin
with finalization of these regulations, there are few manufacturing
activities that cannot, theoretically, give rise to a finding of
\"technical\" adulteration. Obviously, it is impractical to fulfill the
requirements of this proposed section for every conceivable
manufacturing activity, so IFC\'s suggested revision focuses on the
manufacturing steps most important to ensuring that a product is free
from actual adulteration, and makes it consistent with proposed
106.100(e)(3). Finally, the IFC\'s suggested language also emphasizes
that it is the responsibility of the manufacturer to identify the
critical points.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.6(c)(2) Monitor the           | Acceptable as proposed.           |
| production and in‑process control |                                   |
| point, step, or stage;            | 106.6(c)(3) Establish standard    |
|                                   | operating procedures to address   |
| 106.6(c)(3) Establish corrective  | when a specification established  |
| action plans for use when a       | in accordance with paragraph      |
| standard or specification         | (c)(1) of this section is not     |
| established in accordance with    | met;                              |
| paragraph (b)(1) of this section  |                                   |
| is not met;                       |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.6(c)(3) Establish ~~corrective action plans for use when a standard
or~~ [standard operating procedures to address when a]{.mark}
specification established in accordance with paragraph ~~(b)(1)~~
[(c)(1)]{.mark} of this section is not met;

IFC Comment

The preamble to the proposed rule for this section states that \"\...the
best way to ensure that a corrective action is appropriate is to
determine the action in advance.\" While it may often be feasible to
establish corrective action plans in advance, a manufacturer cannot be
expected to foresee all future circumstances that may require reliance
on a corrective action plans and to predict how it will operate.
Certainly, the expectation and hope that an established corrective
action plan can be applied to a problem is valid; however, many
circumstances may have a different set of elements to be considered and
they might require a case-by-case analysis. Consequently, the IFC\'s
language requires a Standard Operating Procedure (\"SOP\") to be created
to deal with results outside of specifications; there would be nothing
to prevent a manufacturer from including typical potential corrective
actions in that SOP, but those actions should not be mandated when they
are irrelevant to the facts of a given situation.

Additionally, FDA's April announcement of the reopening of the comment
period requested comments on the specific changes in current activities
that would be required for companies to comply with the proposal.
Corrective actions are based on scientific judgment and past
experiences. If each specification needs to be tested to failure, the
cost would be huge and would certainly prevent or severely limit new
product development. Moreover, given the complex and multi-factorial
aspects of infant formula production and the occasional failure of
finished products to meet specifications, it is questionable whether
such speculative actions would provide applicable guidance in a specific
instance. If instead, scientific judgment supported by empirical
evidence were allowed to determine which specifications should be
challenged, some corrective action procedures might be identified in
advance, but they would be limited to those situations that one would
reasonably expect to encounter.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.6(c)(4) Review the results of   106.6(c)(4) Review the results of
  the monitoring required by          the monitoring required by
  paragraph (c)(2) of this section,   paragraph (c)(2) of this section,
  and review and evaluate the public  and review and evaluate whether
  health significance of any          deviations from specifications that
  deviations from standards or        have been established in accordance
  specifications that have been       with paragraph (c)(1) of this
  established in accordance with      section have public health
  paragraph (c)(1) of this section.   significance. This review shall be
  This review shall be conducted by   conducted by an individual
  an individual qualified by training qualified by training and
  and experience to conduct such      experience to conduct such reviews;
  reviews; and                        and
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.6(c)(4) Review the results of the monitoring required by paragraph
(c)(2) of this section, and review and evaluate ~~the public health
significance of any~~ [whether]{.mark} deviations from ~~standards or~~
specifications that have been established in accordance with paragraph
(c)(1) of this section [have public health significance]{.mark}. This
review shall be conducted by an individual qualified by training and
experience to conduct such reviews; and

IFC Comment

See the IFC's General Comment entitled Specifications. This proposed
regulation incorporates the requirement to set specifications at the
outer acceptability limits. The IFC is strongly opposed to this
philosophy. Presently, IFC members utilize tight control limits, as
distinguished from the broad outer limits that appear to be desired by
FDA. If a tight limit is not met, a formal review is conducted and
material disposition decisions are made based on that review. If the
situation potentially involves a public health concern, the proper
review by qualified individuals occurs. However, not all specifications
involve concerns with public health significance. For example, shipper
cartons that are found with a printing color that differs a shade or so
from the tight color standard would not justify a public health
significance evaluation.

IFC suggestions to address its opposition to the philosophy of the
proposal on outer limit specifications include adding a definition for
specification which permits manufacturers to establish specifications
with tight limits, and that a result lying outside the tight
specification does not trigger automatic rejection, but instead triggers
a documented review. That is reflected above in the changes suggested by
the IFC.

**Rest of page intentionally left blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.6(c)(5) Establish Record      | Acceptable as proposed.           |
| keeping procedures, in accordance |                                   |
| with Sec. 106.100(e)(3), that     |                                   |
| ensure that compliance with the   |                                   |
| requirements of this section is   |                                   |
| documented.                       |                                   |
+-----------------------------------+-----------------------------------+
| **106.10 Controls to prevent      | **106.10 Controls to prevent      |
| adulteration by workers.**        | adulteration by workers.**        |
|                                   |                                   |
| 106.10(a) There shall be          | Delete                            |
| sufficient personnel, qualified   |                                   |
| by training and experience, to    | or                                |
| perform all operations, including |                                   |
| all required Record keeping, in   | 106.10(a) The manufacturer shall  |
| the manufacture, processing,      | designate sufficient personnel,   |
| packing, and holding of each      | qualified by training and         |
| infant formula and to supervise   | experience, to perform all        |
| such operations to ensure that    | operations, including all         |
| they are correctly and fully      | required recordkeeping, in the    |
| performed.                        | manufacture, processing, packing, |
|                                   | and holding of each infant        |
|                                   | formula and to supervise such     |
|                                   | operations to ensure that they    |
|                                   | are correctly and fully           |
|                                   | performed.                        |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

[Delete]{.mark}

[or]{.mark}

106.10(a) ~~There~~ [The manufacturer]{.mark} shall ~~be~~
[designate]{.mark} sufficient personnel, qualified by training and
experience, to perform all operations, including all required
recordkeeping, in the manufacture, processing, packing, and holding of
each infant formula and to supervise such operations to ensure that they
are correctly and fully performed.

IFC Comment

See the IFC's General Comment entitled Redundancy and Overly
Prescriptive. The Food GMPs have numerous provisions relating to
personnel. (See, e.g., section 110.10). The IFC questions whether the
extensive, specific proposed provisions relating to personnel are all
necessary.

The only standard by which one can demonstrate that "\...sufficient
personnel qualified by training and experience, to perform all
operations\..." have been employed by the manufacturer is by
demonstrating that an unadulterated infant formula can be routinely
manufactured. Other provisions of the existing and proposed regulations
already require that unadulterated products be routinely manufactured.
Thus, compliance with CGMP requirements should be adequate without the
Agency\'s evaluation of internal staffing matters. Proposed section
106.10(a) is redundant with existing regulations and with other
provisions of the proposed regulations and should be removed.

If FDA does not accept the IFC\'s suggested deletion and keeps this
section in the final regulation, the preamble should acknowledge that
\"sufficiency\" is determined by the manufacturer, based on its
knowledge of its manufacturing and quality assurance systems. The
suggested revision incorporates this concept. Moreover, current training
programs have been designed by the manufacturer to allow personnel to
perform their required tasks. If FDA were to require different or more
extensive training than deemed appropriate by the manufacturer, there
would certainly be a large cost incurred by some manufacturers to
implement and track those additional training programs.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.10(b) Personnel working       | Delete.                           |
| directly with infant formula,     |                                   |
| infant formula raw materials,     |                                   |
| infant formula packaging, or      |                                   |
| infant formula equipment or       |                                   |
| utensil contact surfaces shall    |                                   |
| practice good personal hygiene to |                                   |
| protect the infant formula        |                                   |
| against contamination. Good       |                                   |
| personal hygiene includes, but is |                                   |
| not limited to:                   |                                   |
+-----------------------------------+-----------------------------------+
| 106.10(b)(1) Wearing clean outer  | Delete.                           |
| garments and, as necessary,       |                                   |
| protective apparel such as head,  | Delete.                           |
| face, hands, and arm coverings;   |                                   |
| and                               |                                   |
|                                   |                                   |
| 106.10(b)(2) Washing hands        |                                   |
| thoroughly in a hand washing      |                                   |
| facility with soap and running    |                                   |
| water at a suitable temperature   |                                   |
| before starting work, after each  |                                   |
| absence from the work station,    |                                   |
| and at any other time when the    |                                   |
| hands may become soiled or        |                                   |
| contaminated.                     |                                   |
+-----------------------------------+-----------------------------------+

#########  IFC Redlined Version

~~106.10(b) Personnel working directly with infant formula, infant
formula raw materials, infant formula packaging, or infant formula
equipment or utensil contact surfaces shall practice good personal
hygiene to protect the infant formula against contamination. Good
personal hygiene includes, but is not limited to:~~

~~106.10(b)(1) Wearing clean outer garments and, as necessary,
protective apparel such as head, face, hands, and arm coverings; and~~

~~106.10(b)(2) Washing hands thoroughly in a hand washing facility with
soap and running water at a suitable temperature before starting work,
after each absence from the work station, and at any other time when the
hands may become soiled or contaminated.~~

IFC Comment

See the IFC's General Comment entitled Redundancy. Section 106.10(b) is
redundant with the existing Food GMPs (§110.10(b)) and should,
therefore, be removed from the final GMP document for infant formula.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.10(c) Any person who reports    Delete.
  that he or she has, or appears by   
  medical examination or supervisory  
  observation to have, an illness,    
  open lesion, including boils,       
  sores, or infected wounds, or any   
  other source of microbial           
  contamination that creates a        
  reasonable possibility that the     
  safety of an infant formula may be  
  adversely affected, shall be        
  excluded from direct contact with   
  ingredients, containers, closures,  
  in-process materials, equipment,    
  utensils, and infant formula        
  product until the condition is      
  corrected or determined by          
  competent medical personnel not to  
  jeopardize the safety of the infant 
  formula.                            
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.10(c) Any person who reports that he or she has, or appears by
medical examination or supervisory observation to have, an illness, open
lesion, including boils, sores, or infected wounds, or any other source
of microbial contamination that creates a reasonable possibility that
the safety of an infant formula may be adversely affected, shall be
excluded from direct contact with ingredients, containers, closures,
in‑process materials, equipment, utensils, and infant formula product
until the condition is corrected or determined by competent medical
personnel not to jeopardize the safety of the infant formula.~~

IFC Comment

See the IFC's General Comment entitled Redundancy. This language is
virtually identical with provisions in the Food GMPs.

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  **106.20 Controls to prevent        **106.20 Controls to prevent
  adulteration caused by              adulteration caused by
  facilities.**                       facilities.**

  106.20(a) Buildings used in the     Acceptable as proposed.
  manufacture, processing, packing,   
  or holding of infant formula shall  
  be maintained in a clean and        
  sanitary condition and shall have   
  space for the separation of         
  incompatible operations, such as    
  the handling of raw materials, the  
  manufacture of the product, and     
  packaging and labeling operations.  

  106.20(b) Separate areas shall be   106.20(b) A control system shall be
  designated for holding raw          established by the manufacturer to
  materials, in-processing materials, control by status the storage and
  and final product infant formula:   use of raw materials, in-process
                                      materials and finished infant
                                      formula. This system shall include
                                      the differentiation of the
                                      following:
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.20(b) ~~Separate areas shall be designated for holding~~ [A control
system shall be established by the manufacturer to control by status the
storage and use of]{.mark} raw materials, in‑processing materials, and
~~final product~~ [finished]{.mark} infant formula[. This system shall
include the differentiation of the following]{.mark}:

######### IFC Comment

See the IFC\'s General Comment regarding Separate Storage Areas. The IFC
believes that the Agency\'s proposal for physical separation of
materials is extremely ill advised and perhaps impossible to implement.
The physical separation of materials is neither practical nor necessary
for the prevention of potential mix-ups during the manufacturing
process. Therefore, it is recommended that this section be reworded as
suggested to indicate that methods other than spatial separation are
permissible for holding raw materials, in-process materials, and
finished infant formula for the avoidance of potential mix-ups.
Computerized inventory control or alternative methods currently used by
IFC members, should be acknowledged as acceptable in the preamble to the
final regulation, as should adequate marking of pallets. The requirement
suggested by the IFC is comparable to that currently in effect for drugs
pursuant to the GMP regulations for pharmaceuticals. The current process
involves segregation of raw materials, released vs. non-released raw
materials and in-process products and finished products, etc. by either
a written card system or electronic tracking mechanism. If the process
needs to be changed to have actual separation between raw materials, in
processing materials and finished product; new facilities, utilities and
infrastructure would need to be provided along with personnel to support
these areas. The impact on resource requirements would be staggering,
potentially hundreds of millions of dollars, with no value added to the
product or benefits to the consumer.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.20(b)(1) Pending release for  | Acceptable as proposed.           |
| use in infant formula production  |                                   |
| or pending release of the final   | 106.20(b)(2) After rejection for  |
| product,                          | use in or as infant formula, and  |
|                                   |                                   |
| 106.20(b)(2) After rejection for  |                                   |
| use in infant formula and before  |                                   |
| disposition, and                  |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.20(b)(2) After rejection for use in [or as]{.mark} infant formula
~~and before disposition~~, and

IFC Comment

Once a decision is made concerning disposition, the requirement for
proper status designation should not end, as it arguably does by the
proposed language. Also, the addition of \"or as\" acknowledges the
possibility that a finished batch may be rejected.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.20(b)(3) After release for use  106.20(b)(3) After release for use
  in infant formula production or     in or as infant formula production
  after release of the final product. or after release of the final
                                      product.
  ----------------------------------- -----------------------------------

# IFC Redlined Version

106.20(b)(3) After release for use in [or as]{.mark} infant formula
production or after release of the final product.

IFC Comment

See comment to 106.20(b)(2).

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.20(c) Lighting shall allow easy Delete.
  identification of raw materials,    
  packaging, labeling, in‑process     
  materials, and finished products    
  that have been released for use in  
  infant formula production and shall 
  permit the easy reading of          
  instruments and controls necessary  
  in processing, packaging, and       
  laboratory analysis. Any lighting   
  fixtures directly over or adjacent  
  to exposed raw materials,           
  in‑process materials, or bulk       
  (unpackaged) finished product shall 
  be protected to prevent glass from  
  contaminating the product in the    
  event of breakage.                  
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.20(c) Lighting shall allow easy identification of raw materials,
packaging, labeling, in‑process materials, and finished products that
have been released for use in infant formula production and shall permit
the easy reading of instruments and controls necessary in processing,
packaging, and laboratory analysis. Any lighting fixtures directly over
or adjacent to exposed raw materials, in‑process materials, or bulk
(unpackaged) finished product shall be protected to prevent glass from
contaminating the product in the event of breakage.~~

######### IFC Comment 

See the General Comment regarding Redundancy. The Food GMPs
(§110.35(b)(5)) fully describe the requirements for proper lighting in
food plants.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.20(d) Air filtration systems,   Delete.
  including prefilters and            
  particulate matter air filters,     
  shall be used on air supplies to    
  production areas where ingredients  
  or infant formula are directly      
  exposed to the atmosphere.          
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.20(d) Air filtration systems, including prefilters and particulate
matter air filters, shall be used on air supplies to production areas
where ingredients or infant formula are directly exposed to the
atmosphere.~~

IFC Comment

See the IFC's General Comments entitled Overly Prescriptive and
Redundancy. The Food GMPs (§110.35(b)(6)) establish requirements for
ventilation. If FDA does not agree that the Food GMPs adequately address
ventilation issues for infant formula manufacturers, it should consider
utilizing language such as: "when there is reason to believe that the
air in a particular area of the plant might result in adulteration of
the product, measures should be taken to prevent such adulteration, by
air filtration or some other means."

In the April 2003 announcement of the reopening of the comment period,
FDA specifically requested comment on the types and costs of air
filtration systems used by infant formula manufacturers and the costs of
making changes. U.S. Infant Formula Manufacturers currently use
prefilters and in certain critical areas, particulate matter air
filters, on their air supplies to production areas and in areas when the
infant formula may be exposed to the atmosphere. Thus, this provision
would not result in the expenditure of any additional funds. IFC
believes a more detailed account of the types and costs of air
filtration systems would be wasteful and would put an undue burden on
industry, when there is no public interest served by insisting on
specific changes in this arena.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.20(e) All rodenticides,         Delete.
  insecticides, fungicides,           
  fumigating agents, and cleaning and 
  sanitizing agents shall be stored   
  and used in a manner that protects  
  against contamination of infant     
  formula.                            
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.20(e) All rodenticides, insecticides, fungicides, fumigating
agents, and cleaning and sanitizing agents shall be stored and used in a
manner that protects against contamination of infant formula.~~

IFC Comment

See IFC's General Comment entitled "Redundancy." Section (e) is
redundant with the Food GMPs (§110.35(b)(2)), and should, therefore, be
removed.

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.20(f)(1) Potable water used in  106.20(c)(1) Potable water used in
  the manufacture of infant formula   infant formula shall meet the
  shall meet the standards prescribed standards prescribed in the
  in the Environmental Protection     Environmental Protection Agency\'s
  Agency\'s (EPA\'s) Primary Drinking (EPA\'s) Primary Drinking Water
  Water Regulations set forth in 40   Regulations set forth in 40 CFR
  CFR part 141, except that the       part 141, except that fluoride
  fluoride level of the water used in removal systems shall be employed
  infant formula manufacturing shall  for fluoridated water supplies. The
  be as low as possible. The water    water shall be supplied under
  shall be supplied under continuous  continuous positive pressure in a
  positive pressure in a plumbing     plumbing system that is free of
  system that is free of defects that defects that could contaminate an
  could contaminate an infant         infant formula.
  formula.                            
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.20(~~f~~[c]{.mark})(1) Potable water used in ~~the manufacture of~~
infant formula shall meet the standards prescribed in the Environmental
Protection Agency\'s (EPA\'s) Primary Drinking Water Regulations set
forth in 40 CFR part 141, except that ~~the fluoride level of the water
used in infant formula manufacturing shall be as low as possible~~
[fluoride removal systems shall be employed for fluoridated water
supplies]{.mark}. The water shall be supplied under continuous positive
pressure in a plumbing system that is free of defects that could
contaminate an infant formula.

######### IFC Comment

The requirement that fluoride levels for ingredient water be \"as low as
possible\" is vague, potentially prohibitively costly, and unnecessary
to prevent any public health concern. Although manufacturers strive to
produce infant formula product with low fluoride levels, different
technologies are utilized to achieve this goal. There is concern that
Agency representatives could take the position that \"as low as
possible\" means the most advanced, most expensive fluoride removal
system available, which could cost millions of dollars to install, along
with substantial increase in on-going operating costs all without any
commensurate benefit to public health.

In order to reflect what we understand to be FDA\'s current position on
the subject of fluoride, the preamble to the final regulation, like the
preamble to the proposed regulation, should state that current practices
in the industry are deemed acceptable.

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.20(f)(2) Manufacturers shall    Acceptable; Renumbered as
  test representative samples of the  106.20(c)(2).
  potable water drawn at a point in   
  the system at which the water is in 
  the same condition that it will be  
  when it is used in infant formula   
  manufacturing.                      

  106.20(f)(3) Manufacturers shall    Acceptable; Renumbered as
  conduct the tests required by       106.20(c)(3).
  paragraph (f)(2) of this section    
  with sufficient frequency to ensure 
  that the water meets the EPA\'s     
  Primary Drinking Water Regulations  
  but shall not conduct these tests   
  less frequently than annually for   
  chemical contaminants, every 4      
  years for radiological              
  contaminants, and weekly for        
  bacteriological contaminants.       

  106.20(f)(4) Manufacturers shall    Acceptable; Renumbered as
  make and retain records, in         106.20(c)(4).
  accordance with §106.100(f)(1), of  
  the frequency and results of        
  testing of the water used in the    
  production of infant formula.       

  106.20(g) There shall be no         Delete.
  backflow from, or cross‑connection  
  between, piping systems that        
  discharge waste water or sewage and 
  piping systems that carry water for 
  infant formula manufacturing.       
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.20(~~f~~[c]{.mark})(2) Manufacturers shall test representative
samples of the potable water drawn at a point in the system at which the
water is in the same condition that it will be when it is used in infant
formula manufacturing.

106.20(~~f~~[c]{.mark})(3) Manufacturers shall conduct the tests
required by paragraph (f)(2) of this section with sufficient frequency
to ensure that the water meets the EPA\'s Primary Drinking Water
Regulations but shall not conduct these tests less frequently than
annually for chemical contaminants, every 4 years for radiological
contaminants, and weekly for bacteriological contaminants.

106.20(~~f~~[c]{.mark})(4) Manufacturers shall make and retain records,
in accordance with §106.100(f)(1), of the frequency and results of
testing of the water used in the production of infant formula.

~~106.20(g) There shall be no backflow from, or cross‑connection
between, piping systems that discharge waste water or sewage and piping
systems that carry water for infant formula manufacturing.~~

######### IFC Comment 

See IFC's General Comment entitled "Redundancy." Section (g) is
redundant with the Food GMPs (§110.37(b)(5)), and should, therefore, be
removed.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.20(h) When steam comes in       Delete.
  direct contact with infant formula, 
  it shall be safe and free of rust   
  and other particulate matter that   
  may contaminate the formula. Boiler 
  water additives in the steam shall  
  be used in accordance with Sec.     
  173.310 of this chapter.            
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.20(h) When steam comes in direct contact with infant formula, it
shall be safe and free of rust and other particulate matter that may
contaminate the formula. Boiler water additives in the steam shall be
used in accordance with 173.310 of this chapter.~~

IFC Comment

See the IFC General Comment entitled Redundancy. Section (h) deals with
both adulterants and additives found in boiler water that may come in
contact with the infant formula. The adulterants provisions are
redundant with provisions of the existing Food GMPs. The provision
concerning the use of food additives in boiler water is entirely
redundant also with 21 CFR §173.310, in that the use of unapproved
boiler water additives renders the food adulterated whether the proposed
new section exists or not. For this reason, the proposed provision,
section (h), duplicates existing regulations and serves no purpose. This
section should be removed from the final regulation.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.20(i) Each infant formula       Delete.
  manufacturing site shall provide    
  its employees with readily          
  accessible toilet facilities and    
  hand washing facilities that        
  include hot and cold water, soap or 
  detergent, and single-service       
  towels and that are maintained in   
  good repair and in a sanitary       
  condition at all times, and that    
  these facilities provide for proper 
  disposal of the sewage. Doors to    
  the toilet facility shall not open  
  into areas where infant formula     
  ingredients, containers, or         
  closures are stored, or where       
  infant formula is processed or      
  stored.                             
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.20(i) Each infant formula manufacturing site shall provide its
employees with readily accessible toilet facilities and hand washing
facilities that include hot and cold water, soap or detergent, and
single‑service towels and that are maintained in good repair and in a
sanitary condition at all times, and that these facilities provide for
proper disposal of the sewage. Doors to the toilet facility shall not
open into areas where infant formula ingredients, containers, or
closures are stored, or where infant formula is processed or stored.~~

IFC Comment

See the IFC's General Comment entitled Redundancy. Section (i) is
redundant with the Food GMPs (110.37(d) and (e)), and should, therefore,
be removed.

If FDA decides that it is not redundant and includes language in the
final regulation, the requirement for single-service sanitary towels in
toilet facilities should be modified to include air driers as an
alternative. This alternative is available under both the food
(110.37(e)(3)) and drug (211.52) GMP. The IFC also questions the value
added by the proposal with respect to its application to finished
inventory storage areas.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  **106.30 Controls to prevent        **106.30 Controls to prevent
  adulteration caused by equipment or adulteration caused by equipment or
  utensils.**                         utensils.**

  106.30(a) Equipment used in the     Acceptable as proposed.
  manufacture, processing, packing or 
  holding of an infant formula shall  
  be of appropriate design and shall  
  be installed to facilitate its      
  intended function and its cleaning  
  and maintenance.                    

  106.30(b) Equipment and utensils    Delete.
  used in the manufacture,            
  processing, packing, or holding of  
  an infant formula shall be          
  constructed so that surfaces that   
  contact ingredients, in-process     
  materials, or infant formula are    
  made of nontoxic materials and are  
  not reactive or absorptive. Such    
  equipment and utensils shall be     
  designed to be easily cleanable and 
  to withstand the environment of     
  their intended use. All surfaces    
  that contact ingredients,           
  in-process materials, or infant     
  formula shall be cleaned,           
  sanitized, and maintained to        
  protect infant formula from being   
  contaminated by any source.         
  Sanitizing agents used on           
  food-contact surfaces must comply   
  with Sec. 178.1010 of this chapter. 
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.30(b) Equipment and utensils used in the manufacture, processing,
packing, or holding of an infant formula shall be constructed so that
surfaces that contact ingredients, in‑process materials, or infant
formula are made of nontoxic materials and are not reactive or
absorptive. Such equipment and utensils shall be designed to be easily
cleanable and to withstand the environment of their intended use. All
surfaces that contact ingredients, in‑process materials, or infant
formula shall be cleaned, sanitized, and maintained to protect infant
formula from being contaminated by any source. Sanitizing agents used on
food‑contact surfaces must comply with 178.1010 of this chapter.~~

######### 

######### IFC Comment

See the IFC\'s General Comment regarding Redundancy. Section (b) is
redundant with the Food GMPs (§110.35(d)), and should, therefore, be
removed.

If FDA opts to include this language despite the redundancy, one
clarification is needed. There are particular areas, most notably in the
infant formula powder manufacturing process, where frequent exposures to
moisture must be avoided in order to prevent the possibility of
microbiological contamination. There are, accordingly, some areas where
wet cleaning is neither practical nor desirable. Although the paragraph
could be interpreted to allow for these unique circumstances, a
clarification statement would remedy this gray area. The Food GMP uses
the terminology \"as necessary\" for special circumstances regarding
cleaning and sanitizing. This addition would address this potential
situation.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.30(c) Manufacturers shall       106.30(b) Manufacturers shall
  ensure that substances, such as     ensure that substances, such as
  lubricants or coolants, that are    lubricants or coolants, that are
  required for operation of infant    required for operation of infant
  formula manufacturing equipment,    formula manufacturing equipment,
  but that would render the infant    but that would render the infant
  formula adulterated if they         formula adulterated if they
  contaminated the formula, do not    contaminated the formula, do not
  come in contact with formula        come in contact with formula
  ingredients, containers, closures,  ingredients, containers and
  or in-process materials or with     closures (prior to the
  infant formula itself.              closing/sealing operation), or
                                      in-process materials or with infant
                                      formula itself in a manner not
                                      permitted by applicable food
                                      additive regulations.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.30(~~c~~[b]{.mark}) Manufacturers shall ensure that substances, such
as lubricants or coolants, that are required for operation of infant
formula manufacturing equipment, but that would render the infant
formula adulterated if they contaminated the formula, do not come in
contact with formula ingredients, containers~~,~~ [and]{.mark}
closures~~, or in‑~~ [(prior to the closing/sealing operation),]{.mark}
or in-process materials or with infant formula itself [in a manner not
permitted by applicable food additive regulations]{.mark}.

IFC Comment

This paragraph requires one clarification. The intent is to avoid the
contact of substances such as lubricants and coolants with ingredients,
containers, closures, in-process materials or the infant formula, which
would result in adulteration through contamination. Although probably
implied, the reference to containers and closures should mean prior to
the closing/sealing operation where the hermetic seal is formed.

Finally, the last phrase has been suggested in order to make it
consistent with applicable food additive regulations.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.30(d)(1) Manufacturers shall    106.30(c)(1) Manufacturers shall
  ensure that instruments used for    ensure that instruments used for
  measuring, regulating, or           measuring, regulating, or
  controlling mixing time and speed,  controlling mixing time and speed,
  temperature, pressure, moisture,    temperature, pressure, moisture,
  water activity, or other parameters water activity, or other parameters
  at points where control is deemed   at points where control is deemed
  necessary to prevent adulteration   critical by the infant formula
  in the processing of an infant      manufacturer to prevent
  formula are accurate, easily read,  adulteration in the processing of
  properly maintained, and present in an infant formula are accurate,
  sufficient number for their         easily read, properly maintained,
  intended use. The instruments and   and present in sufficient number
  controls shall be tested for        for their intended use. The
  accuracy (calibrated) against a     instruments and controls shall be
  known reference standard before     tested for accuracy (calibrated)
  first use and thereafter at routine against a known reference standard
  intervals, as specified in writing  on or before first use and
  by the manufacturer of the          thereafter at routine intervals, as
  instrument or control, or as        specified in writing by the
  otherwise deemed necessary to       manufacturer of the instrument or
  ensure the accuracy of the          control, or as otherwise deemed
  instrument. The known reference     necessary by the infant formula
  standard shall be certified for     manufacturer to ensure the accuracy
  accuracy at routine intervals       of the instrument. The known
  specified in writing by the         reference standard shall be
  manufacturer of the instrument, or  certified for accuracy at routine
  as otherwise deemed necessary to    intervals specified in writing by
  ensure the accuracy of the          the manufacturer of the instrument,
  instrument. Manufacturers shall     or as otherwise deemed necessary by
  make and retain records of the      the infant formula manufacturer to
  accuracy checks in accordance with  ensure the accuracy of the
  Sec. 106.100(f)(2).                 instrument. Manufacturers shall
                                      make and retain records of the
                                      accuracy checks in accordance with
                                      Sec. 106.100(f)(2).
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.30(~~d~~[c]{.mark})(1) Manufacturers shall ensure that instruments
used for measuring, regulating, or controlling mixing time and speed,
temperature, pressure, moisture, water activity, or other parameters at
points where control is deemed ~~necessary~~ [critical by the infant
formula manufacturer]{.mark} to prevent adulteration in the processing
of an infant formula are accurate, easily read, properly maintained, and
present in sufficient number for their intended use. The instruments and
controls shall be tested for accuracy (calibrated) against a known
reference standard [on or]{.mark} before first use and thereafter at
routine intervals, as specified in writing by the manufacturer of the
instrument or control, or as otherwise deemed necessary [by the infant
formula manufacturer]{.mark} to ensure the accuracy of the instrument.
The known reference standard shall be certified for accuracy at routine
intervals specified in writing by the manufacturer of the instrument, or
as otherwise deemed necessary [by the infant formula
manufacturer]{.mark} to ensure the accuracy of the instrument.
Manufacturers shall make and retain records of the accuracy checks in
accordance with Sec. 106.100(f)(2).

IFC Comment

There is no objection to the concept of calibration in this proposed
section, but it could prove unduly burdensome if \"drug\" type
compliance standards are applied to it. Including the qualification that
the infant formula manufacturer bears the final responsibility for
determining the frequency and scope of testing will help assure that the
standard applied to infant formula is appropriate. Because of the broad
scope and number of instruments to which this rule will be applicable,
it is possible that certain of these instruments may need to be in use
while they are being calibrated. Therefore, it is suggested adding the
words \"on or\" before first use to describe the timing of the initial
certification.

In the Agency's April 2003 announcement of the reopening of the comment
period, FDA requests comments on how often and under what conditions
manufacturers now calibrate instruments and controls against a known
standard and the adequacy of current procedures. U.S. Infant Formula
Manufacturers have established calibration and preventative maintenance
(PM) schedules for the appropriate pieces of equipment. As with the
issue of validation, priorities for calibrations and PM are linked to
criticality in regard to product quality and safety. Procedures and
schedules are aligned according to the criticality assessments, which
will vary from company to company, and are often based on the
recommendations of the instrument supplier. Results of calibrations and
PM's are trended. If trending data reflects a need to adjust the
frequency, changes are made as required. For example, instruments used
to monitor and release Infant Formula Products are calibrated at regular
intervals. Most instruments are calibrated at three or six month
intervals. A few instruments are calibrated at intervals longer or
shorter based on experience while others are standardized at the time of
use. Individual instrument performance is monitored and intervals
adjusted based on historical performance. Process-monitoring equipment
is typically calibrated at the location of the instrument installation.
Traceable transfer standards are used to perform calibration at the
location. Portable equipment (hand-held) is typically calibrated in an
instrumentation lab in a standard environment.

Instruments are scheduled for calibration on a planned and periodic
basis. Standards used to verify calibration are traceable to NIST or a
recognized industry standard. Calibrations are performed per a written
procedure with data recorded both before and after any adjustment if
made. Whenever critical instruments are found significantly
out-of-tolerance, they are reviewed and their impact on measurements is
assessed. Assessment includes impact of any offset generally using data
from back-up line instruments verifying performance to specification.

To conclude, the regulation should simply require that calibrations and
preventive maintenance be performed on pre-established schedules and
according to written procedures as determined by the infant formula
manufacturer, based on information from the equipment supplier where
applicable. If the new regulations require that all instruments need to
be calibrated routinely, regardless of their function, this would
require either the removal of all instruments not deemed critical by the
infant formula manufacturer, or the addition of significant new
personnel along with extensive systems to coordinate and track the
calibration program.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.30(d)(2) Instruments and        Acceptable; Renumbered as
  controls that cannot be adjusted to 106.30(c)(2).
  agree with the reference standard   
  shall be repaired or replaced.      

  106.30(d)(3) If calibration of an   Acceptable; Renumbered as
  instrument (testing for accuracy    106.30(c)(3).
  against a known reference standard) 
  shows that a specification or       
  standard for a point where control  
  is deemed necessary to prevent      
  adulteration has not been met, a    
  written evaluation of all affected  
  product, and of any actions that    
  need to be taken with respect to    
  that product, shall be made, in     
  accordance with §106.100(f)(2).     

  106.30(e)(1) The temperature in     Acceptable; Renumbered as
  cold storage compartments that are  106.30(d)(1).
  used to store raw materials,        
  in‑process materials, or final      
  product, and in thermal processing  
  equipment used at points where      
  temperature control is necessary to 
  prevent adulteration, shall be      
  monitored with such frequency as is 
  necessary to ensure that            
  temperature control is maintained.  

  106.30(e)(2) Cold storage           106.30(d)(2) Cold storage
  compartments shall be maintained at compartments shall be maintained at
  a temperature of 40 deg. F (4.4     a temperature confirmed by the
  deg. C) or below.                   manufacturer to assure the quality
                                      and safety of raw or in-process
                                      materials.
  ----------------------------------- -----------------------------------

######### IFC Redlined Version

106.30(~~d~~[c]{.mark})(2) Instruments and controls that cannot be
adjusted to agree with the reference standard shall be repaired or
replaced.

106.30(~~d~~[c]{.mark})(3) If calibration of an instrument (testing for
accuracy against a known reference standard) shows that a specification
or standard for a point where control is deemed necessary to prevent
adulteration has not been met, a written evaluation of all affected
product, and of any actions that need to be taken with respect to that
product, shall be made, in accordance with §106.100(f)(2).

106.30(~~e~~[d]{.mark})(1) The temperature in cold storage compartments
that are used to store raw materials, in‑process materials, or final
product, and in thermal processing equipment used at points where
temperature control is necessary to prevent adulteration, shall be
monitored with such frequency as is necessary to ensure that temperature
control is maintained.

106.30(~~e~~[d]{.mark})(2) Cold storage compartments shall be maintained
at a temperature ~~of 40 deg. F (4.4 deg. C), or below~~ [confirmed by
the manufacturer to assure the quality and safety of in-process
materials.]{.mark}

######### IFC Comment

See the IFC Comment regarding Overly Prescriptive. Defining cold storage
only as 40F or lower is incompatible with the manufacture of quality
infant formula. Such a prescriptive rule is arbitrary and potentially
detrimental to the product. It is the practice of IFC members to cool
in-process materials to temperatures that minimize the growth of
microorganisms in the unsterile mix. In some situations, such as the
long-term storage of aqueous solutions of nutrients that might support
microbial growth, the use of 40F as a storage temperature is well
established to be appropriate and can thus be justified.

However, many materials stored at low temperatures in infant formula
plants do not require the use of 40F to ensure stability. In some cases,
the use of temperatures this low may create quality problems involving
mix destabilization and non-homogeneity, which could theoretically
result in the final product being adulterated. (It should be noted that
if it were necessary to insure that the temperature *never* rose above
40F, the materials would actually have to be held at even lower
temperatures most of the time, in order to allow a \"margin\".) The
short period of time that some materials are held does not justify the
use of a 40F storage temperature. Thus, mandating an absolute maximum
temperature *for* *all purposes* is not necessary to protect public
health and would require additional capital investments for cooling
capacity that would not add value to the product.

In summary, cold temperature storage conditions must be left up to the
manufacturer to determine and be commensurate with batch sizes, hold
times, and other important considerations that are not susceptible to
prescription by regulatory requirements. The IFC believes that simply
announcing the end point to be achieved, e.g., \"cold storage will be
maintained at temperatures that prevent growth of pathogenic
microorganisms,\" is the preferable alternative.

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.30(e)(3)(i) Cold storage        Acceptable; Renumbered as
  compartments and thermal processing 106.30(d)(3)(i).
  equipment shall be equipped with    
  easily readable, accurate           
  temperature‑indicating devices.     

  106.30(e)(3)(ii) Thermal processing 106.30(d)(3)(ii) Thermal processing
  equipment shall be equipped with    equipment shall meet the
  temperature-recording devices that  requirements of 21 C.F.R. Part 113.
  will reflect the true temperature   Temperature monitoring of cold
  on a continuing basis. Cold storage storage compartments shall be of
  compartments shall be equipped with sufficient frequency to assure
  either temperature-recording        proper control. Manufacturers shall
  devices that will reflect the true  make and retain records, in
  temperature, on a continuing basis, accordance with Sec. 106.100(f)(3),
  within the compartment or, in lieu  of the temperatures indicated or
  of a temperature-recording device,  recorded by these devices.
  a high temperature alarm or a       
  maximum-indicating thermometer that 
  has been verified to function       
  properly. If the manufacturer uses  
  either of the latter options, it    
  shall maintain a temperature log in 
  which it notes temperature with     
  such frequency as is necessary to   
  achieve control. Manufacturers      
  shall make and retain records, in   
  accordance with Sec. 106.100(f)(3), 
  of the temperatures indicated or    
  recorded by these devices.          
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.30(~~e~~[d]{.mark})(3)(i) Cold storage compartments and thermal
processing equipment shall be equipped with easily readable, accurate
temperature‑indicating devices.

106.30(~~e~~[d]{.mark})(3)(ii) Thermal processing equipment shall ~~be
equipped with temperature‑recording devices that will reflect the true
temperature on a continuing basis. Cold~~ [meet the requirements of 21
C.F.R. Part 113. Temperature monitoring of cold]{.mark} storage
compartments shall be ~~equipped with either temperature‑recording
devices that will reflect the true temperature, on a continuing basis,
within the compartment or, in lieu of a temperature‑recording device, a
high temperature alarm or a maximum‑indicating thermometer that has been
verified to function properly. If the manufacturer uses either of the
latter options, it shall maintain a temperature log in which it notes
temperature with such frequency as is necessary to achieve~~ [of
sufficient frequency to assure proper]{.mark} control. Manufacturers
shall make and retain records, in accordance with Sec. 106.100(f)(3), of
the temperatures indicated or recorded by these devices.

IFC Comment

See the IFC\'s Recurring Comments regarding Redundancy. Thermometer
recording device requirements are governed by 21 CFR Part 113, with
which this proposal is redundant. However, the requirement that the
device will reflect the true temperature *conflicts* with 21 CFR Part
113, which requires a bias so that it reads no higher than the
mercury-in-glass thermometer. This proposal also conflicts with
106.30(e)(4) which also indicates the need for bias. 21 CFR Part 113
more accurately reflects the needs of a thermal processing system, and
the infant formula GMP should simply refer to this regulation.

Regarding the cold temperature storage temperature monitoring
requirements, it is unnecessary to require recording devices or high
temperature alarms. Temperature monitoring can be acceptably achieved
through periodic manual recordings with sufficient frequency to assure
proper temperature control. The large volume liquid mixes in the infant
formula manufacturing process do not demonstrate significant temperature
changes over time. IFC members typically are involved with volumes of
30,000 to 250,000 pounds of liquid mix. Shifts in temperature in these
volumes are extremely slow and do not warrant the increased capital
investment of recording devices and temperature alarms. Thus, it is easy
to see why manual recordings at pre-determined intervals are more than
adequate to monitor cold temperature storage conditions.

Finally, the preamble states that for calibration of thermometers for
cold storage temperature measurements, \"Manufacturers should do so at
least at the beginning and end of each production day\...\" This
frequency is totally unwarranted and would require significant extra
resources to accomplish with absolutely no benefit. Again, the
importance of these cold storage temperature measurements is grossly
exaggerated in the proposal. The Agency is proposing a calibration
frequency that is far more stringent than measurement devices for
thermal food processing, which is a process of critical importance. The
frequency for calibration of cold storage temperature measurement
devices should be determined by the manufacturer based on the volume,
hold time and location in the manufacturing process.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.30(e)(4) When a                 Delete.
  temperature-recording device is     
  used, such device shall not read    
  higher than the calibrated          
  temperature-indicating device for   
  thermal processing equipment or     
  lower than the reference            
  temperature-indicating device for   
  cold storage compartments.          
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.30(e)(4) When a temperature‑recording device is used, such device
shall not read higher than the calibrated temperature‑indicating device
for thermal processing equipment or lower than the reference
temperature‑indicating device for cold storage compartments.~~

######### IFC Comment

See the IFC General Comments regarding Redundancy. Again, the bias
requirement for thermal process recording devices is redundant with 21
CFR Part 113. Simply referencing this regulation is sufficient, as is
recommended in the IFC\'s comment to proposed 106.30(e)(ii). However,
the proposal to bias cold storage temperature recorders is totally
inappropriate. The proposal appears to equate the importance of a very
slight temperature deviation for the sterilization process with a very
slight temperature deviation for the cold storage compartment. The two
situations are radically different. For example, a 1F drop in the
sterilization temperature would have a significant effect on the process
lethality as determined by the process authority and could result in the
failure to meet commercial sterility; whereas a 1F increase in the
temperature of a cold storage compartment would have a very small impact
on the growth of microorganisms. As mentioned in the IFC\'s comments to
106.30(e)(ii), there is no need for recording devices or high
temperature alarms for cold storage compartments, and there certainly is
no justification to require a bias in their recording measurements.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.30(f) Equipment and utensils    106.30(e) Equipment and utensils
  used in the manufacture of infant   used in an operating production
  formula shall be cleaned,           line for the manufacture of infant
  sanitized, and maintained at        formula shall be cleaned and
  regular intervals to prevent        sanitized at regular intervals as
  adulteration of the infant formula. determined by the manufacturer to
  An individual qualified by training be necessary to prevent
  or experience to conduct such a     adulteration of the infant formula.
  review shall check all cleaning,    An individual qualified by training
  sanitizing, and maintenance to      or experience to conduct such a
  ensure that it has been             review shall check all cleaning and
  satisfactorily completed.           sanitizing, to ensure that it has
  Manufacturers shall make and retain been satisfactorily completed.
  records on equipment cleaning,      Manufacturers shall make and retain
  sanitizing, and maintenance, in     records in accordance with Sec.
  accordance with Sec. 106.100(f)(4). 106.100(f)(4).
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.30(~~f~~[e]{.mark}) Equipment and utensils used in [an operating
production line for]{.mark} the manufacture of infant formula shall be
cleaned~~,~~ [and]{.mark} sanitized~~, and maintained~~ at regular
intervals [as determined by the manufacturer to be necessary]{.mark} to
prevent adulteration of the infant formula. An individual qualified by
training or experience to conduct such a review shall check all
cleaning~~,~~ [and]{.mark} sanitizing, ~~and maintenance~~ to ensure
that it has been satisfactorily completed. Manufacturers shall make and
retain records ~~on equipment cleaning, sanitizing, and maintenance,~~
in accordance with Sec. 106.100(f)(4).

IFC Comment

See the IFC General Comment regarding Redundancy. Clarification is
needed for the requirement regarding \"regular intervals\" of cleaning.
If a certain production line, which requires daily cleaning and
sanitizing, is taken out of service for some time, the \"regular
intervals\" will no longer apply to this idle line. The Agency probably
meant to couple \"regular intervals\" with lines that are operational.

The IFC is also confused by the inclusion of \"maintained\" and
\"maintenance\" in this proposed section. If the intention of those
words relates to major equipment repair, the IFC has no objection with
their inclusion. If, however, it is intended to include every minor
action that is taken to \"maintain\" equipment, then the proposal
becomes extremely burdensome. It is potentially far too broad in the
context of on-line equipment control. Coupled with this is the need to
make and retain documentation, which would be extensive if every
maintenance activity (e.g., changing an \"O\" ring) had to be
documented. Because of the IFC\'s concern, it has suggested deleting the
words \"maintained\" and \"maintenance\" in this section.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.30(g) Compressed air or other   Delete.
  gases that are mechanically         
  introduced into infant formula,     
  that are used to clean any          
  equipment, or that come into        
  contact with any other surface that 
  contacts ingredients, in-process    
  materials, or infant formula shall  
  be treated in such a way that their 
  use will not contaminate the infant 
  formula with unlawful indirect food 
  additives or other chemical,        
  physical, or microbiological        
  contaminants. When compressed gases 
  are used at product filling         
  machines to replace air removed     
  from the headspace of containers,   
  the manufacturer shall install a    
  0.5 micrometer or smaller filter as 
  close to the end of the gas line    
  that feeds gas into the space, as   
  practical.                          
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.30(g) Compressed air or other gases that are mechanically
introduced into infant formula, that are used to clean any equipment, or
that come into contact with any other surface that contacts ingredients,
in‑process materials, or infant formula shall be treated in such a way
that their use will not contaminate the infant formula with unlawful
indirect food additives or other chemical, physical, or microbiological
contaminants. When compressed gases are used at product filling machines
to replace air removed from the headspace of containers, the
manufacturer shall install a 0.5 micrometer or smaller filter as close
to the end of the gas line that feeds gas into the space, as
practical.~~

IFC Comment

See the IFC General Comment regarding Redundancy. Under existing
regulations, the introduction of unlawful indirect additives or
adulterants into infant formulas, by way of gases or by any other means,
is already unlawful. Therefore, section (g) should be removed, as it is
redundant and serves no useful purpose.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.35 Controls to prevent          Delete.
  adulteration due to automatic       
  (mechanical or electronic)          
  equipment.                          
  ----------------------------------- -----------------------------------

#########  IFC Redlined Version

~~106.35 Controls to prevent adulteration due to automatic (mechanical
or electronic) equipment.~~

IFC Comment

See the IFC\'s General Comment regarding Validation, recommending that
finalization of section 106.35 be postponed until an appropriate task
force can be convened to work out the details of its wording and
implementation. If such a task-force approach is not acceptable to the
Agency, then it is essential that the following issues be addressed in
any final rule based on this proposal: (1) distinguishing
food-compliance validation standards from drug-compliance standards; (2)
limiting the scope of \"validation\" requirements to critical control
points identified by the manufacturer; and (3) confirming the
releasability of any product manufactured during \"validation\"
processes if it complies with the requirements of the Infant Formula
Act. Although the IFC continues to believe that postponement and a
task-force approach would be the best way to achieve appropriate
regulation in this area, we have listed the remaining subsections of
section 106.35 below, along with our suggestions for addressing the
issues identified above.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.35(a)(1) For the purposes of  | Delete, based on the IFC\'s       |
| this section, \"hardware\" means  | Comment to proposed 106.35.       |
| all automatic equipment,          |                                   |
| including mechanical and          | Delete, based on the IFC\'s       |
| electronic equipment (including   | Comment to proposed 106.35.       |
| computers), that is used in       |                                   |
| production or quality control of  | Delete, based on the IFC\'s       |
| a infant formula.                 | Comment to proposed 106.35.       |
|                                   |                                   |
| 106.35(a)(2) For the purposes of  | Delete, based on the IFC\'s       |
| this section, \"software\" means  | Comment to proposed 106.35.       |
| any programs, procedures, rules,  |                                   |
| and associated documentation used |                                   |
| in the operation of a system.     |                                   |
|                                   |                                   |
| 106.35(a)(3) For the purposes of  |                                   |
| this section, \"system\" means a  |                                   |
| collection of components          |                                   |
| (including software and hardware) |                                   |
| organized to accomplish a         |                                   |
| specific function or set of       |                                   |
| functions in a specified          |                                   |
| environment.                      |                                   |
|                                   |                                   |
| 106.35(a)(4) For the purposes of  |                                   |
| this section, \"validation\"      |                                   |
| means establishing documented     |                                   |
| evidence that provides a high     |                                   |
| degree of assurance that a system |                                   |
| will consistently produce a       |                                   |
| product meeting its predetermined |                                   |
| specifications and quality        |                                   |
| characteristics.                  |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

~~106.35(a)(1) For the purposes of this section, \"hardware\" means all
automatic equipment, including mechanical and electronic equipment
(including computers), that is used in production or quality control of
a infant formula.~~

~~106.35(a)(2) For the purposes of this section, \"software\" means any
programs, procedures, rules, and associated documentation used in the
operation of a system.~~

~~106.35(a)(3) For the purposes of this section, \"system\" means a
collection of components (including software and hardware) organized to
accomplish a specific function or set of functions in a specified
environment.~~

~~106.35(a)(4) For the purposes of this section, \"validation\" means
establishing documented evidence that provides a high degree of
assurance that a system will consistently produce a product meeting its
predetermined specifications and quality characteristics.~~

IFC Comment

The IFC refers the Agency once again to the IFC\'s General Comment on
Validation, where the Council has gone into detail about the problems
inherent in applying this implied drug criterion to infant formula
processing - problems which include an cost burden without attendant
public health benefits, a disincentive to innovation and continuous
process improvement, and the redundancy of mandating front-end
validation to a process which is already required, by law, to be tested
along so many critical parameters at the finished-product stage. While
many aspects of the "validation" concept are already in use in infant
formula manufacture, we highly recommend that a task force be utilized
to determine how and to what extent appropriate aspects of the
\"validation\" concept should be incorporated into infant formula GMPs.

If such an approach is not acceptable, however, the IFC suggests that at
the very least, (a) FDA clarify what acceptable \"validation\" processes
for infant formula would be in order to distinguish it from the
\"validation\" used in drug manufacture, (b) FDA acknowledge that it is
appropriate to leave to the manufacturer the identification of the
critical control points to which validation should be applied; and (c)
FDA confirm the releasability of any product manufactured during
\"validation\" processes if it complies with the requirements of the
Infant Formula Act.

**Rest of page intentionally left blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.35(b)(1) All systems shall be | Delete                            |
| designed, installed, tested, and  |                                   |
| maintained in a manner that will  | or                                |
| ensure that they are capable of   |                                   |
| performing their intended         | 106.35(a)(1) All critical systems |
| function and of producing or      | shall be designed, installed,     |
| analyzing infant formula in       | tested, and maintained in a       |
| accordance with this subpart and  | manner that will ensure that they |
| subpart C of this part.           | are capable of performing their   |
|                                   | intended function and of          |
|                                   | producing or analyzing infant     |
|                                   | formula in accordance with this   |
|                                   | subpart and subpart C of this     |
|                                   | part.                             |
+-----------------------------------+-----------------------------------+
| 106.35(b)(2) The infant formula   | Delete                            |
| manufacturer shall ensure that    |                                   |
| hardware is routinely calibrated, | or                                |
| inspected, and checked according  |                                   |
| to written procedures.            | 106.35(a)(2) The infant formula   |
|                                   | manufacturer shall ensure that    |
|                                   | critical hardware is routinely    |
|                                   | inspected and checked according   |
|                                   | to written procedures.            |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

[Delete]{.mark}

[or]{.mark}

106.35(~~b~~[a]{.mark})(1) All [critical]{.mark} systems shall be
designed, installed, tested, and maintained in a manner that will ensure
that they are capable of performing their intended function and of
producing or analyzing infant formula in accordance with this subpart
and subpart C of this part.

[Delete]{.mark}

[or]{.mark}

106.35(~~b~~[a]{.mark})(2) The infant formula manufacturer shall ensure
that [critical]{.mark} hardware is routinely ~~calibrated,~~
inspected~~,~~ and checked according to written procedures.

IFC Comment

See the IFC\'s suggested addition of the definition of \"critical\" in
the definitions section of the regulation. (IFC suggested 106.3(v)). The
IFC also suggests that \"calibrated\" be deleted, because it applies to
instrumentation, not hardware.

**Rest of page intentionally left blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.35(b)(3) The infant formula   | Delete                            |
| manufacturer shall check and      |                                   |
| document the accuracy of input    | or                                |
| into, and output generated by,    |                                   |
| any system used in the production | 106.35(a)(3) The infant formula   |
| or quality control of an infant   | manufacturer shall check and      |
| formula. The degree and frequency | document the accuracy of input    |
| of input/output verification      | into, and output generated by,    |
| shall be based on the complexity  | any critical system used in the   |
| and reliability of the system and | production or quality control of  |
| the level of risk associated with | an infant formula. The degree and |
| the safe operation of the system. | frequency of input/output         |
|                                   | verification shall be based on    |
|                                   | the manufacturer\'s assessment of |
|                                   | the complexity and reliability of |
|                                   | the system and the level of risk  |
|                                   | associated with the safe          |
|                                   | operation of the system. Quality  |
|                                   | evaluations should be used to     |
|                                   | substantiate the adequacy of the  |
|                                   | checks required by this section.  |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

[Delete]{.mark}

[or]{.mark}

106.35(~~b~~[a]{.mark})(3) The infant formula manufacturer shall check
and document the accuracy of input into, and output generated by, any
[critical]{.mark} system used in the production or quality control of an
infant formula. The degree and frequency of input/output verification
shall be based on the [manufacturer\'s assessment of the]{.mark}
complexity and reliability of the system and the level of risk
associated with the safe operation of the system. [Quality evaluations
should be used to substantiate the adequacy of the checks required by
this section.]{.mark}

IFC Comment

The degree and frequency of input/output verification should be based on
the manufacturer\'s assessment of the complexity and reliability of the
system and the level of risk associated with the safe operation of the
system. Nutrient test results should be used to substantiate the
adequacy of the checks required by this section. The manufacturer should
be responsible not only to determine which systems are critical to the
prevention of adulteration but also to make appropriate assessments of
the degree and frequency of verification necessary. The reference to
nutrient testing reinforces the required testing and emphasizes the
importance that testing plays in the assessment of new production
systems. The accuracy of the input and output generated from an
automated system is assessed by quality evaluations. If all automated
systems need to be tested to prevent errors from faulty data entry,
programming or equipment malfunction, new operator procedures and coding
standards to include error trapping provisions will need to be developed
at a cost that is not warranted and will not provide any additional
security to the consumer.

**Rest of page intentionally left blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.35(b)(4) The infant formula   | Delete                            |
| manufacturer shall ensure that    |                                   |
| all systems are validated before  | or                                |
| their first use to manufacture    |                                   |
| commercial product.               | 106.35(a)(4) The infant formula   |
|                                   | manufacturer shall ensure that    |
|                                   | all critical systems are checked  |
|                                   | as per 106.35(b)(3) before the    |
|                                   | release of commercial product     |
|                                   | initially manufactured with these |
|                                   | systems.                          |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

[Delete]{.mark}

[or]{.mark}

106.35(~~b~~[a]{.mark})(4) The infant formula manufacturer shall ensure
that all [critical]{.mark} systems are ~~validated before their first
use to manufacture~~ [checked as per 106.35(b)(3) before the
release]{.mark} of commercial product [initially manufactured with these
systems]{.mark}.

IFC Comment

While most \"validation\" processes begin prior to the manufacturing of
commercial product, the first commercial batch may be produced as part
of the validation process. Assuming that such a batch meets all the
requirements of the Infant Formula Act, there is no basis for rejecting
it. If all systems need to be validated prior to the manufacture of any
infant formula, this would result in a very large expense (up to
hundreds of thousands of dollars) to destroy the product.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.35(b)(5) The infant formula   | Delete                            |
| manufacturer shall ensure that    |                                   |
| any system that is modified is    | or                                |
| revalidated after the             |                                   |
| modification and before use of    | 106.35(a)(5) The infant formula   |
| the modified system to            | manufacturer shall ensure that    |
| manufacture commercial product.   | any critical system that is       |
| All modifications to software     | modified is reassessed after the  |
| shall be made by a designated     | modification and before release   |
| individual and shall be checked   | of any infant formula             |
| by the infant formula             | manufactured with the modified    |
| manufacturer to ensure that       | system. All modifications to      |
| infant formula that is produced   | critical software shall be made   |
| or analyzed using the modified    | by a designated individual and    |
| software complies with this       | shall be checked by the infant    |
| subpart and with subpart C of     | formula manufacturer to ensure    |
| this part.                        | that infant formula that is       |
|                                   | produced or analyzed using the    |
|                                   | modified software complies with   |
|                                   | this subpart and with subpart C   |
|                                   | of this part.                     |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

[Delete]{.mark}

[or]{.mark}

106.35(~~b~~[a]{.mark})(5) The infant formula manufacturer shall ensure
that any [critical]{.mark} system that is modified is ~~revalidated~~
[reassessed]{.mark} after the modification and before ~~use of~~
[release of any infant formula manufactured with]{.mark} the modified
system ~~to manufacture commercial product~~. All modifications to
[critical]{.mark} software shall be made by a designated individual and
shall be checked by the infant formula manufacturer to ensure that
infant formula that is produced or analyzed using the modified software
complies with this subpart and with subpart C of this part.

IFC Comment

See the IFC\'s General Comment regarding Validation. Additionally, FDA's
April announcement of the reopening of the comment period requested
comments on the specific changes in current activities that would be
required for companies to comply with proposal. Currently, only selected
people can make revisions to software; however, additional documented
training prior to allowing the person to have access may be required by
this regulation.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.35(c) The infant formula      | Delete                            |
| manufacturer shall make and       |                                   |
| retain records, in accordance     | or                                |
| with Sec. 106.100(f)(5),          |                                   |
| concerning automatic (mechanical  | 106.35(b) The infant formula      |
| or electronic) equipment.         | manufacturer shall make and       |
|                                   | retain necessary records, in      |
|                                   | accordance with Sec.              |
|                                   | 106.100(f)(5), concerning         |
|                                   | critical automatic (mechanical or |
|                                   | electronic) equipment.            |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

[Delete]{.mark}

[or]{.mark}

106.35(~~c~~[b]{.mark}) The infant formula manufacturer shall make and
retain [necessary]{.mark} records, in accordance with Sec.
106.100(f)(5), concerning [critical]{.mark} automatic (mechanical or
electronic) equipment.

IFC Comment

See the IFC\'s General Comment regarding Validation and Recordkeeping,
as well as the IFC comment on the suggested definition of \"critical\"
at 106.3(v).

**Rest of page intentionally left blank**

  -----------------------------------------------------------------------
  FDA Proposed Regulation             IFC Suggested Language
  ----------------------------------- -----------------------------------
  **106.40 Controls to prevent        **106.40 Controls to prevent
  adulteration caused by ingredients, adulteration caused by ingredients,
  containers, and closures.**         containers, and closures.**

  106.40(a) The only substances that  Delete.
  may be used in infant formulas are  
  food ingredients whose use in       
  infant formula is safe and suitable 
  under the applicable food safety    
  provisions of the Federal Food,     
  Drug, and Cosmetic Act; that is,    
  the substance is generally          
  recognized as safe (GRAS) for such  
  use, is used in accordance with the 
  agency\'s food additive             
  regulations, or is authorized by a  
  prior sanction.                     

  106.40(b) Infant formula containers Delete.
  and closures shall not be reactive  
  or absorptive so as to affect the   
  safety of the infant formula, and   
  all packaging material that comes   
  in contact with infant formula      
  shall be composed of substances     
  that are GRAS for use in or on      
  food, GRAS for their intended use   
  in food packaging, authorized by a  
  prior sanction issued by the        
  agency, or authorized for use as an 
  indirect food additive. Any         
  packaging material that comes in    
  contact with infant formula shall   
  be used in accordance with any      
  prescribed limitations.             
  -----------------------------------------------------------------------

IFC Redlined Version

~~106.40(a) The only substances that may be used in infant formulas are
food ingredients whose use in infant formula is safe and suitable under
the applicable food safety provisions of the Federal Food, Drug, and
Cosmetic Act; that is, the substance is generally recognized as safe
(GRAS) for such use, is used in accordance with the agency\'s food
additive regulations, or is authorized by a prior sanction.~~

~~106.40(b) Infant formula containers and closures shall not be reactive
or absorptive so as to affect the safety of the infant formula, and all
packaging material that comes in contact with infant formula shall be
composed of substances that are GRAS for use in or on food, GRAS for
their intended use in food packaging, authorized by a prior sanction
issued by the agency, or authorized for use as an indirect food
additive. Any packaging material that comes in contact with infant
formula shall be used in accordance with any prescribed limitations.~~

IFC Comment

See the IFC\'s General Comments regarding Redundancy. Under existing law
and regulations, it is illegal to use an ingredient in an infant formula
that is not GRAS, an approved food additive, or prior-sanctioned for
such use. The same is true for packaging materials. Therefore, sections
(a) and (b) are redundant and should be removed.

In addition, neither 106.40(a) nor 106.40(b) accurately reflects either
current agency practice or the law. Proposed Section 106.40(a) actually
can be read to be at odds with the GRAS notification process (in effect
since 1997) which merely offers a "no objection" to GRAS status as
opposed to a determination of GRAS status. Similarly, Section 106.40(b)
does not reference the food contact substances Amendments of 1997. These
omissions simply underscore the wisdom and value of not proposing such a
section: for not only does such a section bear the potential to be
redundant but also runs the real risk of being antiquated by future
policy and legislative developments.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.40(c) Ingredients, containers,  Acceptable; Renumbered as
  and closures used in the            106.40(a).
  manufacture of infant formula shall 
  be identified with a batch or lot   
  number to be used in recording      
  their disposition.                  

  106.40(d) Infant formula            106.40(b) Infant formula
  manufacturers shall develop written manufacturers shall develop written
  specifications for their acceptance specifications for ingredients,
  or rejection of ingredients,        containers, and closures used as
  containers, and closures used in    components in infant formula
  infant formula manufacture. These   manufacture and packaging.
  specifications shall stipulate the  
  standards for acceptance or         
  rejection of such ingredients,      
  containers, and closures as well as 
  the procedures for determining      
  whether the ingredients,            
  containers, and closures meet that  
  standard. An individual qualified   
  by training or experience shall     
  conduct an investigation of a       
  finding that any ingredients,       
  containers, or closures used in a   
  batch of infant formula failed to   
  meet any of the manufacturer\'s     
  specifications.                     
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.40(~~c~~[a]{.mark}) Ingredients, containers, and closures used in
the manufacture of infant formula shall be identified with a batch or
lot number to be used in recording their disposition.

106.40(~~d~~[b]{.mark}) Infant formula manufacturers shall develop
written specifications for ~~their acceptance or rejection of~~
ingredients, containers, and closures used [as components]{.mark} in
infant formula manufacture~~. These specifications shall stipulate the
standards for acceptance or rejection of such ingredients, containers,
and closures as well as the procedures for determining whether the
ingredients, containers, and closures meet that standard. An individual
qualified by training or experience shall conduct an investigation of a
finding that any ingredients, containers, or closures used in a batch of
infant formula failed to meet any of the manufacturer\'s
specifications~~ [and packaging]{.mark}.

IFC Comment

See the IFC General Comment regarding Specifications. The IFC has
suggested deleting a major portion of this proposal because it is
covered in both 106.3(t), the suggested definition for
\"Specifications,\" and 106.6(c)(3) of the IFC suggestions and comments.
Furthermore, the purpose and extent of the required investigation are
unclear. Although, as modified, the language appears to be acceptable,
several statements in the preamble are very troubling and deserve
comment. First, the preamble suggests that indigenous nutrients should
be included in raw material specifications and standards for acceptance
or rejection. For certain ingredients, IFC members test for indigenous
nutrient levels. However, the testing for indigenous nutrients in these
cases is not for acceptance/rejection of the lot, but to determine the
actual nutrient levels, which can be factored into specific batch
formulations. For other ingredients, such as condensed skim milk, IFC
members have an extensive history in its use in infant formula and they
can predict within a narrow range indigenous nutrient levels. Because of
the experience with this ingredient, and the fact that the condensed
skim milk provides 100% of several of the final product\'s nutrients,
there is no need to assay the ingredient for specific batch
formulations. Therefore, it is appropriate not to assay condensed skim
milk for all indigenous nutrients. All nutrients required to be present
in infant formula are tested and assured on each batch, as required by
the Infant Formula Act, so any theoretical problems that might be
presented would be detected through routine, legally mandated in-process
and finished product testing. Requiring that raw materials be tested for
all indigenous nutrients has significant impact on laboratory space,
manpower, operating costs and potentially quality, all with no increased
assurance of benefit to the final product or the consumer. As indicated
in the actual language of the proposed rule, testing requirements for
raw materials should be determined by the manufacturer.

Second, the preamble suggests that contaminants be included in the raw
material specifications and standards for acceptance or rejection except
as provided in compendial standards such as USP. This is inappropriate
and unworkable. There are significant questions to be considered, such
as how to decide which contaminants to test for in each ingredient, the
determinations of acceptable/unacceptable levels, and detection vs.
quantification scenarios. Even if one were to address these questions,
the inclusion of routine contaminant testing in the infant formula
industry would be grossly impractical due to the sophistication of the
testing involved and the exorbitantly high costs associated with
compliance. Again, testing requirements for raw materials should be
determined by the manufacturer.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.40(e) Ingredients, containers | 106.40(c) Ingredients, containers |
| and closures shall be stored in   | and closures shall be controlled  |
| areas clearly designated for:     | by a system that clearly          |
|                                   | designates:                       |
| 106.40(e)(1) Materials pending    |                                   |
| release for use,                  | Acceptable; Renumbered as         |
|                                   | 106.40(c)(1).                     |
| 106.40(e)(2) Materials released   |                                   |
| for use, or                       | Acceptable; Renumbered as         |
|                                   | 106.40(c)(2).                     |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.40(~~e~~[c]{.mark}) Ingredients, containers and closures shall be
~~stored in areas~~ [controlled by a system]{.mark} [that]{.mark}
clearly ~~designated for~~ [designates]{.mark}:

106.40(~~e~~[c]{.mark})(1) Materials pending release for use,

106.40(~~e~~[c]{.mark})(2) Materials released for use, or

IFC Comment

See the IFC\'s General Comment regarding Separate Storage Areas and
earlier comments to 106.20(b).

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.40(e)(3) Materials rejected for 106.40(c)(3) Materials rejected for
  use in infant formula production.   use in infant formula production.
  Any lot of ingredients, containers, Any lot of ingredients, containers,
  or closures that does not meet the  or closures that has been rejected
  manufacturer\'s specifications      shall be controlled under a
  shall be rejected and controlled    quarantine system designed to
  under a quarantine system designed  prevent its use in the manufacture
  to prevent its use in the           of infant formula, unless and until
  manufacture of infant formula.      it is disposed of or reconditioned
                                      and found acceptable.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.40(~~e~~[c]{.mark})(3) Materials rejected for use in infant formula
production. Any lot of ingredients, containers, or closures that ~~does
not meet the manufacturer\'s specifications shall be rejected and~~ [has
been rejected shall be]{.mark} controlled under a quarantine system
designed to prevent its use in the manufacture of infant formula~~.~~[,
unless and until it is disposed of or reconditioned and found
acceptable.]{.mark}

######### IFC Comment

See the IFC\'s General Comments regarding Specifications. The Agency\'s
proposal includes the requirement that raw material specifications be
set at the extreme acceptability limits. This poses the same problems as
noted in the cited General Comment and the IFC\'s comments for
106.6(c)(1). The language suggested by the IFC removes references to
specifications without removing the intention of the proposal to
quarantine rejected materials until disposition activities are
concluded.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.40(f) If an ingredient, a       106.40(d) If the manufacturer
  container, or a closure that has    determines that an ingredient, a
  been tested and examined is exposed container, or a closure that has
  to air, heat, or other conditions   been tested and examined is exposed
  that may adversely affect it, the   to conditions that could be
  ingredient, container, or closure   expected to adversely affect it,
  shall be retested or reexamined to  the ingredient, container, or
  ensure that it still meets the      closure shall be retested or
  manufacturer\'s specifications.     reexamined to ensure its
                                      acceptability for use in the
                                      manufacturing process.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.40(~~f~~[d]{.mark}) If [the manufacturer determines that]{.mark} an
ingredient, a container, or a closure that has been tested and examined
is exposed to ~~air, heat, or other~~ conditions that ~~may~~ [could be
expected to]{.mark} adversely affect it, the ingredient, container, or
closure shall be retested or reexamined to ensure ~~that it still meets
the manufacturer\'s specifications.~~ [its acceptability for use in the
manufacturing process.]{.mark}

IFC Comment

The requirement to reexamine or retest any ingredient, container or
closure, if it is found by the infant formula manufacturer to have been
exposed to adverse storage conditions, is reasonable. However, this
section can, logically, only apply when the manufacturer has knowledge
of the potentially adverse conditions. To document control of all
storage areas, additional recording charts might be needed to provide
continuous monitoring.

The preamble suggests that indigenous nutrients should be included in
raw material specifications and standards for acceptance or rejection.
For certain ingredients, indigenous nutrient levels are tested, however,
the testing for indigenous nutrients in these cases is usually not for
acceptance/rejection of the lot, but to determine the actual nutrient
levels which can be factored into specific batch formulations. For other
ingredients, such as condensed skim milk, IFC members have an extensive
history in its use in infant formula and they can predict within a
narrow range indigenous nutrient levels. All nutrients required to be
present in infant formula are tested and assured on each batch, as
required by the Infant Formula Act, so any theoretical problems that
might be presented would be detected through routine, legally mandated
in-process and finished product testing. Requiring that raw materials be
tested for all indigenous nutrients would have a huge impact on
laboratory space, manpower, operating costs and potentially quality, all
with no increased assurance of benefit to the final product or the
consumer.

The preamble also suggests that contaminants be included in the raw
material specifications and standards for acceptance or rejection except
as provided in compendia standards such as USP. There are significant
questions to be considered, such as how to decide which contaminants to
test for in each ingredient, the determinations of
acceptable/unacceptable levels, and detection vs. quantification
scenarios. The inclusion of routine contaminant testing in the infant
formula industry would be impractical due to the sophistication of the
testing involved and the very high costs associated with compliance.
Contaminant testing is still undefined, so the program cost could vary
significantly depending on the scope and volume of testing. If the
testing included inorganic and organic compounds that would represent a
broad range of contaminants (heavy metals, pesticides, herbicides,
volatiles and semivolatiles), and the requirement is to test all
ingredients being used in infant formula on an ongoing basis, cost would
be astronomical. Moreover, the primary responsibility for meeting
specifications regarding contaminants lies with the ingredient supplier,
so as a matter of routine, a certificate of analysis or continuing
guaranty from that supplier should be sufficient. Again, any testing
requirements for raw materials should be determined by the infant
formula manufacturer.

  -----------------------------------------------------------------------
  FDA Proposed Regulation             IFC Suggested Language
  ----------------------------------- -----------------------------------
  106.40(g) Manufacturers shall make  Acceptable; Renumbered as
  and retain records, in accordance   106.40(e).
  with §106.100(f)(6), on the         
  ingredients, containers, and        
  closures used in the manufacture of 
  infant formula.                     

  -----------------------------------------------------------------------

IFC Redlined Version

106.40(~~g~~[e]{.mark}) Manufacturers shall make and retain records, in
accordance with §106.100(f)(6), on the ingredients, containers, and
closures used in the manufacture of infant formula.

  -----------------------------------------------------------------------
  FDA Proposed Regulation             IFC Suggested Language
  ----------------------------------- -----------------------------------
  **106.50 Controls to prevent        **106.50 Controls to prevent
  adulteration during                 adulteration during
  manufacturing.**                    manufacturing.**

  106.50(a)(1) Manufacturers shall    Acceptable as proposed.
  prepare and follow a written master 
  manufacturing order that            
  establishes controls and procedures 
  for the production of an infant     
  formula.                            

  106.50(a)(2) The manufacturer shall Acceptable as proposed.
  make and retain records, in         
  accordance with §106.100(e), that   
  include complete information        
  relating to the production and      
  control of the batch. An individual 
  qualified by training or experience 
  shall conduct an investigation of   
  any deviations from the master      
  manufacturing order and any         
  corrective actions taken.           

  106.50(a)(3) Changes made to the    Acceptable as proposed.
  master manufacturing order shall be 
  drafted, reviewed, and approved by  
  a responsible official and include  
  an evaluation of the effect of the  
  change on the nutrient content and  
  the suitability of the formula for  
  infants.                            

  106.50(b) The manufacturer shall    Acceptable as proposed.
  establish controls to ensure that   
  each raw or in-process ingredient   
  required by the master              
  manufacturing order is examined by  
  one person and checked by a second  
  person or system. This checking     
  will ensure that the correct        
  ingredient is added during the      
  manufacturing process, that the     
  ingredient has been released for    
  use in infant formula, and that the 
  correct weight or measure of the    
  ingredient is added to the batch.   
  -----------------------------------------------------------------------

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.50(c) The manufacturer shall    106.50(c) The manufacturer shall
  identify the contents, including    establish a system that permits it
  the processing stage and the lot or to determine the major equipment
  batch number of a batch of infant   systems used during the production
  formula, of all compounding and     of a batch of an infant formula.
  storage containers, processing      
  lines, and major equipment used     
  during the production of a batch of 
  an infant formula.                  
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.50(c) The manufacturer shall ~~identify the contents, including the
processing stage and the lot or batch number of a batch of infant
formula, of all compounding and storage containers, processing lines,
and major equipment~~ [establish a system that permits it to determine
the major equipment systems]{.mark} used during the production of a
batch of an infant formula.

IFC Comment

The IFC is unclear what the Agency means by \"identify\" as that term
relates to the contents of equipment, processing lines and storage
tanks. If the intent is physically to label these items, then the
proposal is totally impractical because multitudes of equipment and
lines are used in the production of infant formula, with several batches
being processed and filled each day. Physical labeling would require a
significant increase in manpower to apply and remove labels several
times daily to accomplish this task with no benefit to the current
operations. If \"identify\" means a system that permits determination of
the location and movement of each batch, that would be a reasonable
requirement.

If the operators need to document all the equipment that is being used
additional personnel will be needed along with a system to track the
equipment, and the resulting cost in manpower and interference with
production timetables would be huge.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.50(d) The manufacturer shall    106.50(d) The manufacturer shall
  establish controls to ensure that   establish and document a system of
  the nutrient levels required by     controls to ensure that the
  Sec. 107.100 of this chapter are    nutrient levels required by Sec.
  maintained in the formula, and that 107.100 of this chapter are
  the formula is not contaminated     maintained in the formula, and that
  with microorganisms or other        the formula is not contaminated
  contaminants. Such controls shall   with microorganisms or other
  include but not be limited to:      contaminants.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.50(d) The manufacturer shall establish [and document a system
of]{.mark} controls to ensure that the nutrient levels required by Sec.
107.100 of this chapter are maintained in the formula, and that the
formula is not contaminated with microorganisms or other contaminants.
~~Such controls shall include but not be limited to:~~

IFC Comment

See the IFC\'s General Comment regarding Prescriptive Regulations. The
intent of this paragraph is sound and is rightfully a part of the GMP
regulations for infant formula. However, the Agency needs only to define
the goal and general intent, as it has in this section, and not define
exact parameters, as it has in the subparagraphs below 106.50(d), that
could unintentionally prevent manufacturers from using other variations
of production that could result in a perfectly acceptable product. For
example, if a manufacturer could package an infant formula without the
removal of air and still meet the nutritional and quality factors
throughout shelf life, the flexibility for this approach should be
allowed within this paragraph. The Agency should stop short of defining
exacting in-process requirements, even as examples, and should let
individual manufacturers determine the best and most economical approach
to producing high quality infant formula that meets the end-points
established by FDA. The manufacturer should then document its intended
approach, as well as its compliance with its own designated control
systems.

**Rest of page intentionally left blank**

  -----------------------------------------------------------------------
  FDA Proposed Regulation             IFC Suggested Language
  ----------------------------------- -----------------------------------
  106.50(d)(1) The mixing time; the   Delete.
  speed, temperature, and flow rate   
  of product; and other critical      
  parameters necessary to ensure the  
  addition of required ingredients    
  to, and the homogeneity of, the     
  formula;                            

  106.50(d)(2) The spray-drying       Delete.
  process for powdered infant         
  formula, including the filtering of 
  the intake air before heating, to   
  prevent microbial and other         
  contamination;                      

  106.50(d)(3) The removal of air     Delete.
  from the finished product to ensure 
  that nutrient deterioration does    
  not occur;                          

  106.50(d)(4) Ensuring that each     Delete.
  container of finished product is    
  properly sealed. Such controls      
  shall involve use of established    
  procedures, specifications, and     
  intervals of examination that are   
  designed by qualified individuals   
  and are sufficient to:              

  106.50(d)(4)(i) Detect visible      Delete.
  closure or seal defects, and        

  106.50(d)(4)(ii) Determine closure  Delete.
  strength through destructive        
  testing. Manufacturers of liquid    
  infant formulas, which are          
  thermally processed low-acid foods  
  packaged in hermetically sealed     
  containers, shall perform such      
  closure integrity testing in        
  accordance with Sec. 113.60(a) of   
  this chapter.                       
  -----------------------------------------------------------------------

IFC Redlined Version

~~106.50(d)(1) The mixing time; the speed, temperature, and flow rate of
product; and other critical parameters necessary to ensure the addition
of required ingredients to, and the homogeneity of, the formula;~~

~~106.50(d)(2) The spray‑drying process for powdered infant formula,
including the filtering of the intake air before heating, to prevent
microbial and other contamination;~~

~~106.50(d)(3) The removal of air from the finished product to ensure
that nutrient deterioration does not occur;~~

~~106.50(d)(4) Ensuring that each container of finished product is
properly sealed. Such controls shall involve use of established
procedures, specifications, and intervals of examination that are
designed by qualified individuals and are sufficient to:~~

~~106.50(d)(4)(i) Detect visible closure or seal defects, and~~

~~106.50(d)(4)(ii) Determine closure strength through destructive
testing. Manufacturers of liquid infant formulas, which are thermally
processed low‑acid foods packaged in hermetically sealed containers,
shall perform such closure integrity testing in accordance with
113.60(a) of this chapter.~~

IFC Comment

See the IFC\'s General Comments regarding Prescriptive Regulations,
Redundancy, and the IFC\'s comments to 106.50(d). The requirements for
closure evaluation are contained in 21 CFR 113 and do not need to be
repeated in this paragraph.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.50(e) The manufacturer shall  | Acceptable as proposed.           |
| establish controls that ensure    |                                   |
| that the equipment used at points |                                   |
| where control is deemed necessary |                                   |
| to prevent adulteration is        |                                   |
| monitored, so that personnel will |                                   |
| be alerted to malfunctions.       |                                   |
+-----------------------------------+-----------------------------------+
| 106.50(f) The manufacturer shall  | Acceptable as proposed.           |
| establish controls that ensure    |                                   |
| that rejected in-process          |                                   |
| materials:                        |                                   |
+-----------------------------------+-----------------------------------+
| 106.50(f)(1) Are clearly          | Acceptable as proposed.           |
| identified as having been         |                                   |
| rejected for use in an infant     |                                   |
| formula;                          |                                   |
+-----------------------------------+-----------------------------------+
| 106.50(f)(2) Are controlled under | Acceptable as proposed.           |
| a quarantine system designed to   |                                   |
| prevent their use in              |                                   |
| manufacturing or processing       |                                   |
| operations for which they are     |                                   |
| unsuitable;                       |                                   |
+-----------------------------------+-----------------------------------+
| 106.50(f)(3) Meet the appropriate | Delete                            |
| specifications, if reprocessed,   |                                   |
| before being released for use in  | or                                |
| infant formula.                   |                                   |
|                                   | 106.50(f)(3) If subjected to      |
|                                   | reprocessing, meet the            |
|                                   | appropriate specifications or     |
|                                   | undergo a documented material     |
|                                   | disposition decision before being |
|                                   | released for further use in       |
|                                   | infant formula.                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

[Delete]{.mark}

[or]{.mark}

106.50(f)(3) [If subjected to reprocessing,]{.mark} ~~M~~[m]{.mark}eet
the appropriate specifications~~, if reprocessed,~~ [or undergo a
documented material disposition decision]{.mark} before being released
for [further]{.mark} use in infant formula.

IFC Comment

If the IFC\'s suggested definition of specifications is accepted, the
IFC suggests deleting this language, because its definition would
address the situation described in this proposed paragraph. See the
IFC\'s General Comment regarding Specifications.

The proposed wording is also awkward. It might mean that in-process
materials for reprocessing or rework must meet specifications prior to
use in infant formula. This would defeat the purpose for rework and
reprocessing, because the purpose of these measures is to correct
in-process deviations and achieve an acceptable finished product. If
this interpretation were correct, this paragraph would have a
significant financial impact on the manufacturer by requiring that all
out of specification in-process material be rejected.

+-----------------+-----------------+-----------------+-----------------+
| FDA Proposed    |                 | IFC Suggested   |                 |
| Regulation      |                 | Language        |                 |
+-----------------+-----------------+-----------------+-----------------+
| **106.55        |                 | **106.55        |                 |
| Controls to     |                 | Controls to     |                 |
| prevent         |                 | prevent         |                 |
| adulteration    |                 | adulteration    |                 |
| from            |                 | from            |                 |
| mi              |                 | mi              |                 |
| croorganisms.** |                 | croorganisms.** |                 |
+-----------------+-----------------+-----------------+-----------------+
| 106.55(a)       |                 | Acceptable as   |                 |
| Manufacturers   |                 | proposed.       |                 |
| of liquid       |                 |                 |                 |
| infant formula  |                 |                 |                 |
| shall comply    |                 |                 |                 |
| with the        |                 |                 |                 |
| procedures      |                 |                 |                 |
| specified in    |                 |                 |                 |
| part 113 of     |                 |                 |                 |
| this chapter    |                 |                 |                 |
| for liquid      |                 |                 |                 |
| infant formula. |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| 106.55(b)       |                 | Acceptable as   |                 |
| Manufacturers   |                 | proposed.       |                 |
| of powdered     |                 |                 |                 |
| infant formula  |                 |                 |                 |
| shall test      |                 |                 |                 |
| representative  |                 |                 |                 |
| samples of      |                 |                 |                 |
| every batch of  |                 |                 |                 |
| the formula at  |                 |                 |                 |
| the final       |                 |                 |                 |
| product stage,  |                 |                 |                 |
| before          |                 |                 |                 |
| distribution,   |                 |                 |                 |
| to ensure that  |                 |                 |                 |
| the infant      |                 |                 |                 |
| formula meets   |                 |                 |                 |
| the             |                 |                 |                 |
| microbiological |                 |                 |                 |
| quality         |                 |                 |                 |
| standards       |                 |                 |                 |
| listed in       |                 |                 |                 |
| paragraph (c)   |                 |                 |                 |
| of this         |                 |                 |                 |
| section.        |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| 106.55(c) Any   |                 | Acceptable as   |                 |
| powdered infant |                 | proposed, with  |                 |
| formula that    |                 | the exceptions  |                 |
| contains any    |                 | in the table    |                 |
| microorganism   |                 | below:          |                 |
| that exceeds    |                 |                 |                 |
| the M value     |                 |                 |                 |
| listed for that |                 |                 |                 |
| microorganism   |                 |                 |                 |
| in Table 1 of   |                 |                 |                 |
| this section    |                 |                 |                 |
| will be deemed  |                 |                 |                 |
| to be           |                 |                 |                 |
| adulterated     |                 |                 |                 |
| under sections  |                 |                 |                 |
| 402 and 412 of  |                 |                 |                 |
| the Federal     |                 |                 |                 |
| Food, Drug, and |                 |                 |                 |
| Cosmetic Act    |                 |                 |                 |
| (the act). FDA  |                 |                 |                 |
| will determine  |                 |                 |                 |
| compliance with |                 |                 |                 |
| the M values    |                 |                 |                 |
| listed below    |                 |                 |                 |
| using the       |                 |                 |                 |
| Bacteriological |                 |                 |                 |
| Analytical      |                 |                 |                 |
| Manual (BAM),   |                 |                 |                 |
| 8th ed. (1995), |                 |                 |                 |
| published by    |                 |                 |                 |
| the AOAC        |                 |                 |                 |
| International   |                 |                 |                 |
| Association of  |                 |                 |                 |
| Official        |                 |                 |                 |
| Analytical      |                 |                 |                 |
| Chemists, which |                 |                 |                 |
| is incorporated |                 |                 |                 |
| by reference in |                 |                 |                 |
| accordance with |                 |                 |                 |
| 5 U.S.C. 552(a) |                 |                 |                 |
| and 1 CFR part  |                 |                 |                 |
| 51. Copies are  |                 |                 |                 |
| available from  |                 |                 |                 |
| the Association |                 |                 |                 |
| of Official     |                 |                 |                 |
| Analytical      |                 |                 |                 |
| Chemists, 481   |                 |                 |                 |
| North Frederick |                 |                 |                 |
| Ave., Suite     |                 |                 |                 |
| 500,            |                 |                 |                 |
| Gaithersburg,   |                 |                 |                 |
| MD 20877, or    |                 |                 |                 |
| may be examined |                 |                 |                 |
| at the Center   |                 |                 |                 |
| for Food Safety |                 |                 |                 |
| and Applied     |                 |                 |                 |
| Nutrition\'s    |                 |                 |                 |
| Library, 200 C  |                 |                 |                 |
| St. SW, rm.     |                 |                 |                 |
| 3321,           |                 |                 |                 |
| Washington, DC, |                 |                 |                 |
| or may be       |                 |                 |                 |
| examined at the |                 |                 |                 |
| Office of the   |                 |                 |                 |
| Federal         |                 |                 |                 |
| Register, 800   |                 |                 |                 |
| North Capitol   |                 |                 |                 |
| St. NW, Suite   |                 |                 |                 |
| 700,            |                 |                 |                 |
| Washington, DC. |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| [Microorgani    | [M              | [Microorgani    | [M              |
| sm]{.underline} | Val             | sm]{.underline} | Value^          |
|                 | ue]{.underline} |                 | 1^]{.underline} |
| Aerobic Plate   |                 | Aerobic Plate   |                 |
| Count (APC)     | 10,000 CFU/gram | Count (APC)     | 10,000 CFU/gram |
|                 | (g).^2^         |                 | (g).^2^         |
| Coliforms^3^    |                 | Ent             |                 |
|                 | 3.05            | erobacteriaceae | 3.0 MPN/g.^4.5^ |
| Fecal           | MPN/g.^4,5^     | (EB)^3^         |                 |
| coliforms^6^    |                 |                 | 0.^7^           |
|                 | 3.05 MPN/g.     | Fecal           |                 |
| *Salmonella*    |                 | coliforms^6^    | 0.^7^           |
|                 | 0.^7^           |                 |                 |
| *Listeria       |                 | *Salmonella*    | 3.0 MPN/g.      |
| monocytogenes*  | 0.^7^           |                 |                 |
|                 |                 | *Staphylococcus | 1000 CFU/g.     |
| *Staphylococcus | 3.05 MPN/g.     | aureus*         |                 |
| aureus*         |                 |                 |                 |
|                 | 100 MPN/g or    | *Bacillus       |                 |
| *Bacillus       | CFU/g.          | cereus*^8^      |                 |
| cereus*^8^      |                 |                 |                 |
+-----------------+-----------------+-----------------+-----------------+
| ^1^ The M value |                 | ^1^ The M value |                 |
| is the maximum  |                 | is the maximum  |                 |
| allowable       |                 | allowable       |                 |
| number of       |                 | number of       |                 |
| microorganisms  |                 | microorganisms  |                 |
| present in 1 g  |                 | present in 1 g  |                 |
| of dry infant   |                 | of dry infant   |                 |
| formula.        |                 | formula.        |                 |
|                 |                 |                 |                 |
| ^2^ CFU/g,      |                 | ^2^ CFU/g,      |                 |
| colony forming  |                 | colony forming  |                 |
| units per g.    |                 | units per g.    |                 |
|                 |                 | Probiotic       |                 |
| ^3^ M values    |                 | infant formulas |                 |
| for coliforms   |                 | are exempted.   |                 |
| greater than    |                 |                 |                 |
| 3.05 are not    |                 | ^3^ M values    |                 |
| violative if    |                 | for EB greater  |                 |
| testing for     |                 | than or equal   |                 |
| fecal coliforms |                 | to 3.0 are not  |                 |
| results in an M |                 | violative if    |                 |
| value equal to  |                 | fecal coliforms |                 |
| or less than    |                 | are not         |                 |
| 3.05.           |                 | confirmed in    |                 |
|                 |                 | the EB test.    |                 |
| ^4^ MPN/g, most |                 |                 |                 |
| probable number |                 | ^4^ MPN/g, most |                 |
| per g.          |                 | probable number |                 |
|                 |                 | per g.          |                 |
| ^5^ The MPN     |                 |                 |                 |
| value of 3.05   |                 | ^5^ The MPN     |                 |
| in this table   |                 | value of 3.0 in |                 |
| is derived from |                 | this table is   |                 |
| the tables of   |                 | derived from    |                 |
| calculated MPN  |                 | the tables of   |                 |
| values that     |                 | calculated MPN  |                 |
| appear in the   |                 | values that     |                 |
| 8th ed. of the  |                 | appear in the   |                 |
| BAM when using  |                 | January 2001    |                 |
| an inoculation  |                 | revision of the |                 |
| series of 0.1,  |                 | 8th ed. of the  |                 |
| 0.01, and       |                 | BAM when using  |                 |
| 0.001g (or ml)  |                 | an inoculation  |                 |
| of the infant   |                 | series of 0.1,  |                 |
| formula sample. |                 | 0.01, and       |                 |
|                 |                 | 0.001g (or ml)  |                 |
| ^6^ No testing  |                 | of the infant   |                 |
| for fecal       |                 | formula sample. |                 |
| coliforms is    |                 |                 |                 |
| required when   |                 | ^6^ No          |                 |
| the M value for |                 | confirmation    |                 |
| coliforms is    |                 | testing for     |                 |
| less than or    |                 | fecal coliforms |                 |
| equal to 3.05.  |                 | is required     |                 |
|                 |                 | when the M      |                 |
| ^7^ None        |                 | value for EB is |                 |
| detected.       |                 | less than 3.0.  |                 |
|                 |                 |                 |                 |
| ^8^ B. cereus   |                 | ^7^ None        |                 |
| testing must be |                 | detected.       |                 |
| performed only  |                 |                 |                 |
| if the APC      |                 | ^8^ *B. cereus* |                 |
| exceeds 100     |                 | testing must be |                 |
| CFU/g.          |                 | performed only  |                 |
|                 |                 | if the APC      |                 |
|                 |                 | exceeds 1000    |                 |
|                 |                 | CFU/g (except   |                 |
|                 |                 | for probiotic   |                 |
|                 |                 | infant          |                 |
|                 |                 | formulas).      |                 |
+-----------------+-----------------+-----------------+-----------------+

IFC Redlined Version (partial for space saving)

+-----------------------------------+-----------------------------------+
| Microorganism                     | M Value[^1^]{.mark}               |
+-----------------------------------+-----------------------------------+
| Aerobic Plate Count (APC)         | 10,000 CFU/gram (g).^2^           |
|                                   |                                   |
| [Enterobacteriaceae               | 3.0~~5~~ MPN/g.^4,5^              |
| (EB)]{.mark}^3^                   |                                   |
|                                   | ~~3.05 MPN/g.~~ [0.^7^]{.mark}    |
| Fecal coliforms^6^                |                                   |
|                                   | 0.^7^                             |
| *Salmonella*                      |                                   |
|                                   | ~~0.^7\ ^~~                       |
| *~~Listeria monocytogenes~~*      |                                   |
|                                   | 3.0~~5~~ MPN/g.                   |
| *Staphylococcus aureus*           |                                   |
|                                   | ~~100~~ [1000]{.mark} CFU/g.      |
| *Bacillus cereus*^8^              |                                   |
+-----------------------------------+-----------------------------------+

^1^ The M value is the maximum allowable number of microorganisms
present in 1 g of dry infant formula.

^2^ CFU/g, colony forming units per g. [Probiotic infant formulas are
exempted.]{.mark}

^3^ M values for [EB]{.mark} ~~coliforms~~ greater than [or equal
to]{.mark} 3.0~~5~~ are not violative if ~~testing for~~ fecal coliforms
[are not confirmed in the EB test]{.mark} ~~results in an M value equal
to or less than 3.05~~.

^4^ MPN/g, most probable number per g.

^5^ The MPN value of 3.0~~5~~ in this table is derived from the tables
of calculated MPN values that appear in [the January 2001 revision
of]{.mark} the 8th ed. of the BAM when using an inoculation series of
0.1, 0.01, and 0.001g (or ml) of the infant formula sample.

^6^ No [confirmation]{.mark} testing for fecal coliforms is required
when the M value for [EB]{.mark} ~~coliforms~~ is less than ~~or equal
to~~ 3.0~~5~~.

^7^ None detected.

^8^ *[B. cereus]{.mark}* testing must be performed only if the APC
exceeds [1000]{.mark} ~~100~~ CFU/g [(except for probiotic infant
formulas)]{.mark}.

######### IFC Comment 

The IFC questions the need to conduct Listeria testing. Historical
screening for Listeria in infant formula products has never revealed the
presence of this organism. In addition, infant formula ingredients and
products undergo several heat treatments. The supplier has already
pasteurized the incoming milk; the in-process infant formula mix is
pasteurized at least once again before drying. These multiple heat
treatments are very effective for microbiological control of infant
formula.

For the testing of *B. cereus*, the proposed specification to 100 CFU/g
maximum allowance is lower than the earlier proposed maximum of 1000
CFU/g. Neither the IFC\'s literature review nor industry field
experience indicates a health concern associated with *B. cereus* levels
of 1000 CFU/g, let alone 100 CFU/g. The infectious dose of *B. cereus*
for infants is unknown. The proposed CFR wording is based upon a concern
for product abuse, i.e., storage of rehydrated product for 24 hours at
26C (79F). Label instructions clearly indicate the need to store
rehydrated product under refrigeration and to discard formula
immediately after feeding.

Because of the Agency's concerns with the emerging, opportunistic
pathogen, *E. sakazakii* -- arising from an outbreak of disease in
premature infants -- FDA's April 2003 announcement of the reopening of
the comment period on this proposal requested comments 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 prevent future outbreaks. The
Agency also requested comment on what other changes, if any, in the
proposed microbiological requirements would be appropriate to ensure the
safety of powdered infant formula and to prevent outbreaks of illness.
Given the excellent safety record of infant formula since the passage of
the act, IFC does not see a real need for additional microbiological
requirements to be added here. In particular, IFC questions the
practicality of including specific microbiological specifications in the
GMP regulations given the length of time required to pass or change such
regulations. Perhaps, when the Agency encounters emerging pathogens of
concern in the future, it could use a mechanism for establishing interim
requirements that is less burdensome than the GMP regulations. A
guidance document, based soundly on scientific and industrial input to
ensure both reliability and feasibility would be easier to create and
manage.

Relevant to a manufacturer\'s intended use of *Bifidobacterium lactis*
strain Bb12 and *Streptococcus thermophilus* strain Th4 as ingredients
in infant formula, the Agency's April announcement requested comment on
what changes, if any, in the proposed microbiological requirements would
be appropriate to provide for powdered infant formula and to ensure its
safety if microorganisms are intentionally added to infant formulas.
It's not clear that the proposed microbiological requirements would have
any negative impact at all on the addition of beneficial organisms to
infant formula. Currently, infant formula products marketed worldwide
may contain anaerobic and/or facultative anaerobic microorganisms that
have been intentionally included ("probiotics"). While it is possible
that some infant formulas supplemented with approved probiotics might
exceed the aerobic plate count, others would not. Those beneficial
bacteria that are anaerobic would not even contribute to the number of
microorganisms in the aerobic plate count (APC) as they would not be
supported with the proper environmental conditions for growth.

Nevertheless, products with intentionally added microorganisms should be
exempt from the proposed product aerobic plate count limit. It is
appropriate for the APC limit to be excluded for this type of product,
as long as it is replaced by more reliance on sanitation-indicative
testing. For example, direct limits for Enterobacteriaceae, would be
placed on these products.  Additional testing that is typically required
only when APC limitations are exceeded (e.g., *B. cereus*) would be
automatically required for such products. This would be similar to the
currently recommended evaluation of cultured dairy products (e.g.,
cottage cheese, yogurt, and sour cream).  

Given that sampling and testing for microbiological endpoints continue
to be areas where there is variability, and thus uncertainty of results,
IFC urges FDA to move forward, in conjunction with the infant formula
industry, toward defining sampling and testing methods in association
with establishing microbiological specifications. Setting up two-class
or three-class plans, as proposed by ICMSF and recognized by Codex,
would be one avenue to pursue toward this aim.

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.55(d) Manufacturers shall make  Acceptable as proposed.
  and retain records, in accordance   
  with §106.100(e)(5)(ii) and (f)(7), 
  on the testing of infant formulas   
  for microorganisms.                 

  **106.60 Controls to prevent        **106.60 Controls to prevent
  adulteration during packaging and   adulteration during packaging and
  labeling of infant formula.**       labeling of infant formula.**

  106.60(a) Manufacturers shall       Acceptable as proposed.
  examine packaged and labeled infant 
  formula during finishing operations 
  to ensure that containers and       
  packages in the lot have the        
  correct label, the correct use‑by   
  date, and the correct code          
  established under §106.80.          

  106.60(b) Labels shall be designed, 106.60(b) Labels shall be designed,
  printed, and applied so that the    printed, and applied so that the
  labels remain legible and attached  labels remain legible and attached
  during the conditions of            during the conditions of
  processing, storage, handling,      processing, storage, handling, and
  distribution, and use.              distribution.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.60(b) Labels shall be designed, printed, and applied so that the
labels remain legible and attached during the conditions of processing,
storage, handling, [and]{.mark} distribution~~, and use~~.

IFC Comment

Labels often have coupons or second-language directions printed on the
inside (i.e., they are \"designed\" and \"printed\" to come off), and
the words \"and use\" in the proposal would negate this consumer
benefit.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.60(c) All infant formulas held  106.60(c) Packaging used to hold
  in a single package shall be the    multiple containers of the same
  same product bearing the same code, type of infant formula shall be
  established under Sec. 106.80.      labeled with the product name, the
  Packaging used to hold multiple     name of the manufacturer,
  containers of infant formula shall  distributor or shipper, and the lot
  be labeled with the product name,   number. Packaging used to hold
  the name of the manufacturer or     containers of different types of
  shipper, and the code.              infant formula shall be labeled
                                      with the product names, the name of
                                      the manufacturer, responsible party
                                      or shipper, a lot number code that
                                      can serve to identify the contents,
                                      and an expiration date reflecting a
                                      shelf life no greater than the
                                      container exhibiting the shortest
                                      expiration date.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.60(c) ~~All infant formulas held in a single package shall be the
same product bearing the same code, established under Sec. 106.80.~~
Packaging used to hold multiple containers of [the same type of]{.mark}
infant formula shall be labeled with the product name, the name of the
manufacturer[, distributor]{.mark} or shipper, and the [lot number.
Packaging used to hold containers of different types of infant formula
shall be labeled with the product names, the name of the manufacturer,
responsible party or shipper, a lot number]{.mark} code [that can serve
to identify the contents, and an expiration date reflecting a shelf life
no greater than the container exhibiting the shortest expiration
date.]{.mark}

IFC Comment

For the majority of cases, an infant formula package holding multiple
containers will be all of the same product bearing the same code.
However, there needs to be an allowance for \"kits,\" which are commonly
used in the industry to familiarize new mothers with infant formula
prior to discharge from the hospital. These kits are designed to hold
samples of different products. Therefore, they necessarily contain
products with different codes and are so labeled. These kits are
assigned a unique lot number for traceability purposes. The IFC believes
that the intention of the Agency is not to eliminate \"kits,\" which
would disserve consumers and hospitals and which would have a
substantial impact on the respective marketing programs of each company.
Therefore, the IFC requests that the regulations be written to allow
\"kits.\"

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **106.70 Controls on the release  | **106.70 Controls on the release  |
| of finished infant formula.**     | of finished infant formula.**     |
|                                   |                                   |
| 106.70(a) The manufacturer shall  | 106.70(a) The manufacturer or     |
| hold, or maintain under its       | responsible party shall hold, or  |
| control, each batch of infant     | maintain under its control, each  |
| formula until it determines that  | batch of infant formula until it  |
| the batch meets all of its        | determines that the batch meets   |
| specifications, including those   | the requirements of 21 CFR Part   |
| adopted to meet the requirements  | 106.                              |
| of Sec. 106.55 on microbiological |                                   |
| contamination and Sec. 106.91(a)  |                                   |
| on quality control procedures,    |                                   |
| and releases the batch for        |                                   |
| distribution.                     |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.70(a) The manufacturer [or responsible party]{.mark} shall hold, or
maintain under its control, each batch of infant formula until it
determines that the batch meets ~~all of its specifications, including
those adopted to meet~~ the requirements of ~~106.55 on microbiological
contamination and 106.91(a) on quality control procedures, and releases
the batch for distribution.~~ [21 CFR Part 106.]{.mark}

IFC Comment

See the IFC\'s General Comment regarding Specifications. As that General
Comment and the comments to 106.6(c)(1) state, the IFC believes that
manufacturers should be encouraged to set tight specifications, and that
the failure to meet such tight specifications should not automatically
result in rejected product. As mentioned previously, product failing to
meet the tighter specifications would be properly reviewed for
disposition purposes. Of course, the manufacturer must meet all
specifications listed in 106.55 and the requirements in 106.91(a), which
are included in the requirements of Part 106.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.70(b) Each batch of infant      106.70(b) Each batch of infant
  formula that fails to meet the      formula that fails to meet the
  manufacturer\'s specifications      requirements of Sec. 106.70(a)
  shall be rejected. Although the     shall be rejected. Although the
  batch may be reprocessed, any batch batch may be reprocessed, any batch
  of infant formula that is           of infant formula that is
  reprocessed shall be shown to meet  reprocessed shall be shown to meet
  the requirements of Sec. 106.70(a)  the requirements of Sec. 106.70(a)
  before it is released.              before it is released.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.70(b) Each batch of infant formula that fails to meet the
~~manufacturer\'s specifications~~ [requirements of Sec.
106.70(a)]{.mark} shall be rejected. Although the batch may be
reprocessed, any batch of infant formula that is reprocessed shall be
shown to meet the requirements of Sec. 106.70(a) before it is released.

IFC Comment

See General Comments regarding Specifications. As noted in 106.6(c)(1)
and 106.50(f)(3), the IFC neither wishes to widen specifications to the
outer acceptability limits nor eliminate the purpose for rework and
reprocessing.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.70(c) An individual qualified   106.70(c) An individual qualified
  by training or experience shall     by training or experience shall
  conduct an investigation of a       conduct an investigation of a
  finding that a batch of infant      finding that a batch of infant
  formula fails to meet any           formula fails to meet any
  manufacturer\'s specifications.     manufacturer\'s or responsible
                                      party\'s specifications in order to
                                      ensure that such failure does not
                                      lead to the release of adulterated
                                      product.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.70(c) An individual qualified by training or experience shall
conduct an investigation of a finding that a batch of infant formula
fails to meet any manufacturer\'s ~~specifications.~~ [or responsible
party\'s specifications in order to ensure that such failure does not
lead to the release of adulterated product.]{.mark}

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer. The
IFC has also suggested language from section 106.40 indicating the
purpose and extent of the required investigation.

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  **106.80 Traceability.**            **106.80 Traceability.**

  106.80(a) Manufacturers shall       Acceptable as proposed.
  ensure traceability by coding       
  infant formulas in conformity with  
  the coding requirements prescribed  
  in §113.60(c) of this chapter for   
  thermally processed low‑acid foods  
  packaged in hermetically‑sealed     
  containers, except as provided in   
  paragraph (b) of this section.      

  106.80(b) Batches of powdered       Acceptable as proposed.
  infant formula that are             
  manufactured in stages over more    
  than 1 day, in lieu of being coded  
  in accordance with §113.60(c) of    
  this chapter, may be coded with a   
  sequential number that identifies   
  the product and the establishment   
  where the product was packed and    
  that permits tracing of all stages  
  of manufacture of that batch,       
  including the year, the days of the 
  year, and the period during those   
  days that the product was packed,   
  and the receipt and handling of raw 
  materials used.                     

  **106.90 Audits of current good     **106.90 Audits of current good
  manufacturing practice.**           manufacturing practice.**

  Manufacturers of an infant formula, Manufacturers of an infant formula,
  or an agent of such manufacturers,  or an agent of such manufacturers,
  shall conduct regularly scheduled   shall conduct regularly scheduled
  audits to determine whether the     audits to determine whether the
  manufacturer has complied with the  manufacturer has complied with the
  current good manufacturing practice current good manufacturing practice
  regulations in this subpart. These  regulations in this subpart. These
  audits shall be performed by an     audits shall be performed by an
  individual who, as a result of      individual who, as a result of
  education, training, and            education, training, and
  experience, is knowledgeable in all experience, is knowledgeable of
  aspects of infant formula           infant formula production and of
  production and of the agency\'s     the agency\'s regulations
  regulations concerning current good concerning good manufacturing
  manufacturing practice but who has  practices but who has no direct
  no direct responsibility for the    responsibility for the matters
  matters being audited.              being audited.
  ----------------------------------- -----------------------------------

IFC Redlined Version

**106.90 ~~‑‑~~Audits of current good manufacturing practice.**

Manufacturers of an infant formula, or an agent of such manufacturers,
shall conduct regularly scheduled audits to determine whether the
manufacturer has complied with the current good manufacturing practice
regulations in this subpart. These audits shall be performed by an
individual who, as a result of education, training, and experience, is
knowledgeable ~~in all aspects~~ of infant formula production and of the
agency\'s regulations concerning good manufacturing practices but who
has no direct responsibility for the matters being audited.

IFC Comment

The Agency proposes that an auditor be knowledgeable in \"all\" aspects
of infant formula production. This is a very lofty expectation given the
complexities of an infant formula production environment which entails
raw materials, blending/mixing, processing, standardization, filling,
sterilization/drying, packing, warehousing, shipping, maintenance,
cleaning, lab testing, documentation control, batch record
review/release, training, etc. The phrase seems to imply that the
auditor must be a supreme expert within the plant who knows all there is
to know about infant formula production.

The IFC believes it is sufficient for an auditor to possess a general
knowledge of these areas, but certainly he or she need not have
knowledge to the depth and extent as the use of the word \"all\" in the
proposal may imply. Such knowledge would entail years of cross training
and constant retraining. The IFC believes that removing the word \"all\"
does not diminish the intent of the Agency in this proposal.

The IFC agrees with the Agency\'s statement that the auditor shall have
\"no direct responsibility for the matters being audited.\" However, the
preamble suggests that the auditor shall have no \"past involvement in
the activities being audited.\" This is a potential \"Catch 22,\" and
troublesome in that the proposed regulations seem to want the auditor to
have knowledge of infant formula production, but have no past
involvement where knowledge might have been gained. It\'s understandable
that the regulations do not want the auditor to evaluate areas in which
he or she had responsibility. It\'s equally understandable that an
auditor should not evaluate an area in which he or she has recently
worked, due to potential biases created by the previous position.
However, a reasonable time should be established after which any concern
about potential bias would dissipate and an auditor could evaluate an
area of previous employment. If the Agency feels the need to specify a
time limit in the regulation, the IFC suggests that limit be one year.
Thus, an auditor would be allowed to audit an area of previous
employment one year after departure.

Finally, the preamble also suggests that \"regularly scheduled audits of
all deviations\" should be incorporated. As stated earlier in
106.6(c)(1), IFC members want the final regulations to allow
specifications much tighter than the outer acceptability limits proposed
by the Agency. See the IFC\'s General Comment regarding Specifications.
This will obviously result in significantly more out-of-specification
situations (which will each require a review for disposition) than will
result if the outer acceptability limits proposed by FDA are required.
It should be appreciated that the increased numbers of deviations under
the IFC\'s proposal does not signify a process out of control, but
instead the inevitable result of a manufacturer\'s desire to keep the
process centered as tightly as possible. If the IFC\'s tighter
specification allowance is incorporated in the final regulation, it does
not feel that the auditor should be required to review \"all\"
deviations. In such a case, the IFC would suggest requiring that a
random sampling of deviations be reviewed.

Rest of page intentionally left blank

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **Subpart C\--Quality Control     | **Subpart C\--Quality Control     |
| Procedures**                      | Procedures**                      |
|                                   |                                   |
| **106.91 General quality          | **106.91 General quality          |
| control.**                        | control.**                        |
|                                   |                                   |
| 106.91(a) *Nutrient testing to    | 106.91(a) *Nutrient testing to    |
| ensure that each batch of infant  | ensure that each batch of infant  |
| formula provides nutrients in     | formula provides nutrients in     |
| accordance with Sec. 107.100.*    | accordance with Sec. 107.100.*    |
| Manufacturers shall test each     | Manufacturers or responsible      |
| batch as follows:                 | parties shall test each batch as  |
|                                   | follows:                          |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.91(a) *Nutrient testing to ensure that each batch of infant formula
provides nutrients in accordance with Sec. 107.100.* Manufacturers [or
responsible parties]{.mark} shall test each batch as follows:

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer.

**Rest of page intentionally left blank**

  -----------------------------------------------------------------------
  FDA Proposed Regulation             IFC Suggested Language
  ----------------------------------- -----------------------------------
  106.91(a)(1) Each nutrient premix   Acceptable as proposed.
  used in the manufacture of an       
  infant formula shall be tested for  
  each nutrient that the manufacturer 
  is relying on the premix to provide 
  to ensure that the premix is in     
  compliance with the manufacturer\'s 
  specifications;                     

  106.91(a)(2) During the             Acceptable as proposed.
  manufacturing process, after the    
  addition of the premix, or at the   
  final‑product‑stage but before      
  distribution, each batch of infant  
  formula shall be tested for at      
  least one indicator nutrient for    
  each of the nutrient premixes used  
  in the infant formula to confirm    
  that the nutrients supplied by each 
  of the premixes are present, in the 
  proper concentration, in the batch  
  of infant formula.                  

  106.91(a)(3) At the                 Acceptable as proposed.
  final‑product‑stage, before         
  distribution of an infant formula,  
  each batch shall be tested for      
  vitamins A, C, E, and thiamin.      

  106.91(a)(4) During the             106.91(a)(4) During the
  manufacturing process or at the     manufacturing process or at the
  final-product-stage, before         final-product-stage, before
  distribution, each batch shall be   distribution, each batch shall be
  tested for all nutrients required   tested for each nutrient required
  to be included in such formula      to be included in such formula
  under Sec. 107.100 of this chapter  under 107.100 of this chapter if
  and for any nutrient added by the   the presence of that nutrient in
  manufacturer for which testing is   the batch has not been confirmed
  not conducted for compliance with   pursuant to testing conducted for
  paragraphs (a)(1) or (a)(3) of this compliance with paragraphs (a)(1),
  section.                            (a)(2) or (a)(3) of this section.
                                      Such testing shall be conducted
                                      using validated test methods.
  -----------------------------------------------------------------------

IFC Redlined Version

106.91(a)(4) During the manufacturing process or at the
final‑product‑stage, before distribution, each batch shall be tested for
~~all nutrients~~ [each nutrient]{.mark} required to be included in such
formula under 107.100 of this chapter ~~and for any nutrient added by
the manufacturer for which testing is not~~ [if the presence of that
nutrient in the batch has not been confirmed pursuant to testing]{.mark}
conducted for compliance with paragraphs (a)(1)[, (a)(2)]{.mark} or
(a)(3) of this section. [Such testing shall be conducted using validated
test methods.]{.mark}

IFC Comment

The IFC suggests several changes to this required testing language. The
Infant Formula Act is soundly based on the principle that infant
formulas must be extensively tested to confirm that they contain
nutrients in conformance with the nutrient table requirements. It would
seem advisable, accordingly, to require the use of validated nutrient
test methods to ensure the accuracy and precision of test results to
determine compliance to the Act. While the Agency has included several
proposals for validation of equipment, software and systems in proposed
106.35, most of which seem unnecessary to the IFC, the requirement for
validated test methods is noticeably missing. To assure that the
nutrient requirements of the Act are met with a high degree of
confidence, the Agency should address methods validation in the final
regulation.

The language suggested by the IFC above attempts to make clearer the
testing requirements for nutrients in premixes. The IFC interprets and
agrees with FDA\'s intent to allow manufacturers or responsible parties
to rely on testing pursuant to (a)(1) (as part of a premix), i.e., that
finished product retesting for nutrients confirmed as part of (a)(1)
premix testing is unnecessary pursuant to this section. Suggested
addition of the phrase, \"if the presence of that nutrient in the batch
has not been confirmed pursuant to testing\" above attempts to clarify
that intent.

The IFC also believes that testing pursuant to (a)(2) should not be
omitted from the list of prior testing recognized as sufficient to avoid
finished product testing. The inclusion of (a)(2) is essential because
(a)(1) alone would only confirm that a nutrient was present at the
appropriate level in the premix, not that it was also present at the
appropriate level in the formula itself.

Finally, the IFC sees no added benefit to the testing of nutrients not
already listed in section 107.100, and has suggested its removal here,
consistent with the charges already suggested for section 106.3(m) the
definition of \"nutrient.\"

Additionally, FDA's April announcement of the reopening of the comment
period requested comments on the specific changes in current activities
that would be required for companies to comply with proposal. All
nutrients required to be included in infant formula under section
107.100 are currently being verified through testing. If FDA requires
that all nutrients added by the manufacturer need to be tested, even
where no quantity is declared on the label, this would add significant
costs for additional laboratory facilities, tests and personnel to
confirm their presence.

**Rest of page intentionally left blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+===================================+===================================+
| 106.91(b) *Stability testing*.    | 106.91(b) *Testing of finished    |
| Every 3 months, manufacturers     | product to confirm that the       |
| shall collect representative      | infant formula provides nutrients |
| samples from the                  | in accordance with Sec. 107.100.* |
| final-product-stage of one batch  | Manufacturers or responsible      |
| of each physical form (powder,    | parties shall test finished       |
| ready-to-feed, or concentrate) of | product as follows:               |
| each infant formula, at each      |                                   |
| manufacturing facility. The       | 106.91(b)(1) *Periodic Analysis*. |
| manufacturer shall test these     | Every 3 months, manufacturers or  |
| samples for each nutrient         | responsible parties shall collect |
| required under Sec. 107.100 of    | representative samples of infant  |
| this chapter and for any nutrient | formula of one batch of each      |
| added by the manufacturer. The    | physical form (powder,            |
| frequency of such testing shall   | ready-to-feed, or concentrate) of |
| be at the beginning, midpoint,    | each infant formula, at each      |
| and end of the shelf life of the  | manufacturing facility. The       |
| infant formula and, depending on  | manufacturer shall test these     |
| the nutrient and its stability    | samples for each nutrient         |
| within the matrix of the          | required under Sec. 107.100 of    |
| formulation, with additional      | this chapter that was not tested  |
| frequency as is necessary to      | directly at the finished product  |
| ensure that such formula complies | stage pursuant to 106.91(a)(4).   |
| with section 412 of the Federal   |                                   |
| Food, Drug, and Cosmetic Act (the | 106.91(b)(2) *Stability testing*. |
| act) throughout the shelf life of | Using representative samples      |
| the infant formula; except that:  | collected from finished product   |
|                                   | batches, the manufacturer shall   |
|                                   | conduct stability analysis for    |
|                                   | selected labile nutrients with    |
|                                   | sufficient frequency to           |
|                                   | substantiate the maintenance of   |
|                                   | nutrient content consistent with  |
|                                   | section 412 of the Federal Food,  |
|                                   | Drug, and Cosmetic Act (the act)  |
|                                   | throughout the shelf life of the  |
|                                   | infant formula.                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.91(b) *~~Stability testing~~ [Testing of finished product to confirm
that the infant formula provides nutrients in accordance with Sec.
107.100.]{.mark}* [Manufacturers or responsible parties shall test
finished product as follows:]{.mark}

[106.91(b)(1) *Periodic Analysis*]{.mark}. Every 3 months, manufacturers
[or responsible parties]{.mark} shall collect representative samples
~~from the final‑product‑stage~~ [of infant formula]{.mark} of one batch
of each physical form (powder, ready‑to‑feed, or concentrate) of each
infant formula, at each manufacturing facility. The manufacturer shall
test these samples for each nutrient required under Sec. 107.100 of this
chapter ~~and for any nutrient added by the manufacturer. The frequency
of such testing shall be at the beginning, midpoint, and end of~~ [that
was not tested directly at the finished product stage pursuant to
106.91(a)(4).]{.mark}

[106.91(b)(2) *Stability testing*. Using representative samples
collected from finished product batches, the manufacturer shall conduct
stability analysis for selected labile nutrients]{.mark} ~~The frequency
of such testing shall be at the beginning, midpoint, and end of~~ [with
sufficient frequency to substantiate the maintenance of nutrient content
consistent]{.mark} ~~throughout the shelf life of the infant formula
and, depending on the nutrient and its stability within the matrix of
the formulation, with additional frequency as is necessary to ensure
that such formula complies~~ [with section 412 of the Federal Food,
Drug, and Cosmetic Act (the act) throughout the shelf life of the infant
formula.]{.mark}~~; except that:~~

IFC Comment

The current infant formula quality control regulations distinguish
between testing performed as a Periodic Analysis (106.30(b)(2)) and as a
Stability Analysis (106.30(b)(3)). This distinction makes sense. These
two testing regimens serve different purposes, and each has worked
independently and effectively over the past decade to provide additional
assurances that required nutrients are present within required ranges in
infant formula.

Periodic analyses serve as a quarterly check that the controls used to
assure the presence of all required nutrients within required ranges in
the finished infant formula are appropriate. Stability analyses, on the
other hand, serve as a check that labile nutrients (i.e., those that
tend to degrade over time) present in infant formula at the finished
product stage do not, over the shelf life of the formula, degrade below
minimum levels. Infant formula manufacturers are required to test
finished products for all nutrients initially and then evaluate for
stability at the end of shelf life. In the new proposal, all nutrients
would need to be tested at a minimum of the beginning, middle and end of
shelf life to substantiate the nutrient content. This additional testing
of all nutrients in addition to the added time point during the shelf
life will require additional personnel, capital and yearly operating
expenses without any real benefit.

FDA\'s proposal has two major problems, however: it combines the two
types of testing inappropriately and the stability testing proposal
requires an excessive number of infant formulas and nutrients to be
routinely analyzed. The IFC feels that it is inappropriate and
unwarranted to combine these two different types of testing. Although
the results of testing generated pursuant to Periodic Analyses can also
be used as the \"beginning\" results for Stability Analyses, that is the
only logical overlap between the two. With regard to stability testing,
because manufacturers typically produce more than one variation of a
single infant formula product, as well as multiple presentation sizes,
the samples required to be set aside for quarterly stability testing
could run into the hundreds.

Because the IFC feels that combining the two types of testing introduces
unwarranted and burdensome additional testing into each other, the IFC
suggests separating proposed 106.91(b) into two subparagraphs: (b)(1)
and (b)(2), Periodic Analyses and Stability Testing, respectively, and
making the additional changes discussed below.

As separated, the requirement to conduct Periodic Analyses is
straightforward. Quarterly, a manufacturer or responsible party must
test a finished batch of each form of infant formula (in each facility)
for all nutrients not analyzed directly in the immediate analysis of
that batch. With respect to stability testing, the IFC submits that the
current regulation requiring stability analyses, 106.30(b)(3),
incorporates all the needed safeguards to assure that infant formula
provides required nutrients within required ranges over the labeled
shelf life of the infant formula. The IFC\'s proposed language simply
incorporates the wording of current 106.30(b)(3) into the proposed
testing regimen.

While the IFC believes that its suggested revisions to the proposal are
justified, the discussion that follows addresses the shortcomings that
it perceives exist in the stability testing contained in FDA\'s
proposal. As proposed, stability testing would add significantly to the
cost of infant formula by requiring that \"all\" nutrients be tested
throughout shelf life, not just the ones that are subject to degradation
or other change. Adding to the cost of infant formula by mandating
manufacturers or responsible parties to test for nutrients a) that are
known to be in the product (from results of the Periodic Analysis and
other testing) and b) do not degrade, even under extreme conditions of
storage, cannot be justified.

Attached are nutritional profiles of infant formula provided to FASEB.
(Attachment O). They demonstrate the IFC\'s point that stability testing
for nondegradable nutrients known to be present in the product at the
start of stability testing will yield no new information and simply add
cost to the product without adding value. These results, which were
developed by the IFC in the context of FASEB\'s review of nutrient
requirements for infant formula, show that certain nutrients are known
not to degrade in infant formula.

The IFC acknowledges the concern expressed by the Agency in the preamble
that \"selected nutrients\" may be chosen for analyses based on past
experience, but that a new infant formula may change the assumptions.
This concern is adequately addressed with the remaining requirement to
test the initial batch of a new infant formula for all nutrients, and to
test it annually thereafter up to the end of its shelf life. The IFC
believes that this testing is appropriate for new infant formulas to
guard against these unexpected changes in assumptions; however, it is
not appropriately applied to infant formulas for which the manufacturer
has experience.

See the IFC General Comment regarding Definition of Manufacturer for the
justification for adding \"or responsible parties\" after
\"manufacturer\" in appropriate places.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.91(b)(1) If the infant formula  106.91(b)(3) If the infant formula
  is a new infant formula,            is a new infant formula,
  manufacturers shall collect a       manufacturers or responsible
  representative sample from the      parties shall collect a
  final-product-stage of each         representative sample from the
  physical form (powder,              final-product-stage of each
  ready-to-feed, or concentrate) of   physical form (powder,
  the first batch of the new infant   ready-to-feed, or concentrate) of
  formula and test these samples      the first batch of the new infant
  according to the requirements of    formula and test these samples
  this section; and                   according to the requirements of
                                      this section; and
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.91(b)(~~1~~[3]{.mark}) If the infant formula is a new infant
formula, manufacturers [or responsible parties]{.mark} shall collect a
representative sample from the final-product‑stage of each physical form
(powder, ready‑to‑feed, or concentrate) of the first batch of the new
infant formula and test these samples according to the requirements of
this section; and

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer.

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.91(b)(2) If an infant formula   106.91(b)(4) If an infant formula
  has been changed in formulation or  has been changed in formulation or
  in processing in a way that does    in processing in a way that does
  not make it a new infant formula    not make it a new infant formula
  but that may affect whether it is   but that may affect whether it is
  adulterated under section 412(a) of adulterated under section 412(a) of
  the act, the manufacturer shall     the act, the manufacturer or
  collect a representative sample     responsible party shall collect a
  from the final-product-stage of     representative sample from the
  each physical form (powder,         final-product-stage of each
  ready-to-feed, or concentrate) of   physical form (powder,
  the first batch of the infant       ready-to-feed, or concentrate) of
  formula and shall test these        the first batch of the infant
  samples according to the frequency  formula and shall test these
  required by this section for each   samples for each nutrient that has
  nutrient that has been or may have  been or may have been significantly
  been affected by the change.        and adversely affected by the
                                      change. The manufacturer or
                                      responsible party shall determine
                                      if stability testing should be
                                      conducted for such a change and the
                                      frequency of such testing, if
                                      deemed necessary.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.91(b)(~~2~~[4]{.mark}) If an infant formula has been changed in
formulation or in processing in a way that does not make it a new infant
formula but that may affect whether it is adulterated under section
412(a) of the act, the manufacturer [or responsible party]{.mark} shall
collect a representative sample from the final-product-stage of each
physical form (powder, ready‑to‑feed, or concentrate) of the first batch
of the infant formula and shall test these samples ~~according to the
frequency required by this section~~ for each nutrient that has been or
may have been [significantly and adversely]{.mark} affected by the
change. [The manufacturer or responsible party shall determine if
stability testing should be conducted for such a change and the
frequency of such testing, if deemed necessary.]{.mark}

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer.

As noted in the IFC\'s comment above, stability testing is not justified
for several non-labile nutrients. For changes identified in this
paragraph, which under proposed 106.140 may have no expected impact on
nutrients at all, it should be left to the manufacturer to determine
whether stability testing is justified and, if so, its frequency. Thus,
even if a change possibly could affect the level of a mineral, it is
sufficient to test for it and confirm its presence at required levels in
the finished product; continuing to confirm its known presence
throughout shelf life is not necessary, since minerals do not degrade.

Infant formula manufacturers currently evaluate all changes to
formulation or processing of an infant formula. In that assessment they
determine if the change will affect the nutrient content of the
formulation and if so, notify the FDA. In the preamble of the proposed
GMP's, FDA has provided examples of changes they would consider
notifiable changes and requiring testing at the required intervals. If
the manufacturer is now required to complete nutrient testing on
additional changes as described in the preamble, additional personnel
will be needed to complete this testing. As stated previously, stability
testing is not justified for several non-labile nutrients. For changes
identified in this paragraph, which under proposed 106.140 may have no
expected impact on nutrients at all, it should be left to the
manufacturer to determine whether stability testing is justified and, if
so, its frequency.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.91(c) Quality control         | Acceptable as proposed.           |
| records. Manufacturers shall make |                                   |
| and retain quality control        |                                   |
| records in accordance with Sec.   |                                   |
| 106.100(e)(5)(i) and (f)(7).      |                                   |
+-----------------------------------+-----------------------------------+
| **106.92 Audits of quality        | **106.92 Audits of quality        |
| control procedures.**             | control procedures.**             |
|                                   |                                   |
| A manufacturer of an infant       | A manufacturer, or an agent       |
| formula, or an agent of such a    | thereof, shall conduct regularly  |
| manufacturer, shall conduct       | scheduled audits, according to    |
| regularly scheduled audits to     | its established practice, to      |
| determine whether the             | determine whether the             |
| manufacturer has complied with    | manufacturer has complied with    |
| the quality control procedures    | the quality control procedures    |
| that are necessary to ensure that | that are necessary to ensure that |
| an infant formula provides        | an infant formula provides        |
| nutrients in accordance with      | nutrients in accordance with      |
| section 412(b) and (i) of the     | section 412(b) and (i) of the     |
| Federal Food, Drug, and Cosmetic  | Federal Food, Drug, and Cosmetic  |
| Act and is manufactured in a      | Act and is manufactured in a      |
| manner designed to prevent        | manner designed to prevent        |
| adulteration of the infant        | adulteration of the infant        |
| formula under section 412(a)(1)   | formula under section 412(a)(1)   |
| and (a)(3) of the Federal Food,   | and (a)(3) of the Federal Food,   |
| Drug, and Cosmetic Act. These     | Drug, and Cosmetic Act. These     |
| audits shall be performed by an   | audits shall be performed by an   |
| individual who, as a result of    | individual who, as a result of    |
| education, training, and          | education, training, and          |
| experience, is knowledgeable in   | experience, is knowledgeable of   |
| all aspects of infant formula     | infant formula production and of  |
| production and of the agency\'s   | the agency\'s regulations         |
| regulations concerning quality    | concerning quality control        |
| control procedures but who has no | procedures but who has no direct  |
| direct responsibility for the     | responsibility for the matters    |
| matters being audited.            | being audited.                    |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

**106.92 Audits of quality control procedures.**

A manufacturer ~~of an infant formula~~, or an agent ~~of such a
manufacturer~~ [thereof]{.mark}, shall conduct regularly scheduled
audits[, according to its established practice,]{.mark} to determine
whether the manufacturer has complied with the quality control
procedures that are necessary to ensure that an infant formula provides
nutrients in accordance with section 412(b) and (i) of the Federal Food,
Drug, and Cosmetic Act and is manufactured in a manner designed to
prevent adulteration of the infant formula under section 412(a)(1) and
(a)(3) of the Federal Food, Drug, and Cosmetic Act. These audits shall
be performed by an individual who, as a result of education, training,
and experience, is knowledgeable ~~in all aspects~~ of infant formula
production and of the agency\'s regulations concerning quality control
procedures but who has no direct responsibility for the matters being
audited.

######### IFC Comments

FDA's April announcement of the reopening of the comment period
requested comments on the specific changes in current activities that
would be required for companies to comply with proposal. The auditor is
expected to possess a general knowledge of the aspects of infant formula
production, however they need not have knowledge to the depth and extent
that the use of the word \"all\" in the proposal may imply. Such
knowledge would entail years of cross training and constant retraining.
Auditors are currently knowledgeable on a wide scope of infant formula
production aspects, including raw materials, blending/mixing,
processing, standardization, filling, sterilization/drying, packing,
warehousing, shipping, maintenance, cleaning, lab testing, documentation
control, batch record review/release, training, etc., as well as how to
conduct routine audits. We note that the proposed regulation
acknowledges that past experience in infant formula production may be
relevant, even though the auditor may have no current responsibility for
the activities being audited.

Because this proposed requirement is very similar to 106.90, please
refer to the IFC\'s comment to that proposed section. The IFC requests
that the same changes as recommended in 106.90 be incorporated in this
section. In addition, we have suggested language clarifying that it is
the manufacturer\'s responsibility to determine what will constitute
\"regularly scheduled audits\" and to establish SOPs for that purpose to
which it will adhere.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **Subpart D\--Conduct of          | **Subpart D\--Conduct of          |
| Audits.**                         | Audits.**                         |
|                                   |                                   |
| **106.94 Audit plans and          | **106.94 Audit plans and          |
| procedures.**                     | procedures.**                     |
|                                   |                                   |
| 106.94(a) Manufacturers shall     | Acceptable as proposed.           |
| develop and follow a written      |                                   |
| audit plan that is available at   |                                   |
| the manufacturing facility for    |                                   |
| FDA inspection.                   |                                   |
+-----------------------------------+-----------------------------------+
| 106.94(b) The audit plan shall    | 106.94(b) The audit plan shall    |
| include audit procedures that set | include audit procedures that set |
| out the methods the manufacturer  | out the methods the manufacturer  |
| uses to determine whether the     | or responsible party uses to      |
| facility is operating in          | determine whether the facility is |
| accordance with current good      | operating in accordance with      |
| manufacturing practice, with the  | current good manufacturing        |
| quality control procedures that   | practice, with the quality        |
| are necessary to assure that an   | control procedures that are       |
| infant formula provides nutrients | necessary to assure that an       |
| in accordance with section 412(b) | infant formula provides nutrients |
| and (i) of the Federal Food,      | in accordance with section 412(b) |
| Drug, and Cosmetic Act, and in a  | and (i) of the Federal Food,      |
| manner designed to prevent        | Drug, and Cosmetic Act, and in a  |
| adulteration of the infant        | manner designed to prevent        |
| formula.                          | adulteration of the infant        |
|                                   | formula.                          |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.94(b) The audit plan shall include audit procedures that set out the
methods the manufacturer [or responsible party]{.mark} uses to determine
whether the facility is operating in accordance with current good
manufacturing practice, with the quality control procedures that are
necessary to assure that an infant formula provides nutrients in
accordance with section 412(b) and (i) of the Federal Food, Drug, and
Cosmetic Act, and in a manner designed to prevent adulteration of the
infant formula.

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.94(c) The audit procedures    | Acceptable as proposed.           |
| shall include, but not be limited |                                   |
| to:                               | Acceptable as proposed.           |
|                                   |                                   |
| 106.94(c)(1) An evaluation of the | 106.94(c)(1)(i) Observing the     |
| production and in-process control | critical manufacturing steps of   |
| system established under Sec.     | infant formula and comparing the  |
| 106.6(b) by:                      | observed process to the written   |
|                                   | production and in-process control |
| 106.94(c)(1)(i) Observing the     | plan required under Sec.          |
| production of infant formula and  | 106.6(b);                         |
| comparing the observed process to |                                   |
| the written production and        |                                   |
| in-process control plan required  |                                   |
| under Sec. 106.6(b);              |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.94(c)(1)(i) Observing the ~~production~~ [critical manufacturing
steps]{.mark} of infant formula and comparing the observed process to
the written production and in‑process control plan required under Sec.
106.6(b);

IFC Comment

This proposal requires the audit to include the observation of infant
formula production and comparing it to the written control plan. This
could be interpreted as requiring observation of every single
manufacturing operation, from ingredient receipt, through manufacturing,
holding and distribution. Such detail during an audit would make the
auditing process an extremely tedious and unwieldy endeavor, and would
result in overly prolonged audits. Auditing may take weeks to accomplish
at this detail. It is also unnecessary, because such comparisons can be
made from less intrusive and resource intensive reviews, such as
spot-checking some operations, while reviewing others based on
production records, interviews, etc.

FDA's April announcement of the reopening of the comment period
requested comments on the specific changes in current activities that
would be required for companies to comply with proposal. This change
would require additional trained personnel to complete this type of
audit, and it would interfere unnecessarily with the focus on high
quality production.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.94(c)(1)(ii) Reviewing records  106.94(c)(1)(ii) Reviewing records
  of the monitoring of points, steps, of representative batches, over
  or stages where control is deemed   multiple days of production, of the
  necessary to prevent adulteration;  monitoring of points, steps, or
  and                                 stages where control is critical to
                                      prevent adulteration; and
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.94(c)(1)(ii) Reviewing records of [representative batches, over
multiple days of production, of]{.mark} the monitoring of points, steps,
or stages where control is ~~deemed necessary~~ [critical]{.mark} to
prevent adulteration; and

IFC Comment

The preamble to this proposed section states that the review of
\"production and in‑process control records\" contemplated by this
section must involve \"all batches produced in a given period of time.\"
Such a requirement could be overwhelming unless it involved a very short
time span. The IFC feels that audits would be more thorough and
beneficial if the record review covered a wider span of time (i.e.,
months), but included \"representative\" batches, as opposed to \"all\"
batches, and \"representative\" records of the most important control
points, i.e., critical points.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.94(c)(1)(iii) Reviewing records 106.94(c)(1)(iii) Reviewing records
  of how deviations from any standard of how deviations from any
  or specification at points, steps,  specification at points, steps, or
  or stages where control is deemed   stages where control is deemed
  necessary to prevent adulteration   necessary to prevent adulteration
  were handled; and                   were handled to assure that the
                                      review was complete; and
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.94(c)(1)(iii) Reviewing records of how deviations from any
~~standard or~~ specification at points, steps, or stages where control
is deemed necessary to prevent adulteration were handled [to assure that
the review was complete]{.mark}; and

IFC Comment

See the IFC General Comment regarding Specifications.

The preamble to this proposal states that the auditor must review the
responses to the deviations to determine \"\... whether the conclusions
and follow-up of these investigations are appropriate for each failure
to meet the specification or standard.\" This is a significantly
different responsibility than that suggested by the proposed language of
the regulation. Although the IFC believes that an auditor must be well
schooled in product quality, it is unrealistic to expect that an auditor
will have the breadth of technical knowledge and background to assess
whether the dispositions, which may involve multiple disciplines in a
company, are \"appropriate.\" A more reasonable expectation is that the
auditor\'s review confirms the completeness and sufficiency of review of
the deviations, rather than trying to determine if the conclusions and
follow-up were appropriate. The language suggested by the IFC aims at
this distinction, and the preamble to the final regulation should also
reflect this point to remove any misimpressions that the proposal\'s
preamble language may have created.

**Rest of page left intentionally blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.94(c)(2) A review of a        | Acceptable as proposed.           |
| representative sample of all      |                                   |
| records maintained in accordance  |                                   |
| with Sec. 106.100(e) and (f).     |                                   |
+-----------------------------------+-----------------------------------+
| **Subpart E\--Quality Factors for | **Subpart E\--Quality Factors for |
| Infant Formulas**                 | Infant Formulas**                 |
|                                   |                                   |
| **106.96 Quality factors in       | **106.96 Quality factors in       |
| infant formulas.**                | infant formulas.**                |
|                                   |                                   |
| 106.96(a) All infant formulas     | 106.96(a) All infant formulas     |
| shall, when fed to infants as a   | shall meet established quality    |
| sole source of nutrition, be of   | factors.                          |
| sufficient quality to meet the    |                                   |
| nutritional requirements for      |                                   |
| healthy growth. The regulations   |                                   |
| set forth in this subpart define  |                                   |
| the minimum quality factors for   |                                   |
| infant formulas.                  |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.96(a) All infant formulas [shall meet established quality
factors]{.mark}~~, when fed to infants as a sole source of nutrition, be
of sufficient quality to meet the nutritional requirements for healthy
growth. The regulations set forth in this subpart define the minimum
quality factors for infant formulas~~.

######### IFC Comment

For the reasons discussed in detail previously, there are legal,
scientific and policy issues supporting the IFC position that it is
inappropriate to establish "healthy growth" or "normal growth" as a
quality factor. The proposal would have required clinical studies to
demonstrate the quality factor of "healthy growth." Although we believe
that it is inappropriate to set a quality factor for "healthy growth,"
we do recognize that there are some instances when a clinical study is
needed. Importantly, the 1986 Guidelines recognize that the manufacturer
is in the best position to assess when a clinical study is needed. IFC
supports the principles in the 1986 Guidelines, which address clinical
studies in the premarket notification section. Thus, IFC believes that
clinical studies should be addressed in section 106.120, which sets
forth the data and information that must be submitted in a premarket
notification. There are almost two decades of industry experience of
submitting clinical studies, not for purposes of supporting a quality
factor for "growth," but when necessary for providing the Agency with
the assurance of nutritional adequacy of the new infant formula.

IFC reiterates its position with regard to the impropriety of
establishing "healthy" or "normal growth" as a quality factor. The
following comments on the proposed rule are offered, nevertheless, to
inform any incorporation of the proposed language into an agency
Guidance document for those situations in which it is determined that a
clinical demonstration of growth is the most appropriate way to
demonstrate bioavailability. IFC suggests adding the phrase "in the
infant population for which they are intended" to accommodate special
infant formulas. The IFC also recommends that the phrase "when fed to
infants as a sole source of nutrition" be moved to consideration for
inclusion in the Guidance.

The IFC also submits that the term "healthy growth" should be changed to
"expected physical growth" throughout the current proposal when
translated into a Guidance. "Expected" is the more meaningful term, and
the only practical way of assessing growth is by physical measurement.
It should also be noted here that attempts have been made in the past to
define, even more specifically and quantitatively, what constitutes
normal physical growth \-- e.g., the AAP consultation\'s discussion of
an acceptable divergence of the mean growth velocity of the experimental
group from that of the control group. Further, the IFC agrees with
FDA\'s apparent conclusion that it would be unwise to establish
quantitative standards at this time, given the evolving scientific
understanding of what is "expected," "normal" or even "optimal" in this
area.

As explained in the General Comments, the Infant Formula Act does not
actually mention "healthy growth" \-- or even "normal growth," used
elsewhere in the proposed regulations. Moreover, the Infant Formula Act
does not define "quality factors" except to say "Quality factors pertain
to the bioavailability of a nutrient and the maintenance of level or
potency of nutrients through an expected shelf life of the product."[^5]
Although, as responsible manufacturers, the industry accepts the
responsibility of producing formulas that provide sufficient and
bioavailable nutrition, industry strongly objects to establishing
"growth," per se, as a quality factor and to the indiscriminate
application of any such requirement. IFC is also concerned about the
Agency\'s tentative conclusion in the preamble that "on a case-by-case
basis additional quality factors may be needed for a specific formula
product." Any such effort to accomplish case-by-case quality factors
would be flawed, because such factors can only be established by notice
and comment rulemaking. Furthermore, regulatorily imposed quality
factors extending beyond bioavailability and sufficiency throughout
shelf life were clearly not intended by Congress.

The IFC supports the Agency\'s offer to provide clinical guidance. Our
key point, however, is that clinical studies are not the only way to
demonstrate bioavailability, and that other evidence may often be
equally convincing and more appropriate.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.96(b) All infant formulas shall Delete.
  be capable of supporting normal     
  physical growth of infants.         
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.96(b) All infant formulas shall be capable of supporting normal
physical growth of infants.~~

######### IFC Comment

Again, IFC objects to this requirement for the reasons already stated.
IFC offers the following comments on the language as proposed, however,
in case similar concepts are incorporated into agency Guidance.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.96(c) All infant formulas     | Acceptable; Renumbered to         |
| shall be formulated and           | 106.96(b).                        |
| manufactured such that the        |                                   |
| protein is of sufficient          |                                   |
| biological quality to meet the    |                                   |
| protein requirements of infants.  |                                   |
+-----------------------------------+-----------------------------------+
| **106.97 Assurances for quality   | **106.97 Assurances for quality   |
| factors.**                        | factors.**                        |
|                                   |                                   |
| 106.97(a) General quality factor  | Delete.                           |
| of normal physical growth.        |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.96(~~c~~[b]{.mark}) All infant formulas shall be formulated and
manufactured such that the protein is of sufficient biological quality
to meet the protein requirements of infants.

~~106.97(a) General quality factor of normal physical growth.~~

## IFC Comment

See General Comments on Assessment of Normal Growth.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.97(a)(1) The manufacturer shall 
  conduct an adequate and             
  well-controlled clinical study, in  
  accordance with good clinical       
  practice, to determine whether an   
  infant formula supports normal      
  physical growth in infants when the 
  formula is fed as the sole source   
  of nutrition.Delete.                
  ----------------------------------- -----------------------------------

#########  IFC Redlined Version

~~106.97(a)(1) The manufacturer shall conduct an adequate and
well-controlled clinical study, in accordance with good clinical
practice, to determine whether an infant formula supports normal
physical growth in infants when the formula is fed as the sole source of
nutrition.~~

######### IFC Comment 

See General Comments on Assessment of Normal Growth. IFC offers the
following comments with the caveat that clinical growth studies should
be conducted for the purpose of demonstrating bioavailability only when
they are the most appropriate such demonstration, and that any specifics
as to the nature and scope of such a study should be incorporated into
agency Guidance rather than a regulation.

See the IFC General Comment regarding Definition of Manufacturer. As
explained in our comments to sections 106.3(j) and 106.3(s), primary
infant formula manufacturers sometimes rely on other manufacturers to
handle specific phases of the manufacture of a given formula. In such a
situation, only the primary manufacturer would be expected to conduct a
clinical study or other assurances of quality factors. We have
suggested, in our comments to section 106.3(s) that the term
"responsible party" be used to designate the primary manufacturer and be
incorporated into the regulations wherever appropriate. Thus, throughout
subpart 106.97, dealing with assurances for quality factors, the term
\"or responsible party\" should be inserted after each reference to the
manufacturer's responsibility to provide such assurances.

Whenever the language \"When fed as the sole source of nutrition\" is
used, it should be followed by \"or as otherwise represented,\" in order
to allow for formulas represented for use only with older infants.

The IFC also suggests adding to the Agency's description of adequate
growth the important qualification that "expected" be interpreted in the
context of the population for whom the formula is intended. The
expectation that infant formulas "shall be capable of supporting normal
physical growth of infants" will vary dependent upon the population.
Some targeted populations have medical conditions whose "normal physical
growth" would be "expected" to be different from that of infants without
a medical condition, in the same way as a premature population cannot be
compared to a full-term population. Although many of these formulas can
be covered within the special infant formula requirements, it would be
best if the broader goal were stated in a way that will be suitable for
all situations -- e.g., "expected physical growth."

It would not be possible to achieve a reasonable scientific consensus on
what additional functions might constitute "healthy growth" as it is
related to nutrition. And, while a manufacturer may choose to assess
functions beyond anthropometric growth (especially if promotional claims
are to be made regarding the use of the new formula), there are no
generally accepted and validated methods for assessing \"healthy\"
growth beyond the anthropometric measures. Many of the tests that might
be used were originally designed to detect individuals with clinically
impaired functions; not to distinguish or attribute significance to the
small differences between individuals or groups, which may be seen in
clinical studies of generally healthy populations.

The AAP consultation did describe means and possible indications for
testing certain key nutrients, which may be affected by changes in
ingredient form or processing. The Agency specifically requested
comments on the feasibility of certain of the AAP's suggestions, and our
detailed comments are provided at the close of our discussion of this
subpart. Suffice it to say, here, that while we agree with the Agency as
to the importance of assessing substantive changes in the manufacturing
process on nutrient bioavailability, a broader definition of growth does
not achieve this objective. And, while the future introduction of novel
ingredients in infant formula (such as components of human milk not
presently in infant formulas) may present new challenges to the
regulatory process, introducing ambiguity and subjectivity into these
regulations is not an appropriate means of responding to this challenge.
Any safety concern with regard to a new ingredient is better handled
under the regulatory rubrics specifically designed for ingredient
evaluation.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.97(a)(1)(i) The manufacturer  | Delete.                           |
| shall:                            |                                   |
|                                   | Delete.                           |
| 106.97(a)(1)(i)(A) Conduct a      |                                   |
| clinical study that is no less    |                                   |
| than 4 months in duration,        |                                   |
| enrolling infants no more than 1  |                                   |
| month old at time of entry into   |                                   |
| the study.                        |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

~~106.97(a)(1)(i) The manufacturer shall:~~

~~106.97(a)(1)(i)(A) Conduct a clinical study that is no less than 4
months in duration, enrolling infants no more than 1 month old at time
of entry into the study.~~

######### IFC Comment

Regarding IFC's recommended deletion of these proposed regulations, see
General Comments on Assessment of Normal Growth. IFC offers comments on
all the following proposed regulations falling under section
106.97(a)(1) with the caveat that clinical growth studies should be
conducted for the purpose of demonstrating bioavailability only when
they are the most appropriate, and any specifics as to the nature and
scope of such a study should be incorporated into agency Guidance rather
than a regulation.

See the IFC General Comment regarding Definition of Manufacturer. As
discussed in the previous comment, the term \"or responsible party\"
should be added after each reference to the manufacturer's
responsibility to provide assurances of quality factors.

In the Agency's April 2003 announcement of the reopening of the comment
period, FDA specifically requested comment on proposed section
106.97(a)(1)(i)(A), to address the FAC recommendation that infants be
enrolled by 14 days of age. The SCF Committee proposed in 1993 that the
nutritional adequacy of all products should be demonstrated by a
longitudinal study on weight and height development over at least 3
months, involving at least 20 babies born at full term and aged less
than one month at the beginning of the study. This study should include,
if necessary, data on plasma levels of albumin and short half-life
proteins, and on the plasma amino acid profile. Consequently, the
selection of 16 weeks or 3 months, or 4 months as originally proposed by
FDA are proposed on the basis of convenience and current well-baby visit
schedules, not on the basis of scientific assessments of sensitivity,
validity or the relationship of growth over this period to health.
Growth studies are usually conducted from approximately 14 days after
birth, which coincides with routine pediatric visits until the infant is
approximately 112 days of age or about 4 months of age (i.e., study
duration of 98 days). Days of age versus weeks or months of age are used
to simplify the calculation of study visits.

IFC believes that the design of the study should address the specific
objectives of the study. If nutritional adequacy of a formula to be fed
during the first year of life is to be assessed, as measured by weight
gain, (per 1988 CON/AAP guidelines) then the study should be initiated
within the first month of life. However, if the formula is for a
different age range, then the design of the study should reflect this
difference. For routine growth studies, infants would ideally be
enrolled by approximately 14 days of age and study measurements (growth)
measured at approximately 14, 28, 56, 84 and 112 days of age. However,
we are aware of no biological reason why any enrollment age short of one
month should be considered to disqualify an infant from such a study.
The primary outcome is growth, expressed as weight gain in g/day (14-112
days). Secondary outcomes are body weight expressed as attained weight
(interval gains) and attained body length. There is a rationale for
inclusion of infants at not later than 14 days of age, because this
early time is the time of greatest nutrient requirement and greatest
sensitivity to nutrient adequacy. It may be preferable to study growth
velocity (g/kg/d), which is yet more sensitive than absolute g/d, thus
requiring fewer infants to achieve the same sensitivity (Butte et al.).

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.97(a)(1)(i)(B) Collect and      Delete.
  maintain data in the study on       
  anthropometric measures of physical 
  growth, including body weight,      
  recumbent length, head              
  circumference, and average daily    
  weight increment, and plot the data 
  on National Center for Health       
  Statistics (NCHS) reference         
  percentile body weight and body     
  length curves. The NCHS growth      
  charts are incorporated by          
  reference in accordance with 5      
  U.S.C. 552(a) and 1 CFR part 51.    
  Copies are available from the       
  Office of Constituent Operations    
  (HFS-565), Center for Food Safety   
  and Applied Nutrition, Food and     
  Drug Administration, 200 C St. SW,  
  Washington, DC 20204, may be        
  examined at the Office of Special   
  Nutritionals (HFS-456), Center for  
  Food Safety and Applied Nutrition,  
  Food and Drug Administration, 200 C 
  St. SW, Washington, DC 20204, or    
  the Office of the Federal Register, 
  800 North Capitol St. NW, Suite     
  700, Washington, DC.                
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.97(a)(1)(i)(B) Collect and maintain data in the study on
anthropometric measures of physical growth, including body weight,
recumbent length, head circumference, and average daily weight
increment, and plot the data on National Center for Health Statistics
(NCHS) reference percentile body weight and body length curves. The NCHS
growth charts are incorporated by reference in accordance with 5 U.S.C.
552(a) and 1 CFR part 51. Copies are available from the Office of
Constituent Operations (HFS-565), Center for Food Safety and Applied
Nutrition, Food and Drug Administration, 200 C St. SW, Washington, DC
20204, may be examined at the Office of Special Nutritionals (HFS-456),
Center for Food Safety and Applied Nutrition, Food and Drug
Administration, 200 C St. SW, Washington, DC 20204, or the Office of the
Federal Register, 800 North Capitol St. NW, Suite 700, Washington, DC.~~

IFC Comment

When AAP-CON provided its 1988 consultation, it recommended rate of
weight gain as the anthropometric parameter for assessing physical
growth because it was felt to be most sensitive and, therefore, more
appropriate. (Indeed, the AAP Handbook on Nutrition maintains that
\"average daily weight increment\" alone provides a sufficient
anthropometric measure of growth.) While collection of data on recumbent
length and head circumference are often obtained simultaneously, their
interpretation is generally secondary as recumbent length measurements
at this age are associated with considerable error and head
circumference is rather resistant to small differences in nutritional
status. This science has not changed since the 1988 AAP-CON
consultation. Thus, the IFC believes that it would be advisable to
simplify both the collection of this data by manufacturers, and its
review by the Agency, by requiring only those data considered to be the
most sensitive, reliable and appropriate for measuring growth. We
recommend that recumbent length continue to be measured as part of the
standard growth protocol, allowing for calculation of BMI and some body
composition measures as needed, but that these data need not be
routinely reported to the Agency.

A randomized clinical study, with or without reference to an outside
standard (e.g., Iowa reference data or CDC/NCHS reference standard), is
the best method to assess whether infants receiving different feeding
regimens differ in terms of a primary outcome parameter. A clinical
trial is defined as a prospective study comparing the effect and value
of intervention(s) against a control in human subjects ([Fundamentals of
Clinical Trials]{.underline}, 1985, Friedman LM, Furberg CD, DeMets DL).
This research methodology is recognized as the most definitive method of
determining whether and intervention has the postulated effect. The
universally agreed reference population that defines healthy growth,
infants breast fed by well-nourished mothers, cannot be included in a
randomized trial.

Since the CDC/NCHS reference standards were recently revised, and since
new science is constantly accumulating which may impact our changing
understanding of what constitutes expected physical growth, it would be
shortsighted to tie the assessment *only* to the currently existing
reference standards. In the Agency's April 2003 announcement of the
reopening of the comment period, it requested comments on whether
manufacturers should still compare their clinical study growth data with
the National Center for Health Statistics (NCHS) growth charts. The FAC
considered other sources of reference data in addition to the NCHS. FDA
states that the FAC "recommended the Iowa reference data as the most
appropriate reference data for comparison because they are longitudinal,
collected over the time period of interest for clinical studies of
infant growth, and collected in a research setting." Our own
recollection of the discussion was not so definitive. Several potential
comparison references were discussed, and while all shed some light on
what constituted expected physical growth, none was found to be
dispositive.

The Iowa reference data, while excellent, may be less accessible than
the CDC/NCHS growth charts, and the growth charts do incorporate some
mechanism for quantitative assessment of growth patterns. However, the
use of individual growth charts is not appropriate to establish whether
one group of infants differs from another group of infants in terms of
growth rates (as described by the 1988 CON/AAP guidelines). In general,
the use of growth curves and historical databases are considered
references, not standards. Furthermore, the use of curves to evaluate
growth of infants could lead to inappropriate conclusions concerning
normal growth. (The Use of NCHS and CDC Growth Charts in Nutritional
Assessment of Young Infants, 2002, Grummer-Strawn LM on behalf of the
CDC Growth Chart Working Group.)

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.97(a)(1)(i)(C) Collect          Delete.
  anthropometric measurements at the  
  beginning of the clinical study, at 
  2 weeks, at 4 weeks, at least       
  monthly thereafter, and at the      
  conclusion of the study.            
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.97(a)(1)(i)(C) Collect anthropometric measurements at the
beginning of the clinical study, at 2 weeks, at 4 weeks, at least
monthly thereafter, and at the conclusion of the study.~~

######### IFC Comment

The frequency of body weight measurements is a protocol detail that
should be provided in clinical study Guidelines, not regulations.
Further, the proposed frequency of measurement is unnecessarily
burdensome to parents facilitating their infants' participation in
growth studies, since several of these times do not coincide with a
regularly scheduled well-baby visit. Clinical trials for new formulas
are often delayed because of the difficulty of recruiting sufficient
numbers of participants.

In 2002, representatives of the infant formula industry prepared a
sample clinical growth study protocol (Attachment M). The days of age
represented above were selected as reasonable time intervals to assess
growth and to coincide with routine pediatric visits. Thus, the changes
indicated above should provide ample data to demonstrate expected
physical growth without introducing added difficulties for the
participants.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.97(a)(1)(ii) The clinical study Delete.
  protocol should:                    

  106.97(a)(1)(ii)(A) Describe the    Delete.
  scientific basis and objectives of  
  the study, the planned control and  
  treatment feeding regimens, the     
  entrance criteria used to enroll    
  infants in the study, the method of 
  randomization used for the          
  assignment of infants to feeding    
  groups, the collection of specific  
  measurements and other data, the    
  methods used to limit sources of    
  bias, and the planned methods of    
  statistical analysis;               
  ----------------------------------- -----------------------------------

##  IFC Redlined Version

~~106.97(a)(1)(ii) The clinical study protocol should:~~

~~106.97(a)(1)(ii)(A) Describe the scientific basis and objectives of
the study, the planned control and treatment feeding regimens, the
entrance criteria used to enroll infants in the study, the method of
randomization used for the assignment of infants to feeding groups, the
collection of specific measurements and other data, the methods used to
limit sources of bias, and the planned methods of statistical
analysis;~~

######### IFC Comment

IFC understands from the April 2003 announcement of the reopening of the
comment period that the Agency intends to remove references to clinical
protocols from the proposed rule and to develop a guidance document
instead on what it recommends be included in a clinical study protocol
for infant formula that is submitted as part of an infant formula
notification under section 412(c) of the act. We support the Agency's
position that it is more appropriate to include information about
clinical study design protocols in a guidance document rather than a
regulation. By codifying it in a regulation, it will be much more
difficult for modifications to be made that are reflective of the
current scientific practices for conducting clinical studies.

We have attached the representative protocol that we developed for
submission to the FAC as an example of what industry recommends be
included in a clinical study protocol for infant formula that is
submitted as part of an infant formula notification under section 412(c)
of the act, in hope it will be considered in the development of that
guidance document (Attachment M).

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.97(a)(1)(ii)(B) Describe the    Delete.
  necessary qualifications and        
  experience of investigators;        

  106.97(a)(1)(ii)(C) Be reviewed and Delete.
  approved by an Institutional Review 
  Board (IRB) in accordance with part 
  56 of this chapter. The             
  manufacturer shall establish        
  procedures to obtain written        
  informed consent from parents or    
  legal representatives of the        
  infants enrolled in the study in    
  accordance with part 50 of this     
  chapter;                            
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.97(a)(1)(ii)(B) Describe the necessary qualifications and
experience of investigators;~~

~~106.97(a)(1)(ii)(C) Be reviewed and approved by an Institutional
Review Board (IRB) in accordance with part 56 of this chapter. The
manufacturer shall establish procedures to obtain written informed
consent from parents or legal representatives of the infants enrolled in
the study in accordance with part 50 of this chapter;~~

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer. As
discussed in previous comments, the term \"or responsible party\" should
be added after each reference to the manufacturer's responsibility to
provide assurances of quality factors.

The IFC\'s suggested substitution of the term \"documented\" for
\"written\" to describe informed consent requirements is intended to
accommodate instances involving illiterate parents who receive informed
consent orally and acknowledge their desire for their child to
participate. While this practice may be interpreted as being in
compliance with the requirement for \"written informed consent,\" the
IFC feels that a simple word change would clarify the acceptance of such
situations.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.97(a)(1)(ii)(D) Explain how the Delete.
  study population represents the     
  population for which the new infant 
  formula is intended and how the     
  study addresses the intended        
  conditions of use of the formula.   
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.97(a)(1)(ii)(D) Explain how the study population represents the
population for which the new infant formula is intended and how the
study addresses the intended conditions of use of the formula.~~

IFC Comment

IFC concurs with FDA that this belongs in the Guidance.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.97(a)(1)(ii)(E) Describe the    Delete.
  sample size calculations and the    
  power calculations and the basis    
  for selecting the sample size and   
  study design;                       

  106.97(a)(1)(ii)(F) Describe the    Delete.
  plan to identify and evaluate any   
  adverse effects;                    

  106.97(a)(1)(ii)(G) Describe the    Delete.
  quality control procedures used to  
  ensure the validity and reliability 
  of the measurements collected.      
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.97(a)(1)(ii)(E) Describe the sample size calculations and the
power calculations and the basis for selecting the sample size and study
design;~~

~~106.97(a)(1)(ii)(F) Describe the plan to identify and evaluate any
adverse effects;~~

~~106.97(a)(1)(ii)(G) Describe the quality control procedures used to
ensure the validity and reliability of the measurements collected.~~

IFC Comment

The language of these proposed regulations is acceptable as proposed for
incorporation into agency Guidance, in that it describes appropriate
quality control measures for discussion in any growth study protocol.
The statements in the preamble, however, seem not to be related to the
purposes of clinical study quality control as the IFC understands them.
Quality control relates to the procedures used to assure that the data
are accurate and appropriately obtained, while the statements in the
preamble appear to speak to the choice of appropriate endpoints in a
clinical study. The two should not be confused, and the preamble to the
final rule should clarify this. Serious adverse events are better
defined and more important than capturing all adverse effects that may
occur in the course of a study as most are not product related. In
addition, many manufacturers will be driven to assess measures of infant
formula \'tolerance\' as a study outcome rather than adverse effects.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.97(a)(1)(ii)(H) Describe and    Delete.
  compare the composition of the test 
  and control formulas.               
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.97(a)(1)(ii)(H) Describe and compare the composition of the test
and control formulas.~~

IFC Comment

As discussed with respect to 106.97(a)(1)(ii)(A), there may be
situations in which a reference appropriate to establishing that an
infant formula supports acceptable growth can also function as a
non-concurrent control in the study itself. In such a case, there would
be no "control formula" to describe.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.97(a)(1)(ii)(I) Describe the    Delete.
  basis upon which the test formula   
  is appropriate for use in           
  evaluating the formula that the     
  manufacturer intends to market, if  
  the test formula used in a study is 
  not identical to the formula that   
  is intended to be marketed in the   
  United States.                      
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.97(a)(1)(ii)(I) Describe the basis upon which the test formula is
appropriate for use in evaluating the formula that the manufacturer
intends to market, if the test formula used in a study is not identical
to the formula that is intended to be marketed in the United States.~~

IFC Comment

IFC concurs with FDA that this belongs in the Guidance.

Rest of page intentionally left blank

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.97(a)(2) The manufacturer may | Delete.                           |
| request an exemption from the     |                                   |
| requirements of paragraph (a)(1)  | Delete.                           |
| of this section if:               |                                   |
|                                   |                                   |
| 106.97(a)(2)(i) The manufacturer  |                                   |
| has similar experience using an   |                                   |
| ingredient, an ingredient         |                                   |
| mixture, or a processing method   |                                   |
| in the production of an infant    |                                   |
| formula marketed in the United    |                                   |
| States and can demonstrate that   |                                   |
| infant formula made with that     |                                   |
| ingredient, ingredient mixture,   |                                   |
| or processing method meets the    |                                   |
| quality factor requirements in    |                                   |
| Sec. 106.96;                      |                                   |
+-----------------------------------+-----------------------------------+
| 106.97(a)(2)(ii) The manufacturer | Delete.                           |
| markets a formulation in more     |                                   |
| than one form (e.g., liquid and   |                                   |
| powdered forms) and can           |                                   |
| demonstrate that the quality      |                                   |
| factor requirements are met by    |                                   |
| the form of the formula that is   |                                   |
| processed using the method that   |                                   |
| has the greatest potential for    |                                   |
| adversely affecting nutrient      |                                   |
| content and bioavailability;      |                                   |
+-----------------------------------+-----------------------------------+
| 106.97(a)(2)(iii) The             | Delete.                           |
| manufacturer can demonstrate that |                                   |
| the requirements of paragraph     |                                   |
| (a)(1) of this section are not    |                                   |
| appropriate for evaluation of a   |                                   |
| specific infant formula, and that |                                   |
| an alternative method or study    |                                   |
| design for showing that the       |                                   |
| formula supports healthy growth   |                                   |
| in infants fed it as their sole   |                                   |
| source of nutrition is available. |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

~~106.97(a)(2) The manufacturer may request an exemption from the
requirements of paragraph (a)(1) of this section if:~~

~~106.97(a)(2)(i) The manufacturer has similar experience using an
ingredient, an ingredient mixture, or a processing method in the
production of an infant formula marketed in the United States and can
demonstrate that infant formula made with that ingredient, ingredient
mixture, or processing method meets the quality factor requirements in
Sec. 106.96;~~

~~106.97(a)(2)(ii) The manufacturer markets a formulation in more than
one form (e.g., liquid and powdered forms) and can demonstrate that the
quality factor requirements are met by the form of the formula that is
processed using the method that has the greatest potential for adversely
affecting nutrient content and bioavailability;~~

~~106.97(a)(2)(iii) The manufacturer can demonstrate that the
requirements of paragraph (a)(1) of this section are not appropriate for
evaluation of a specific infant formula, and that an alternative method
or study design for showing that the formula supports healthy growth in
infants fed it as their sole source of nutrition is available.~~

## IFC Comment

See the IFC General Comment regarding Definition of Manufacturer and
Premarket Notification. The provision that an exemption \"may be
available\" based on a requirement to \"demonstrate\" that a
manufacturer or responsible party has experience with an ingredient, an
ingredient mixture, or a processing method constitutes premarket
approval, not notification. Since 1986, FDA has permitted manufacturers
to make the determination contemplated by this section, and the IFC is
not aware of any problems that have been created.

The Agency's April 2003 announcement of the reopening of the comment
period asked for comments regarding what requirements the Agency should
establish to determine when manufacturers must conduct clinical growth
studies for a new or reformulated infant formula. IFC believes that
there are instances when clinical studies may be necessary as proposed
by IFC in section 106.120(b)(6). Thus, the "exemptions" provided in this
proposed rule -- as amended by our suggested changes -- better describe
those situations that would not trigger the need for a clinical growth
study. In 2002, U.S. Infant Formula Manufacturers developed the
"Decision Tree for Documentation of Nutritional Adequacy of a New or
Change Infant Formula" (Attachment K) and "Decision Tree Chart for
Documentation of Nutritional Adequacy of a New or Changed Infant
Formula," (Attachment L) for consideration by the FAC, to which the
Agency refers in its April announcement. These documents discuss, in
greater detail, various changes to infant formula and the documentation
required for such changes to support nutritional adequacy. These
documents are appended here, as well, for agency consideration.

The IFC also believes that \"similar experience\" should be relevant,
regardless of whether it occurred in the United States or elsewhere.

IFC believes that the choice of the representative formula should not be
based solely on greatest adverse nutrient effect. For example, if a
product has two forms, one a liquid, ready-to-feed formula for hospital
use only, and the other a powder formula for retail use, it may be more
appropriate to study the form that is intended for long term use (i.e.,
the powder) as opposed to the very short term formula (i.e., the
liquid), which actually may have the greatest nutrient effect. The IFC
believes that the manufacturer must be given responsibility for
determining the most representative form to test.

On those occasions when studies have already been carried out on a form
of the product, which meets neither of the above criteria, but cannot
reasonably be expected to differ significantly from the form in question
(in terms of nutrient levels or availability), those studies should also
be able to provide the basis for exemption from additional studies. To
require duplicative studies on forms of a product which do not differ
significantly would be difficult to justify on an ethical basis.

######### 

The IFC appreciates FDA\'s recognition of the flexibility necessary to
accommodate different products as well as evolution in clinical study
design. Also, it should be noted that a formula may not necessarily be
intended as a \"sole source of nutrition\" and consideration should be
given to those situations in this paragraph.

\"Healthy growth\" should be changed to the alternative term, \"expected
physical growth,\" since the latter is the more meaningful term and the
more objectively measurable criterion.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.97(b) Specific quality factor | Acceptable; Renumbered 106.97(a). |
| for protein quality of infant     |                                   |
| formula.                          | 106.97(a)(1) The manufacturer or  |
|                                   | responsible party shall collect   |
| 106.97(b)(1) The manufacturer     | and maintain data that establish  |
| shall collect and maintain data   | that the biological quality of    |
| that establish that the           | protein in an infant formula is   |
| biological quality of protein in  | sufficient to meet the protein    |
| an infant formula is sufficient   | requirements of infants. The      |
| to meet the protein requirements  | manufacturer or responsible party |
| of infants. The manufacturer      | shall establish the biological    |
| shall establish the biological    | quality of the protein in its     |
| quality of the protein in its     | infant formula with any AOAC      |
| infant formula by demonstrating   | approved method, including the    |
| that the protein source supports  | Protein Efficiency Ratio (PER)    |
| adequate growth using the Protein | rat bioassay described in the     |
| Efficiency Ratio (PER) rat        | \"Official Methods of Analysis of |
| bioassay described in the         | the Association of Official       |
| \"Official Methods of Analysis of | Analytical Chemists,\" 16th ed.,  |
| the Association of Official       | sections 43.3.04 and 43.3.05,     |
| Analytical Chemists,\" 16th ed.,  | \"AOAC Official Method 960.48     |
| sections 43.3.04 and 43.3.05,     | Protein Efficiency Ratio Rat      |
| \"AOAC Official Method 960.48     | Bioassay\" which is incorporated  |
| Protein Efficiency Ratio Rat      | by reference in accordance with 5 |
| Bioassay\" which is incorporated  | U.S.C. 552(a) and 1 CFR part 51.  |
| by reference in accordance with 5 | Copies are available from the     |
| U.S.C. 552(a) and 1 CFR part 51.  | Association of Official           |
| Copies are available from the     | Analytical Chemists, 481 North    |
| Association of Official           | Frederick Ave., Suite 500,        |
| Analytical Chemists, 481 North    | Gaithersburg, MD 20857, or the    |
| Frederick Ave., Suite 500,        | Office of Special Nutritionals    |
| Gaithersburg, MD 20857, or the    | (HFS-456), Center for Food Safety |
| Office of Special Nutritionals    | and Applied Nutrition, Food and   |
| (HFS-456), Center for Food Safety | Drug Administration, 200 C St.    |
| and Applied Nutrition, Food and   | SW, Washington, DC 20204, or may  |
| Drug Administration, 200 C St.    | be examined at the Office of the  |
| SW, Washington, DC 20204, or may  | Federal Register, 800 North       |
| be examined at the Office of the  | Capitol St. NW, Washington, DC.   |
| Federal Register, 800 North       | If the manufacturer is unable to  |
| Capitol St. NW, Washington, DC.   | conduct a PER rat bioassay        |
| If the manufacturer is unable to  | because of the composition of the |
| conduct a PER rat bioassay        | protein in the formula, then it   |
| because of the composition of the | shall demonstrate that the amino  |
| protein in the formula, then it   | acid composition of the protein   |
| shall demonstrate that the amino  | meets the known amino acid        |
| acid composition of the protein   | requirements of infants for whom  |
| meets the known amino acid        | the formula is intended.          |
| requirements of infants for whom  |                                   |
| the formula is intended.          |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.97(~~b~~[a]{.mark}) Specific quality factor for protein quality of
infant formula.

106.97(~~b~~[a]{.mark})(1) The manufacturer [or responsible
party]{.mark} shall collect and maintain data that establish that the
biological quality of protein in an infant formula is sufficient to meet
the protein requirements of infants. The manufacturer [or responsible
party]{.mark} shall establish the biological quality of the protein in
its infant formula [with any AOAC approved method, including]{.mark}
~~by demonstrating that the protein source supports adequate growth
using~~ the Protein Efficiency Ratio (PER) rat bioassay described in the
\"Official Methods of Analysis of the Association of Official Analytical
Chemists,\" 16th ed., sections 43.3.04 and 43.3.05, \"AOAC Official
Method 960.48 Protein Efficiency Ratio Rat Bioassay\" which is
incorporated by reference in accordance with 5 U.S.C. 552(a) and 1 CFR
part 51. Copies are available from the Association of Official
Analytical Chemists, 481 North Frederick Ave., Suite 500, Gaithersburg,
MD 20857, or the Office of Special Nutritionals (HFS-456), Center for
Food Safety and Applied Nutrition, Food and Drug Administration, 200 C
St. SW, Washington, DC 20204, or may be examined at the Office of the
Federal Register, 800 North Capitol St. NW, Washington, DC. If the
manufacturer is unable to conduct a PER rat bioassay because of the
composition of the protein in the formula, then it shall demonstrate
that the amino acid composition of the protein meets the known amino
acid requirements of infants for whom the formula is intended.

IFC Comment

IFC believes that the regulations should recognize other AOAC methods as
they become available.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.97(b)(2) The manufacturer may   Acceptable; Renumbered as
  request an exemption from the       106.97(a)(2).
  requirements of paragraph (b)(1) of 
  this section if:                    

  106.97(b)(2)(i) The protein source, Acceptable; Renumbered as
  including any processing method     106.97(a)(2)(i).
  used to produce the protein source, 
  is already used in another infant   
  formula marketed in the United      
  States, manufactured by the same    
  manufacturer, and the manufacturer  
  can demonstrate that such infant    
  formula meets the quality factor    
  requirements prescribed in Sec.     
  106.96;                             

  106.97(b)(2)(ii) The protein        Acceptable; Renumbered as
  source, including any processing    106.97(a)(2)(ii).
  methods used to produce the protein 
  source, is not a major change from  
  the infant formula it replaces, and 
  the manufacturer can demonstrate    
  that the infant formula it replaces 
  meets the quality factor            
  requirements prescribed in Sec.     
  106.96.                             
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.97(~~b~~[a]{.mark})(2) The manufacturer may request an exemption
from the requirements of paragraph (b)(1) of this section if:

106.97(~~b~~[a]{.mark})(2)(i) The protein source, including any
processing method used to produce the protein source, is already used in
another infant formula marketed in the United States, manufactured by
the same manufacturer, and the manufacturer can demonstrate that such
infant formula meets the quality factor requirements prescribed in Sec.
106.96;

106.97(~~b~~[a]{.mark})(2)(ii) The protein source, including any
processing methods used to produce the protein source, is not a major
change from the infant formula it replaces, and the manufacturer can
demonstrate that the infant formula it replaces meets the quality factor
requirements prescribed in Sec. 106.96.

**Rest of page left intentionally blank**

**FDA\'s Request for Comments on Additional Quality Factors**

IFC Comment

The Agency requested comments whether additional quality factors,
specifically for fat, calcium, and phosphorus bioavailability, should be
established. Each of these is commented upon below: References are
provided in a footnote.

**Fat**: The IFC concurs with FDA that there is no current practical and
generally accepted alternative to fat balance studies for assessing
total fat bioavailability. Even so, contrary to what is stated in the
preamble, fat balance studies are in fact technically difficult to
perform well and are conducted at very few research centers.[^6] Such
studies are much more useful for comparing formulas than for assessing
adequacy of a formula, and cross-over designs add much to the
sensitivity of this test.^1^ Adding to the limitations of these studies
is the fact that the level of fat malabsorption which leads to clinical
or body composition effects is not well defined and may not be 15%, as
stated in the preamble. Furthermore, fat balance studies are relatively
invasive, requiring several days of hospitalization. One could argue
that this hospitalization was unnecessary and, therefore, unethical. All
in all, these studies are not appropriate as quality factor requirements
and should continue to be performed only at the discretion of the
manufacturer.

**Iron**: Regarding iron, the creation of a quality factor for iron is
complicated by the presence in the U.S. market of formulas with varying
levels of iron fortification, some of which are nutritionally adequate
from the standpoint of iron and others which may not be adequate, but
still meet the standards of the Act. It makes little sense to develop a
quality factor for a nutrient, which is not required in nutritionally
adequate amounts in formulas for healthy infants. This issue generated
substantial comment among the members of the FASEB/LSRO panel examining
nutrient requirements for infant formulas. No quality factor
recommendation is appropriate until and unless the Act is modified to
establish a required level of bioavailable iron. Moreover, two factors
indicate that any eventual quality factor for iron might better be
limited to animal assays of bioavailability, rather than any additional
measures incorporated into a standard growth study. Those factors are
(a) that the CBC, which may be used to help assess iron nutriture in
later infancy, is not sensitive to iron depletion before four months of
age when the standard growth study would be conducted,^3^ and (b) that
the direct measurement of the iron status of infants would require
invasive blood tests which are not routine assessments in healthy
infants before 9 months of age.^4^ We suggest that such studies in
infants only be performed when the manufacturer believes they may help
assess effects of a specific formula or ingredient.

**Calcium and Phosphorus**: Again, the current state of the art is
comparative balance data, but there is a high level of study-to-study
and laboratory-to-laboratory variability in the assay.^2^ As with fat
balance, the use of cross-over designs increases the sensitivity of this
test.^1^ Given the tendency of balance studies to become more positive
with higher intakes, the use of comparable levels of minerals in
comparison formulas is generally desirable. Overall, it would be
inadvisable to establish a universal quality factor based on the status
of this test.^5^ Alkaline phosphatase determination would be of no value
in balance studies as the time course of its response is slower than the
brief period of a balance study. There are also age-specific,
gestational and other nutrient effects, which complicate its
interpretation. Newer measures of assessing bone mineralization directly
hold considerable promise and may eventually provide the basis for a
quality factor when methods become more standardized and more normative
data become available for infants. In the meantime, however, there is no
measure available, which has demonstrated reliable predictive
value.^6-8^

In conclusion, based on the state of the science in each of these areas,
the IFC believes that some of the studies discussed may be appropriately
used by infant formula manufacturers on a voluntary basis in order to
substantiate product claims, but that none of these studies reaches to a
level of validity and reliability that would justify its designation as
a quality factor requirement at this time. Beyond their scientific
status, these additional biochemical indicators would make growth
studies much more difficult to perform. Parents and guardians are less
likely to consent to and continue participation of their infant in
growth studies if blood sampling and other invasive testing are
required. Thus, the IFC suggests that such studies only be performed in
situations where the manufacturer believes they are necessary to assess
specific effects of a formula or ingredient.

1.  Procedures for collection of urine and feces and for metabolic
    balance studies. *In* Fomon SJ. Nutrition of Normal Infants. Mosby,
    St. Louis, 1993; pp 459-464.

2.  Ernst JA, Curse WK, Lemmons JA. Metabolic balance studies in
    premature infants. Clinics in Perinatology 1995; 22:117-93.

3.  Schwartz E., Iron deficiency anemia. *In* Behrman RE, Kliegman RM,
    Arvin AM eds Nelson Textbook of Pediatrics. WB Saunders Co.,
    Philadelphia, 1996; p 1387.

4.  American Academy of Pediatrics. Recommendations for preventive
    pediatric health care. AAP, Elk Grove, 1995.

5.  Avioli LV. Calcium and Phosphorus in Shils ME and Young VR Modern
    Nutrition. *In* Health and Disease. Lea and Febiger, Philadelphia,
    1988; pp 147-149.

6.  Picaud J-C, Rigo J., Nyamugabo K., et al. Evaluation of dual-energy
    x-ray absorptiometry for body-composition assessment in piglets and
    term human neonates. Am J Clin Nutr 1996; 63: 157-63.

7.  Modlesky CM, Lewis RD, Yetman KA, et al. Comparison of body
    composition and bone mineral measurements from two DXA instruments
    in young men. Am J Clin Nutr 1996; 64:669-76.

8.  Brunton JA, Bayley HS, Atkinson SA. Validation and application of
    dual-energy x-ray absorptiometry to measure bone mass and body
    composition in small infants. Am J Clin Nutr 1993; 58: 839-45.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| In newly redesignated subpart F,  | Acceptable as proposed.           |
| Sec 106.100 is amended by         |                                   |
| revising paragraphs (e), (f),     |                                   |
| (g),(j) and (k)(3), and by        |                                   |
| removing and reserving paragraph  |                                   |
| (h) to read as follows:           |                                   |
+-----------------------------------+-----------------------------------+
| **106.100 Records**               | **106.100 Records**               |
|                                   |                                   |
| \* \* \* \*                       | \* \* \* \*                       |
|                                   |                                   |
| 106.100(e) *Batch production and  | 106.100(e) *Batch production and  |
| control records*. For each batch  | control records*. For each batch  |
| of infant formula, manufacturers  | of infant formula, manufacturers  |
| shall prepare and maintain        | shall prepare and maintain        |
| records that include complete     | records that include complete     |
| information relating to the       | information relating to the       |
| production and control of the     | production and control of the     |
| batch. These records shall        | batch. The records that are       |
| include but are not limited to:   | necessary under this paragraph    |
|                                   | are:                              |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.100(e) *Batch production and control records*. For each batch of
infant formula, manufacturers shall prepare and maintain records that
include complete information relating to the production and control of
the batch. ~~These records shall include but are not limited to:~~ [The
records that are necessary under this paragraph are:]{.mark}

IFC Comment

See the IFC General Comment regarding Recordkeeping. Regarding the
suggested deletion of \"but are not limited to,\" see the IFC General
Comment on Recordkeeping for an explanation of the need to focus on only
\"necessary\" records, as dictated in the statute.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(1) The master            106.100(e)(1) The master
  manufacturing order. The master     manufacturing order. The master
  manufacturing order shall include   manufacturing order shall include:
  but is not limited to:              

  106.100(e)(1)(i) The significant    Acceptable as proposed.
  steps in the production of the      
  batch and the date on which each    
  significant step occurred;          

  106.100(e)(1)(ii) The identity of   106.100(e)(1)(ii) The identity of
  equipment and processing lines used the major equipment systems used in
  in producing the batch, if the      producing the batch, if the plant
  plant in which the formula is made  in which the formula is made
  includes more than one set of       includes more than one equipment
  equipment or more than one          system;
  processing line;                    
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.100(e)(1) The master manufacturing order. The master manufacturing
order shall include ~~but is not limited to~~:

106.100(e)(1)(ii) The identity of [the major]{.mark} equipment ~~and
processing lines~~ [systems]{.mark} used in producing the batch, if the
plant in which the formula is made includes more than one ~~set of~~
equipment ~~or more than one processing line~~ [system]{.mark};

IFC Comment

While it is reasonable to require the identity of processing systems and
filling lines if more than one are available, it is not reasonable to
expect that every transfer line, hook-up station, jumper and valve will
be documented. Again, infant formula manufacturing involves multitudes
of equipment pieces and lines; the itemization of these for every batch
would require significant resources with no practical benefits.

Current procedures document the main equipment that is used to
manufacture a batch. However if the operators will need to document all
the equipment that is being used, which includes processing lines,
tanks, storage containers, and major equipment additional personnel will
be needed at a large expense to the manufacturer with no additional
benefit to the consumer.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(1)(iii) The identity of  Acceptable as proposed.
  each batch or lot of ingredients,   
  containers, and closures used in    
  producing the batch of formula;     

  106.100(e)(1)(iv) The amount of     Acceptable as proposed.
  each ingredient to be added to the  
  batch of infant formula and a check 
  (verification) that the correct     
  amount was added; and               

  106.100(e)(1)(v) Copies of all      106.100(e)(1)(v) Copies of all
  labeling used and the results of    primary container labels used and
  examinations conducted during the   the results of examinations
  finishing operations to provide     conducted during the finishing
  assurance that containers and       operations to provide assurance
  packages in the lot have the        that containers and packages in the
  correct label.                      lot have the correct label.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.100(e)(1)(v) Copies of all ~~labeling~~ [primary container
labels]{.mark} used and the results of examinations conducted during the
finishing operations to provide assurance that containers and packages
in the lot have the correct label.

IFC Comment

A sample of the primary container label is included in each batch
record. However, since larger sized trays, cartons and shippers are also
considered labels, their inclusion would substantially increase the size
of the batch record. Thus, if all labeling materials were included, a
system with significantly more storage space would be needed.

The requirement that all examinations of the packaging materials be
retained with the batch records also creates a system and storage
problem. All packaging materials are accepted through a packaging
acceptance program. Results of the examinations are kept in a separate
location, but are easily accessible when necessary. If the results were
to be kept in each batch record, additional systems would be needed to
combine testing with the batch records. Unnecessarily complicating the
batch record may also interfere with the speedy review of those records
during production audits and complaint-surveillance.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(2) Any deviations from   106.100(e)(2) Any deviations from
  the master manufacturing order and  the master manufacturing order and
  any corrective actions taken        any specific actions taken to
  because of the deviations.          adjust or correct a batch in
                                      response to a deviation.
  ----------------------------------- -----------------------------------

#########  IFC Redlined Version

106.100(e)(2) Any deviations from the master manufacturing order and any
~~corrective~~ [specific]{.mark} actions taken [to adjust or correct a
batch in response to a deviation]{.mark} ~~because of the deviations~~.

IFC Comment

Requiring documentation of any deviations to appear in a batch record is
straightforward. Requiring corrective actions to appear in the same
batch record would seem to make sense, but may not always be practical
over the course of time. If the corrective action is immediate, then its
inclusion in the batch record would be expected. However, some
deviations require investigation and research over an extended period of
time and potentially involve the evaluation of multiple batches before a
final corrective action can be agreed upon. In these cases, it would be
very unwieldy to put a copy into each of the affected batch records
after the fact. However, it is a simple matter to access the relevant
corrective actions by other means. If the batch record, deviation report
and resulting action, if any, were required to be stored in the same
filing system, additional tracking systems would need to be developed,
with no commensurate benefit to the public health.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(3) Documentation, in     106.100(e)(3) Documentation, in
  accordance with Sec. 106.6(c), of   accordance with Sec. 106.6(c), of
  the monitoring at any point, step,  the monitoring at any point, step,
  or stage in their production        or stage in their production
  process where control is deemed     process where control is deemed
  necessary to prevent adulteration.  critical to prevent adulteration.
  These records shall include, but    The records that are necessary
  not be limited to:                  under this paragraph shall include:

  106.100(e)(3)(i) A list of the      106.100(e)(3)(i) A list of the
  standards or specifications         specifications established at each
  established at each point, step, or point, step, or stage in their
  stage in their production process   production process where control is
  where control is deemed necessary   deemed necessary by the
  to prevent adulteration including   manufacturer.
  documentation of the scientific     
  basis for each standard or          
  specification;                      
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.100(e)(3) Documentation, in accordance with Sec. 106.6(c), of the
monitoring at any point, step, or stage in their production process
where control is deemed ~~necessary~~ [critical]{.mark} to prevent
adulteration. ~~These records~~ [The records that are necessary under
this paragraph]{.mark} shall include~~, but not be limited to~~:

106.100(e)(3)(i) A list of the ~~standards or~~ specifications
established at each point, step, or stage in their production process
where control is deemed necessary ~~to prevent adulteration including
documentation of the scientific basis for each standard or
specification;~~ [by the manufacturer.]{.mark}

IFC Comment

As discussed in its General Comment entitled \"Specifications,\" its
suggested addition of a definition of \"specifications\" to the
regulation and its comment to 106.6(c)(1), the IFC believes that
specifications must be allowed to be set at tighter limits than those
envisioned in the outer acceptability limits approach. If the FDA does
not agree with the IFC\'s approach and definition for specifications,
any inclusion in the final regulation of references to
\"specifications\" will create problems for the IFC members. As
discussed earlier in these comments, documentation of the scientific
basis for each specification, using an outer-limits approach, would take
years of work and would not provide any commensurate benefits to the
public health.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(3)(ii) The actual values 106.100(e)(3)(ii) The actual values
  obtained during the monitoring      obtained during the monitoring
  operation, any deviations from      operation, any deviations from
  established standards or            established specifications, and any
  specifications, and any corrective  specific actions taken to adjust or
  actions taken;                      correct a batch in response to a
                                      deviation;
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.100(e)(3)(ii) The actual values obtained during the monitoring
operation, any deviations from established ~~standards or~~
specifications, and any ~~corrective~~ [specific]{.mark} actions taken
[to adjust or correct a batch in response to a deviation]{.mark};

IFC Comment

See the IFC comments to 106.100(e)(2) and 106.100(e)(3)(i).

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(3)(iii) Identification   Acceptable as proposed.
  of the person monitoring each       
  point, step, or stage in their      
  production process where control is 
  deemed necessary to prevent         
  adulteration.                       

  106.100(e)(4) The conclusions and   Acceptable as proposed.
  follow-up, along with the identity, 
  of the individual qualified by      
  training or experience who          
  investigated:                       

  106.100(e)(4)(i) Any deviation from 106.100(e)(4)(i) Any deviation from
  the master manufacturing order and  the master manufacturing order and
  any corrective actions taken;       any specific actions taken to
                                      adjust or correct a batch in
                                      response to a deviation;
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.100(e)(4)(i) Any deviation from the master manufacturing order and
any ~~corrective~~ [specific]{.mark} actions taken [to adjust or correct
a batch in response to a deviation]{.mark};

######### IFC Comment

Same comment as noted in 106.100(e)(2).

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(4)(ii) A finding that a  Acceptable as proposed, subject to
  batch or any of its ingredients     the comment below.
  failed to meet the infant formula   
  manufacturer\'s specifications; and 
  ----------------------------------- -----------------------------------

IFC Comment

See the IFC\'s General Comment regarding \"Specifications\" and its
statements throughout its comments with its concern about the definition
and operation of this term. Based on the IFC\'s belief that permitting
tight specifications enhances the quality of infant formula, this
language is acceptable so long as tight specifications are permitted by
the final regulation and exceeding those tight specifications or
standards does not lead to automatic rejection and/or adulteration.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(4)(iii) A failure to     Delete.
  meet any specification or standard  
  at any point, step, or stage in the 
  production process where control is 
  deemed necessary to prevent         
  adulteration.                       
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.100(e)(4)(iii) A failure to meet any specification or standard at
any point, step, or stage in the production process where control is
deemed necessary to prevent adulteration.~~

IFC Comment

See the IFC\'s General Comment regarding \"Specifications.\" Also, this
proposed language is redundant with (e)(4)(i) above.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(5) The results of all    106.100(e)(5) The results of all
  testing performed on the batch of   testing performed on the batch of
  infant formula, including testing   infant formula, including testing
  on the in-process batch, at the     on the in-process batch, at the
  final-product stage, and on         final-product stage and on finished
  finished product throughout the     product. The results recorded shall
  shelf life of the product. The      include:
  results recorded shall include but  
  are not limited to:                 
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.100(e)(5) The results of all testing performed on the batch of
infant formula, including testing on the in‑process batch, at the
final‑product stage~~,~~ and on finished ~~product throughout the shelf
life of the~~ product. The results recorded shall include ~~but are not
limited to~~:

IFC Comment

The requirement to include all stability test results in the individual
batch records represents a large additional administrative burden to
current practice of manufacturers and can easily be avoided by requiring
that shelf life testing results be made available to the Agency upon
request, either by outside communication or by inspection. If a
requirement were made to store the data with the manufacturing work
order, an additional system would need to be developed to link the data
at an additional cost with no commensurate benefit to the public health
or additional quality to the product.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(5)(i) The results of all Acceptable as proposed, subject to
  quality control testing conducted,  the comment below.
  in accordance with Sec. 106.91(a)   
  and (b), to verify that each        
  nutrient required by Sec. 107.100   
  of this chapter is present in each  
  batch of infant formula at the      
  level required by Sec. 107.100, and 
  that any nutrient added by the      
  manufacturer is present at the      
  appropriate level with:             

  106.100(e)(5)(i)(A) A summary table Acceptable as proposed, subject to
  identifying the stages of the       renumbering if (B) is deleted as
  manufacturing process at which the  suggested.
  nutrient analysis for each required 
  nutrient under §106.91(a) is        
  conducted, and                      

  106.100(e)(5)(i)(B) A summary table Delete.
  on the stability testing program,   
  including the nutrients tested and  
  the frequency of testing of         
  nutrients throughout the shelf life 
  of the product under Sec.           
  106.91(b); and                      
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.100(e)(5)(i)(B) A summary table on the stability testing program,
including the nutrients tested and the frequency of testing of nutrients
throughout the shelf life of the product under 106.91(b); and~~

IFC Comment

A summary table on the stability testing program results should be
required, but its storage limited to inclusion in the file with all
shelf life testing results, which may be maintained separate from
individual batch records. Also, see the IFC\'s comment to 106.100(e)(5).

**Rest of page left intentionally blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(e)(5)(ii) For powdered      Acceptable as proposed.
  infant formula, the results of any  
  testing conducted in accordance     
  with §106.55(b) to verify           
  compliance with the microbiological 
  quality standards in §106.55(c).    

  106.100(f) Manufacturers shall make 106.100(f) Manufacturers shall make
  and retain all records pertaining   and retain all the following
  to current good manufacturing       necessary records pertaining to
  practice as described in subpart B  current good manufacturing practice
  of this part, including but not     as described in subpart B of this
  limited to:                         part:
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.100(f) Manufacturers shall make and retain all [the following
necessary]{.mark} records pertaining to current good manufacturing
practice as described in subpart B of this part~~, including but not
limited to~~:

IFC Comment

See the IFC\'s General Comment to Recordkeeping.

**Rest of page left intentionally blank**

  -----------------------------------------------------------------------
  FDA Proposed Regulation             IFC Suggested Language
  ----------------------------------- -----------------------------------
  106.100(f)(1) Records, in           Acceptable as proposed.
  accordance with §106.20(f)(3), of   
  the frequency and results of        
  testing of the water used in the    
  production of infant formula;       

  106.100(f)(2) Records, in           106.100(f)(2) Records, in
  accordance with §106.30(d), of      accordance with §106.30(d), of
  accuracy checks of instruments and  accuracy checks of instruments and
  controls. A certification of        controls. A certification of
  accuracy of any known reference     accuracy of any known reference
  standard used and a history of      standard used and a history of
  recertification shall be            recertification shall be
  maintained. At a minimum, such      maintained. At a minimum, such
  records shall specify the           records shall specify the
  instrument or control being         instrument or control being
  checked, the date of the accuracy   checked, the date of the accuracy
  check, the standard used, the       check, the standard used, the
  calibration method used, the        calibration method used, the
  results found, any actions taken if results found, any actions taken if
  the instrument is found to be out   the instrument is found to be out
  of calibration, and the initials or of calibration, and the initials or
  name of the individual performing   name of the individual performing
  the test. If calibration of an      the test. If calibration of an
  instrument (testing for accuracy    instrument (testing for accuracy
  against a known reference standard) against a known reference standard)
  shows that a specification or       shows that a specification at a
  standard at a point, step, or stage point, step, or stage in the
  in the production process where     production process where control is
  control is deemed necessary to      deemed necessary to prevent
  prevent adulteration has not been   adulteration has not been met, a
  met, a written evaluation of all    written evaluation of all affected
  affected product, and any actions   product, and any actions that need
  that need to be taken with respect  to be taken with respect to that
  to that product, shall be made.     product, shall be made.

  106.100(f)(3) Records, in           Acceptable as proposed.
  accordance with §106.30(e)(3)(ii),  
  of the temperatures monitored for   
  cold storage compartments and       
  thermal processing equipment.       

  106.100(f)(4) Records, in           106.100(f)(4) Records, in
  accordance with Sec. 106.30(f), on  accordance with Sec. 106.30(f), on
  equipment cleaning, sanitizing, and equipment cleaning, sanitizing and
  maintenance that show the date and  critical maintenance that show the
  time of such cleaning, sanitizing,  date and time of such cleaning,
  and maintenance and the lot number  sanitizing and critical
  of each batch of infant formula     maintenance. The person performing
  processed between equipment         and checking the cleaning,
  start-up and shutdown for cleaning, sanitizing and critical maintenance
  sanitizing, and maintenance. The    shall date and sign or initial the
  person performing and checking the  record indicating that the work was
  cleaning, sanitizing, and           performed.
  maintenance shall date and sign or  
  initial the record indicating that  
  the work was performed.             
  -----------------------------------------------------------------------

IFC Redlined Version

106.100(f)(2) Records, in accordance with §106.30(d), of accuracy checks
of instruments and controls. A certification of accuracy of any known
reference standard used and a history of recertification shall be
maintained. At a minimum, such records shall specify the instrument or
control being checked, the date of the accuracy check, the standard
used, the calibration method used, the results found, any actions taken
if the instrument is found to be out of calibration, and the initials or
name of the individual performing the test. If calibration of an
instrument (testing for accuracy against a known reference standard)
shows that a specification ~~or standard~~ at a point, step, or stage in
the production process where control is deemed necessary to prevent
adulteration has not been met, a written evaluation of all affected
product, and any actions that need to be taken with respect to that
product, shall be made.

106.100(f)(4) Records, in accordance with Sec. 106.30(f), on equipment
cleaning, sanitizing~~,~~ and [critical]{.mark} maintenance that show
the date and time of such cleaning, sanitizing~~,~~ and
[critical]{.mark} maintenance ~~and the lot number of each batch of
infant formula processed between equipment startup and shutdown for
cleaning, sanitizing, and maintenance~~. The person performing and
checking the cleaning, sanitizing~~,~~ and [critical]{.mark} maintenance
shall date and sign or initial the record indicating that the work was
performed.

######### IFC Comment

The proposed requirement to document all lot numbers of batches produced
between all equipment cleaning, sanitizing and maintenance is an
overwhelming administrative requirement that is not needed on a day to
day basis. Certainly the records should have sufficient detail and
reference points (time, location, etc.) to allow reconstruction of this
type of information if needed. It is a current practice in all
manufacturing facilities to clean, sanitize and maintain equipment and
utensils, as needed to prevent adulteration of infant formulas at
regular intervals defined by the manufacturing facility. Review of all
cleaning and sanitizing of CIP'd systems is currently in place.
Maintenance of equipment is ongoing and is not necessarily recorded for
all equipment. If manufacturers were required to record all maintenance,
regardless of whether it is part of a critical process, as well as the
lot number of the relevant batches manufactured between the times of
maintenance, this would add significant cost to the manufacturing
process with no added benefit or safety to the customer. The additional
documentation that would be needed to record all of the cleaning,
sanitizing and maintenance along with relevant batches manufactured
during that time, would require an entirely new tracking system at an
very large cost.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.100(f)(5) Records, in         | Delete                            |
| accordance with Sec. 106.35(c),   |                                   |
| on all automatic (mechanical or   | or                                |
| electronic) equipment used in the |                                   |
| production or quality control of  | 106.100(f)(5) Records, in         |
| infant formula. These records     | accordance with Sec. 106.35(c),   |
| shall include but not be limited  | on all automatic (mechanical or   |
| to:                               | electronic) equipment used in the |
|                                   | production or quality control of  |
|                                   | infant formula. These records     |
|                                   | shall include:                    |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

[Delete]{.mark}

[or]{.mark}

106.100(f)(5) Records, in accordance with Sec. 106.35(c), on all
automatic (mechanical or electronic) equipment used in the production or
quality control of infant formula. These records shall include ~~but not
be limited to~~:

IFC Comment

See the IFC General Comments regarding Validation and comments on 106.35
where the IFC recommends that any validation provisions of the proposal
be deleted or at least postponed. On the basis of IFC\'s suggestion, it
has suggested deletion of all recordkeeping related to validation. If
the suggestion to delete is not accepted, see the IFC\'s General Comment
to Recordkeeping regarding the suggested revision to the proposal\'s
language.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(f)(5)(i) A list of all      Delete.
  systems used with a description of  
  computer files and the inherent     
  limitations of each system;         

  106.100(f)(5)(ii) A copy of all     Delete.
  software used;                      

  106.100(f)(5)(iii) Records that     Delete.
  document installation, calibration, 
  testing or validation, and          
  maintenance of the systems used;    

  106.100(f)(5)(iv) A list of all     Delete.
  persons authorized to create or     
  modify software;                    

  106.100(f)(5)(v) Records that       Delete.
  document modifications to software, 
  including the identity of the       
  person who modified the software;   

  106.100(f)(5)(vi) Records that      Delete.
  document retesting or revalidation  
  of modified systems; and            

  106.100(f)(5)(vii) A backup file of Delete.
  data entered into a computer or     
  related system. The backup file     
  shall consist of a hard copy or     
  alternative system, such as         
  duplicate diskettes, tapes, or      
  microfilm, designed to ensure that  
  backup data are exact and complete, 
  and that they are secure from       
  alteration, inadvertent erasures,   
  or loss.                            
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.100(f)(5)(i) A list of all systems used with a description of
computer files and the inherent limitations of each system;~~

~~106.100(f)(5)(ii) A copy of all software used;~~

~~106.100(f)(5)(iii) Records that document installation, calibration,
testing or validation, and maintenance of the systems used;~~

~~106.100(f)(5)(iv) A list of all persons authorized to create or modify
software;~~

~~106.100(f)(5)(v) Records that document modifications to software,
including the identity of the person who modified the software;~~

~~106.100(f)(5)(vi) Records that document retesting or revalidation of
modified systems; and~~

~~106.100(f)(5)(vii) A backup file of data entered into a computer or
related system. The backup file shall consist of a hard copy or
alternative system, such as duplicate diskettes, tapes, or microfilm,
designed to ensure that backup data are exact and complete, and that
they are secure from alteration, inadvertent erasures, or loss.~~

IFC Comment

See the IFC\'s comments to 106.35 and to 106.100(f)(5).

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.100(f)(6) Records, in           106.100(f)(6) Records, in
  accordance with §106.40(g), on      accordance with §106.40(g), on
  ingredients, containers, and        ingredients, containers, and
  closures used in the manufacture of closures used in the manufacture of
  infant formula. These records shall infant formula. The records that
  include, but are not limited to:    are necessary under this paragraph
                                      are:
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.100(f)(6) Records, in accordance with 106.40(g), on ingredients,
containers, and closures used in the manufacture of infant formula. [The
records that are necessary under this paragraph are]{.mark} ~~These
records shall include, but are not limited to~~:

IFC Comment

See the IFC\'s General Comment concerning Recordkeeping.

**Rest of page left intentionally blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.100(f)(6)(i) The identity and | Acceptable as proposed.           |
| quantity of each lot of           |                                   |
| ingredients, containers, and      |                                   |
| closures;                         |                                   |
+-----------------------------------+-----------------------------------+
| 106.100(f)(6)(ii) The name of the | Acceptable as proposed.           |
| supplier;                         |                                   |
+-----------------------------------+-----------------------------------+
| 106.100(f)(6)(iii) The            | Acceptable as proposed.           |
| supplier\'s lot numbers;          |                                   |
+-----------------------------------+-----------------------------------+
| 106.100(f)(6)(iv) The name and    | Acceptable as proposed.           |
| location of the manufacturer of   |                                   |
| the ingredient, container, and    |                                   |
| closure, if different from the    |                                   |
| supplier;                         |                                   |
+-----------------------------------+-----------------------------------+
| 106.100(f)(6)(v) The date of      | Acceptable as proposed.           |
| receipt;                          |                                   |
+-----------------------------------+-----------------------------------+
| 106.100(f)(6)(vi) The receiving   | Acceptable as proposed.           |
| code as specified; and            |                                   |
+-----------------------------------+-----------------------------------+
| 106.100(f)(6)(vii) The results of | Acceptable as proposed.           |
| any test or examination           |                                   |
| (including retesting and          |                                   |
| reexamination) performed on the   |                                   |
| ingredients, containers, and      |                                   |
| closures and the conclusions      |                                   |
| derived there from and the        |                                   |
| disposition of all ingredients,   |                                   |
| containers, or closures.          |                                   |
+-----------------------------------+-----------------------------------+
| 106.100(f)(7) A full description  | Acceptable as proposed.           |
| of the methodology used to test   |                                   |
| powdered infant formula to verify |                                   |
| compliance with the               |                                   |
| microbiological quality standards |                                   |
| of §106.55(c) and the methodology |                                   |
| used to do quality control        |                                   |
| testing, in accordance with       |                                   |
| §106.91(a) and (b).               |                                   |
+-----------------------------------+-----------------------------------+
| None.                             | 106.100(f)(8) Results of          |
|                                   | stability testing performed       |
| 106.100(g) The manufacturer shall | pursuant to 106.91(b)(2).         |
| maintain all records pertaining   |                                   |
| to distribution of the infant     | 106.100(g) The manufacturer shall |
| formula, including records that   | maintain all records pertaining   |
| show that products produced for   | to the manufacturer\'s            |
| export only are exported. Such    | distribution of the infant        |
| records shall include, but not be | formula, including records for    |
| limited to, all information and   | products produced for export      |
| data necessary to effect and      | only. The records required under  |
| monitor recalls of the            | this paragraph are those          |
| manufacturer\'s infant formula    | providing the information and     |
| products in accordance with       | data necessary to effect and      |
| subpart E of part 107 of this     | monitor recalls of the            |
| chapter.                          | manufacturer\'s infant formula    |
|                                   | products in accordance with       |
|                                   | subpart E of part 107 of this     |
|                                   | chapter.                          |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

[106.100(f)(8) Results of stability testing performed pursuant to
106.91(b)(2).]{.mark}

106.100(g) The manufacturer shall maintain all records pertaining to
[the manufacturer\'s]{.mark} distribution of the infant formula,
including records ~~that show that~~ [for]{.mark} products produced for
export only ~~are exported. Such records shall include, but not be
limited to, all~~. [The records required under this paragraph are those
providing the]{.mark} information and data necessary to effect and
monitor recalls of the manufacturer\'s infant formula products in
accordance with subpart E of part 107 of this chapter.

IFC Comment

It is reasonable to expect the manufacturer to maintain distribution
records regarding shipment of infant formula under the manufacturer\'s
control. Once into the retailer/customer/consumer/exporter\'s hands, the
manufacturer can no longer be responsible for obtaining or keeping these
records. The IFC believes that the Agency did not intend to suggest that
the manufacturer had responsibility after product left its control, and
requests confirmation of that in the preamble to the final rule.

The FDA should also realize that sometimes manufacturers ship to a
customer who, in turn, intends it for export only. Because the
manufacturer is not responsible for the actual exportation, the
manufacturer would have no records regarding distribution of the
material after it is turned over to the exporter.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.100(h) \[Reserved\]           | Acceptable as proposed.           |
|                                   |                                   |
| \* \* \* \* \*                    |                                   |
|                                   |                                   |
| 106.100(j) The manufacturer shall |                                   |
| make and retain records           |                                   |
| pertaining to regularly scheduled |                                   |
| audits, including the audit plans |                                   |
| and procedures, the findings of   |                                   |
| the audit, and a listing of any   |                                   |
| changes made in response to these |                                   |
| findings. The manufacturer shall  |                                   |
| make readily available for        |                                   |
| authorized inspection the audit   |                                   |
| plans and procedures and a        |                                   |
| statement of assurance that the   |                                   |
| regularly scheduled audits are    |                                   |
| being conducted. The findings of  |                                   |
| the audit and any changes made in |                                   |
| response to these findings shall  |                                   |
| be maintained for the time period |                                   |
| required under §106.100(n), but   |                                   |
| need not be made available to     |                                   |
| FDA.                              |                                   |
+-----------------------------------+-----------------------------------+
| 106.100(k)(3) When there is a     | 106.100(k)(3) When there is a     |
| reasonable possibility of a       | reasonable possibility of a       |
| causal relationship between the   | causal relationship between the   |
| consumption of an infant formula  | consumption of an infant formula  |
| and an infant\'s death, the       | and an infant\'s death, the       |
| manufacturer shall, within 15     | responsible party shall, within   |
| days of receiving such            | 15 days of receiving such         |
| information, conduct an           | information, conduct an           |
| investigation and notify the      | investigation and notify the      |
| agency as required in Sec.        | agency as required in Sec.        |
| 106.150.                          | 106.150.                          |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.100(k)(3) When there is a reasonable possibility of a causal
relationship between the consumption of an infant formula and an
infant\'s death, the ~~manufacturer~~ [responsible party]{.mark} shall,
within 15 days of receiving such information, conduct an investigation
and notify the agency as required in Sec. 106.150.

IFC Comment

See the IFC\'s General Comment regarding Definition of Manufacturer. For
this type of notification (as for a new infant formula submission or
verification), any duplication of the responsible party\'s efforts by
co-packers would serve no useful purpose.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **Subpart G\--Registration,       | **Subpart G\--Registration,       |
| Submission, and Notification      | Submission, and Notification      |
| Requirements**                    | Requirements**                    |
|                                   |                                   |
| **106.110 New infant formula      | **106.110 New infant formula      |
| registration.**                   | registration.**                   |
|                                   |                                   |
| 106.110(a) Before a new infant    | Acceptable as proposed subject to |
| formula may be introduced or      | the Comment below.                |
| delivered for introduction into   |                                   |
| interstate commerce, the          |                                   |
| manufacturer of such formula      |                                   |
| shall register with the Food and  |                                   |
| Drug Administration, Center for   |                                   |
| Food Safety and Applied           |                                   |
| Nutrition, Office of Special      |                                   |
| Nutritionals, Division of         |                                   |
| Programs and Policy Enforcement   |                                   |
| (HFS‑455), Infant Formula         |                                   |
| Coordinator, 200 C St. SW,        |                                   |
| Washington, DC 20204. An original |                                   |
| and two copies of this            |                                   |
| registration shall be submitted.  |                                   |
+-----------------------------------+-----------------------------------+

IFC Comment

The IFC\'s recommended changes are indicated below under the specific
proposed provision to which each relates. The IFC recognizes that there
may be multiple registrations submitted to FDA in cases where multiple
manufacturers/responsible parties are involved in a manufacturing
operation. However, there are potential benefits in having all parties
involved in infant formula manufacturing operations known to FDA, and
because the registration process accomplishes this, the IFC has not
suggested that it be changed.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.110(b) The new infant formula | Acceptable as proposed.           |
| registration shall include:       |                                   |
|                                   | Acceptable as proposed.           |
| 106.110(b)(1) The name of the new |                                   |
| infant formula,                   |                                   |
+-----------------------------------+-----------------------------------+
| 106.110(b)(2) The name of the     | 106.110(b)(2) The name of the     |
| manufacturer,                     | manufacturer and of the           |
|                                   | responsible party if other than   |
|                                   | the manufacturer,                 |
+-----------------------------------+-----------------------------------+
| 106.110(b)(3) The place of        | 106.110(b)(3) The place of        |
| business of the manufacturer, and | business of the manufacturer and  |
|                                   | of the responsible party if other |
|                                   | than the manufacturer, and        |
+-----------------------------------+-----------------------------------+
| 106.110(b)(4) All establishments  | 106.110(b)(4) The names and       |
| at which the manufacturer intends | addresses of all establishments   |
| to manufacture such new infant    | at which the manufacturer or      |
| formula.                          | responsible party intends to      |
|                                   | manufacture such new infant       |
|                                   | formula.                          |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.110(b)(2) The name of the manufacturer [and of the responsible party
if other than the manufacturer]{.mark},

106.110(b)(3) The place of business of the manufacturer~~,~~ and [of the
responsible party if other than the manufacturer]{.mark}, and

106.110(b)(4) ~~All~~ [The names and addresses of all]{.mark}
establishments at which the manufacturer [or responsible party]{.mark}
intends to manufacture such new infant formula.

IFC Comment

The IFC believes that FDA would benefit from knowing when a co packer or
ancillary manufacturer is involved. Therefore, it suggests that a
manufacturer be asked to identify the responsible party who contracted
its services. Similarly, responsible parties should be asked to identify
all the manufacturers it will use. While the registration form that FDA
develops probably will require names and addresses, it is preferable to
make it required information.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **106.120 New infant formula      | **106.120 New infant formula      |
| submission.**                     | submission.**                     |
|                                   |                                   |
| 106.120(a) At least 90 days       | 106.120(a) At least 90 days       |
| before a new infant formula is    | before a new infant formula is    |
| introduced or delivered for       | introduced or delivered for       |
| introduction into interstate      | introduction into interstate      |
| commerce, a manufacturer shall    | commerce, a responsible party     |
| submit notice of its intent to do | shall submit notice of its intent |
| so to the Food and Drug           | to do so to the Food and Drug     |
| Administration at the address     | Administration at the address     |
| given in Sec. 106.110(a). An      | given in Sec. 106.110(a). An      |
| original and two copies of the    | original and two copies of the    |
| notice of its intent to do so     | notice of its intent to do so     |
| shall be submitted.               | shall be submitted.               |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.120(a) At least 90 days before a new infant formula is introduced or
delivered for introduction into interstate commerce, a ~~manufacturer~~
[responsible party]{.mark} shall submit notice of its intent to do so to
the Food and Drug Administration at the address given in Sec.
106.110(a). An original and two copies of the notice of its intent to do
so shall be submitted.

IFC Comment

For a new infant formula, duplicate notifications by manufacturer\'s and
co-packers would serve no useful purpose.

**Rest of page left intentionally blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.120(b) The new infant formula | Acceptable as proposed.           |
| submission shall include:         |                                   |
|                                   | Acceptable as proposed.           |
| 106.120(b)(1) The name and        |                                   |
| physical form (e.g., powder,      | Acceptable as proposed.           |
| ready‑to feed, or concentrate) of |                                   |
| the infant formula;               |                                   |
|                                   |                                   |
| 106.120(b)(2) An explanation of   |                                   |
| why the formula is a new infant   |                                   |
| formula;                          |                                   |
+-----------------------------------+-----------------------------------+
| 106.120(b)(3) The quantitative    | Acceptable as proposed subject to |
| formulation of each form of the   | the comment below.                |
| infant formula that is the        |                                   |
| subject of the notice in units    |                                   |
| per volume (for liquid formulas)  |                                   |
| or units per dry weight (for      |                                   |
| powdered formulas). When          |                                   |
| applicable, the submission shall  |                                   |
| include a description of any      |                                   |
| reformulation of the infant       |                                   |
| formula, including a listing of   |                                   |
| each new or changed ingredient    |                                   |
| and a discussion of the effect of |                                   |
| such changes on the nutrient      |                                   |
| levels in the formulation;        |                                   |
+-----------------------------------+-----------------------------------+

IFC Comment

The Agency proposes that quantitative formulations be submitted in
units/volume for liquids. Contrary to the preamble statement that infant
formula manufacturers have such a listing as part of the master
manufacturing order, formulations are routinely listed and have
traditionally been submitted to the Agency in units/weight. However,
although it will require the use of conversion factors, the formulations
can be submitted in units/volume if so desired.

The term \"quantitative formulation\" needs to be defined. Does it still
envision a table of nutrients as well as a table of ingredients? The IFC
recommends against changing to units/volume (for liquids) or units per
dry weight (for powders) for a nutrient table, since the per 100 kcal
format is already generated for label use and is easy to compare across
product forms. If the change to units/volume or units per dry weight is
finalized, FDA needs to clarify what volume or weight should be used as
the denominator (100 ml, liter, kilo?) and whether the information
should be provided \"as sold\" or \"as fed.\"

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.120(b)(4) A description, when   106.120(b)(4) A description, when
  applicable, of any change in        applicable, of any significant
  processing of the infant formula.   change in processing of the infant
  Such description shall identify the formula.
  specific change in processing,      
  including side-by-side, detailed    
  schematic diagrams comparing the    
  new processing to the previous      
  processing (including processing    
  times and temperatures);            
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.120(b)(4) A description, when applicable, of any change in
processing of the infant formula. ~~Such description shall identify the
specific change in processing, including side‑by‑side, detailed
schematic diagrams comparing the new processing to the previous
processing (including processing times and temperatures);~~

IFC Comment

To date, a narrative description of the change has been acceptable. A
general schematic is also provided showing the current process and the
revised process if appropriate, however, times and temperatures have not
been included. The schematic allows changes to be highlighted for a
complete review of the change to occur. Mandating side-by-side, detailed
schematic diagrams of current and new systems, including times,
temperatures, etc. would require substantial amounts of additional
administrative support to the current level needed to prepare
submissions. If the infant formula manufacturer were to meet this new
request for times and temperatures on the schematic, a new document
system would need to be designed to develop and track the flow diagrams.
This would require new computer programs and additional resources with
no added safety to the customer.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.120(b)(5) Assurance that the    Acceptable as proposed.
  infant formula will not be marketed 
  unless the formula meets the        
  quality factor requirements of      
  section 412(b)(1) of the Federal    
  Food, Drug, and Cosmetic Act (the   
  act) and the nutrient content       
  requirements of section 412(i) of   
  the act.                            

  106.120(b)(5)(i) Assurance that the Acceptable as proposed.
  formula meets the quality factor    
  requirements, which are set forth   
  in subpart E of this part, shall be 
  provided by a submission that       
  complies with Sec. 106.121.         

  106.120(b)(5)(ii) Assurance that    Acceptable as proposed.
  the formula complies with the       
  nutrient content requirements,      
  which are set forth in §107.100 of  
  this chapter, shall be provided by  
  a statement assuring that the       
  formula will not be marketed unless 
  it meets the nutrient requirements  
  of §107.100 of this chapter, as     
  demonstrated by testing required    
  under subpart C of this part;       
  ----------------------------------- -----------------------------------

+-----------------------------------+-----------------------------------+
| None.                             | 106.120(b)(6)(i) A responsible    |
|                                   | party that has not previously     |
|                                   | manufactured infant formula for   |
|                                   | sale in the U.S. market must      |
|                                   | support the premarket             |
|                                   | notification with a clinical      |
|                                   | study.                            |
|                                   |                                   |
|                                   | 106.120(b)(6)(ii) Clinical        |
|                                   | studies also may be necessary     |
|                                   | when a current manufacturer or    |
|                                   | responsible party predicts, based |
|                                   | on its experience or theory, that |
|                                   | a major change could have         |
|                                   | possible significant adverse      |
|                                   | impact on bioavailability of      |
|                                   | nutrients and when chemical       |
|                                   | testing or other scientific       |
|                                   | information are unavailable to    |
|                                   | rule out such an adverse impact.  |
|                                   |                                   |
|                                   | 106.120(b)(6)(iii) The            |
|                                   | manufacturer shall determine the  |
|                                   | scope, degree and complexity of   |
|                                   | any needed clinical testing, on a |
|                                   | case-by-case basis. The           |
|                                   | particular elements of the study  |
|                                   | shall take into account           |
|                                   | Guidelines issued by FDA          |
|                                   | regarding clinical study protocol |
|                                   | and design and endpoints needed   |
|                                   | to support potential claims.      |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

######### 

[106.120(b)(6)(i) A responsible party that has not previously
manufactured infant formula for sale in the U.S. market must support the
premarket notification with a clinical study.]{.mark}

[]{.mark}

[106.120(b)(6)(ii) Clinical studies also may be necessary when a current
manufacturer or responsible party predicts, based on its experience or
theory, that a major change could have possible significant adverse
impact on bioavailability of nutrients and when chemical testing or
other scientific information are unavailable to rule out such an adverse
impact.]{.mark}

[]{.mark}

######### [106.120(b)(6)(iii) The manufacturer shall determine the scope, degree and complexity of any needed clinical testing, on a case-by-case basis. The particular elements of the study shall take into account Guidelines issued by FDA regarding clinical study protocol and design and endpoints needed to support potential claims.]{.mark} 

######### IFC Comments

There are certain circumstances in which a premarket notification should
include a clinical study demonstrating the bioavailability of the infant
formula. Indeed, the industry and the agency collectively developed
guidelines in 1986 that defined "major changes" and established a
framework for ascertaining whether a clinical study would be advisable
for demonstrating the bioavailability of nutrients in a new or
reformulated infant formula. *FDA*, *Guidelines Concerning Notification
and Testing of Infant Formulas*, 1986. Congress recognized the wisdom of
these 1986 guidelines by incorporating them into the 1986 Amendments to
the Infant Formula Act. The Infant Formula Act provides that "for
purposes of this paragraph, the term 'major change' has the meaning
given to such term in section 106.30(c)(2) of title 21, Code of Federal
Regulations (as in effect on August 1, 1986), *and* *guidelines issued
thereunder."* FFDCA § 412(c)(2) (*emphasis added)*. The phrase
"*guidelines issued thereunder*" is a direct reference to the 1986
Guidelines. The incorporation of the 1986 Guidelines into the statutory
language restricts the agency's ability to deviate from the
well-established principles contained in those guidelines.

The 1986 Guidelines define "major change" and provide examples of the
changes in formulation and/or processing that would be viewed as a major
change. The 1986 Guidelines also establish the following recommendations
for clinical studies for new and reformulated infant formulas.

> FDA has recognized that premarket clinical evaluation in humans may be
> appropriate whenever certain changes affecting the nutritional profile
> of an infant formula are made, particularly in the case of new or
> reformulated products. FDA has also recognized that the degree and
> complexity of the clinical testing needed will vary according to the
> extent of the changes in the formula. Until guidelines are developed,
> it is therefore understood that the scope of the clinical testing
> necessary for new and reformulated infant formulas will be decided by
> the manufacturer on a case-by-case basis and that the chemical testing
> alone for major reformulation may not be sufficient to determine
> adequacy of the product.

The new proposed 106.120(b)(6) is modeled after the regulatory framework
established by the 1986 Guidelines and sanctioned by Congress through
the incorporation of these guidelines in the Infant Formula Act. The
rationale for placement of the proposed regulations regarding clinical
studies in section 106.120 for 90-day notifications stems directly from
the 1986 amendments to the Infant Formula Act. The Infant Formula Act
incorporates the 1986 Guidelines in section 412(c)(2), the section that
defines "new infant formulas" that would require the submission of a
premarket notification. Congress notably did not include this reference
to the 1986 Guidelines in the section of the Infant Formula Act that
addressed quality factors (FFDCA § 412(b)(1)) or the section regarding
the inclusion in infant formula premarket notifications of data
demonstrating that the infant formula meets the quality factor
requirements (FFDCA § 412(d)(1)(C)). The incorporation of the 1986
Guidelines in Section 412(b)(2) further supports the IFC position that
growth should not be defined as a quality factor that would be
demonstrated through clinical studies.

The proposed section 106.120(b)(6) includes clinical studies as part of
the data and information that would, when necessary, be included in a
premarket notification. This is accomplished, not by defining growth as
a quality factor and mandating clinical studies demonstrating
growth---as proposed by FDA---but by including a provision in section
106 identifying the instances in which clinical studies should be
included in a premarket notification. The new section 106.120(b)(6)
provisions proposed by industry codify the industry and agency practices
that have been in place for almost two decades and that have proven
effective in assuring the integrity of infant formulas.

The new section 106.120(b)(6)(i) would require a responsible party that
has not previously manufactured infant formula for sale in the U.S. to
include the results of a clinical study in the premarket notification.
This proposed provision reflects the well-established FDA practice of
requiring a new responsible party to conduct a clinical study
demonstrating that the company is capable of complying with the
stringent formulation and manufacturing requirements before entering the
U.S. infant formula market. Infant formulas are unique food products in
that the infant formula generally provides the only source of nutrition
for a young infant. The manufacturer must have practices and procedures
in place to make certain that the infant formula will provide all of the
nutrients needed for the growing infant in a biologically available form
and matrix. In addition, the vulnerability of the infant population to
disease and infection requires adherence to strict sanitation, quality
and other standards. By requiring a new responsible party to conduct a
clinical study before entering the market place, the agency can be
assured that the new responsible party will be capable of producing an
infant formula that supports growth. The new section 106.120(b)(6)(i)
reflects this well-established practice by mandating a clinical study
for a new responsible party that has not previously manufactured infant
formula in the United States.

The new proposed section 106.120(b)(6)(ii) recognizes that clinical
studies may be necessary to support a premarket notification for a
"major change" submitted by a manufacturer or responsible party that is
currently marketing an infant formula in the United States. A clinical
study would be conducted when the manufacturer's experience or theory
would predict a possible significant adverse impact on the
bioavailability of nutrients in the new or reformulated infant formula
and when chemical testing or other scientific information are
unavailable to rule out the possibility of such an adverse impact. This
standard is similar, although not identical, to the definition of "major
change" found in the 1986 Guidelines. Industry experience has
demonstrated that a clinical study is not needed to support every "major
change" in formulation and/or processing. The industry experience has
shown, however, that some "major changes" are of a sufficient magnitude
or nature to require evaluation in a clinical study to make certain that
the change will not have a significant adverse impact on the
bioavailability of nutrients in the infant formula.

The final provision of the new proposed regulation, section
106.120(b)(6)(iii), would clarify that it is up to the manufacturer to
determine the scope, degree, and complexity of the clinical study on a
case-by-case basis. This provision incorporates the standard established
by the 1986 Guidelines and recognizes that the manufacturer is in the
best position to assess the likely impact on nutrient bioavailability of
the proposed "major change" to the infant formula and the type of study
that will be needed to support such a change. The proposed regulatory
provision also would recognize that the manufacturer should conduct any
such clinical study in accordance with clinical study, protocol and
design guidelines that would be issued by the agency.

In conclusion, the new proposed sections 106.120(b)(6)(i), (ii), and
(iii), would codify into the regulations the practices and procedures
that have been in-place since 1986. These practices and procedures are
based on the language found in the 1986 Guidelines, which have been
incorporated by reference into the Infant Formula Act. Importantly, the
standard created by the 1986 Guidelines and which IFC proposes to codify
in the final regulations, provides the flexibility that is needed for
ascertaining when a clinical study should be conducted. There have been
numerous innovations to infant formulas since 1986. The industry has
proven that it can responsibly evaluate proposed major changes to
formulations and determine whether the change requires a clinical study
to assess the impact of the change on the bioavailability of the
nutrients in the infant formula.

  ----------------------------------- -----------------------------------
  106.120(b)(6) Assurance that the    Acceptable; Renumbered as
  processing of the infant formula    106.120(b)(7).
  complies with section 412(b)(2) of  
  the act. Such assurance shall       
  include but not be limited to:      

  106.120(b)(6)(i) A statement that   Acceptable; Renumbered as
  the formula will be produced in     106.120(b)(7)(i).
  accordance with subparts B and C of 
  this part;                          

  106.120(b)(6)(ii) The basis on      Delete.
  which each ingredient meets the     
  requirements of Sec. 106.40(a),     
  e.g., that it is an approved food   
  additive, that it is authorized by  
  a prior sanction issued by the      
  agency, or that it is GRAS for its  
  intended use. Any claim that an     
  ingredient is GRAS shall be         
  supported by a citation to the      
  agency\'s regulations or by an      
  explanation, including a list of    
  published studies and a copy of     
  those publications, for why, based  
  on the published studies, there is  
  general recognition of the safety   
  of the use of the ingredient in     
  infant formula.                     
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.120(b)(~~6~~[7]{.mark}) Assurance that the processing of the infant
formula complies with section 412(b)(2) of the act. Such assurance shall
include but not be limited to:

106.120(b)(~~6~~[7]{.mark})(i) A statement that the formula will be
produced in accordance with subparts B and C of this part;

~~106.120(b)(6)(ii) The basis on which each ingredient meets the
requirements of 106.40(a), e.g., that it is an approved food additive,
that it is authorized by a prior sanction issued by the agency, or that
it is GRAS for its intended use. Any claim that an ingredient is GRAS
shall be supported by a citation to the agency\'s regulations or by an
explanation, including a list of published studies and a copy of those
publications, for why, based on the published studies, there is general
recognition of the safety of the use of the ingredient in infant
formula.~~

IFC Comment

The IFC believes that this section should be deleted. See the IFC
Comment to 106.40(a) and it's General Comments regarding Premarket
Notification and Redundancy. The Agency\'s proposal constitutes
premarket approval of the ingredients used in infant formulas, i.e.,
such ingredients must be demonstrated safe to the Agency's satisfaction
that an ingredient is GRAS for its intended use. The IFC respectfully
but strongly disagrees with FDA\'s legal interpretation. In promulgating
the Infant Formula Act, Congress clearly intended that the law be used
to ensure that the manufacturer produce formulas that meet the Infant
Formula Act nutrient composition requirements and that are not
contaminated with substances or organisms that might adulterate the
product. Congress did not intend to give FDA premarket approval
authority over infant formula. Nor did it need or intend to give FDA
additional premarket approval authority, beyond that already given FDA
under Sections 402 and 409 of the FFDCA, over food ingredients employed
in formula.

21 CFR 170.30 describes requirements for independent GRAS
determinations, as well as the requirements under which FDA will affirm,
in response to voluntary applications, that an ingredient is GRAS;
however, 21 CFR 170.30 in no way mandates that the information the
manufacturer is relying upon be submitted to the Agency or formally
acknowledged or listed as GRAS. Of course, in many or most cases
manufacturers will, in the interest of reducing regulatory
uncertainties, find it in their own self-interest to submit such
information; however, such submissions should remain voluntary, as they
always have been. It should remain proper for the manufacturer to go to
market without submitting this information, just as it remains the
manufacturer\'s responsibility to ensure the safety and suitability of
its individual infant formula products.

Finally, if FDA retains this language in modified form to remove the
premarket approval objection, the word \"newly added\" should be
inserted before \"ingredient\" to make it clear that the information
provided to FDA need not relate to all ingredients in the infant
formula.

IFC would like to remind the Agency that it is of critical importance to
keep the purpose of the Infant Formula Act in perspective. The Infant
Formula Act really was an effort, arising directly out of troublesome
nutrient delivery failures, to ensure the nutritional quality of infant
formula. It is in this specific context that the fundamental affirmative
requirements of the Infant Formula Act take on meaning. For example, the
quality factor, GMP, record retention, testing, in-process controls
among just a few of the IFA's requirements *all* reasonably relate to
ensuring the *nutritional quality* of infant formula. The Infant Formula
Act in this context is, thus, an "overlay" on FDA's already substantial
authority provided by the FFDCA to ensure the safety and proper labeling
of food. It is that underlying Act that continues to provide the
critical tools for ensuring the safety of infant formula.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.120(c) For products for export  106.120(c) For products for export
  only, a manufacturer may submit, in only and in compliance with Section
  lieu of the information required    801(e) of the Act, the information
  under paragraph (b) of this         under paragraph (b) of this section
  section, a statement that the       is not required and need not be
  infant formula meets the            submitted.
  specifications of the foreign       
  purchaser, does not conflict with   
  the laws of the country to which it 
  is intended for export, is labeled  
  on the outside of the shipping      
  package to indicate that it is      
  intended for export only, and will  
  not be sold or offered for sale in  
  domestic commerce.                  
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.120(c) For products for export only [and in compliance with Section
801(e) of the Act, the information under paragraph (b) of this section
is not required and need not be submitted]{.mark}~~, a manufacturer may
submit, in lieu of the information required under paragraph (b) of this
section, a statement that the infant formula meets the specifications of
the foreign purchaser, does not conflict with the laws of the country to
which it is intended for export, is labeled on the outside of the
shipping package to indicate that it is intended for export only, and
will not be sold or offered for sale in domestic commerce~~.

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer and
Infant Formulas Intended For Export.

IFC believes this provision is adequately covered under the FDA Export
Reform Enhancement Act (Public Law 104-134, as amended Public Law
104-180) and the resultant regulations 21 CFR Part 1 entitled "Exports:
Notification and Recordkeeping Requirements."

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.120(d) The submission will not  106.120(d) The submission will not
  constitute notice under section 412 constitute notice under section 412
  of the act unless it complies fully of the act unless it complies fully
  with paragraph (b) of this section, with paragraph (b) of this section,
  and the information that it         and the information that it
  contains is set forth in a manner   contains is set forth in a manner
  that is readily understandable. The that is readily understandable. The
  agency will notify the submitter if agency will notify the submitter
  the notice is not adequate because  within 10 working days if the
  it does not meet the requirements   notice is not complete because it
  of section 412(c) and (d) of the    does not meet the requirements of
  act.                                section 412(c) and (d) of the act.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.120(d) The submission will not constitute notice under section 412
of the act unless it complies fully with paragraph (b) of this section,
and the information that it contains is set forth in a manner that is
readily understandable. The agency will notify the submitter [within 10
working days]{.mark} if the notice is not ~~adequate~~ [complete]{.mark}
because it does not meet the requirements of section 412(c) and (d) of
the act.

######### IFC Comment

Manufacturers who make a new infant formula submission under 106.120
need certainty for planning purposes. If FDA\'s notice of inadequacy is
received well into what has been planned to be a 90-day review period,
the planning process will be seriously disrupted. Accordingly, a
submission should get immediate review for completeness.

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.120(e) If a new infant formula  106.120(e) If a new infant formula
  submission is adequate, FDA will    submission is complete and includes
  acknowledge its receipt and notify  all requirements of 106.120(b), FDA
  the manufacturer of the date of     will acknowledge its receipt and
  receipt. The date that the agency   notify the submitter of the date of
  receives the new infant formula     the receipt. The date that the
  submission is the filing date for   agency receives the new infant
  the submission. The manufacturer    formula submission is the filing
  shall not market the new infant     date for the submission. The
  formula before the date that is 90  manufacturer shall not market the
  days after the filing date.         new infant formula before the date
                                      that is 90 days after the filing
                                      date.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.120(e) If a new infant formula submission is ~~adequate~~ [complete
and includes all requirements of 106.120(b)]{.mark}, FDA will
acknowledge its receipt and notify the ~~manufacturer~~
[submitter]{.mark} of the date of [the]{.mark} receipt. The date that
the agency receives the new infant formula submission is the filing date
for the submission. The manufacturer shall not market the new infant
formula before the date that is 90 days after the filing date.

IFC Comment

See the IFC General Comment regarding Premarket Notification. The IFC is
concerned that the Agency might wish to delay the starting date for the
90-day period when the notification is complete, but there are questions
or disagreement with the content. The act requires that manufacturers
give a 90-day advance notice to the Agency prior to marketing a new
infant formula. Unlike drugs, there are no explicit pre-market approval
requirements for infant formula. While the IFC agrees that the
notification must be complete and understandable, and the product must
satisfy the nutritional requirements for the intended use, the marketing
of an infant formula should not be held up while the Agency takes issue
with some minor elements of the notification.

The IFC believes that the 90-day clock must begin when the Agency
receives a notification that supplies information for all paragraphs
listed in 106.120. Running of the 90 day clock should be based on
completeness, and not on the Agency\'s immediate judgment of agreement
with the contents. If there are questions or concerns regarding the
content of the notification, these should be worked out between the
Agency and the manufacturer after the 90-day clock has started.

Rest of page intentionally left blank

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.120(f) If the manufacturer      106.120(f) If the submitter
  provides additional information in  provides additional information in
  support of a new infant formula     support of a new infant formula
  submission, the agency will         submission, the agency will
  determine whether the additional    determine whether the additional
  information is a substantive        information is a substantive
  amendment to the new infant formula amendment to the new infant formula
  submission. If the agency           submission. If the agency
  determines that the new submission  determines that the new submission
  is a substantive amendment, FDA     is a substantive amendment, FDA
  will assign the new infant formula  will assign the new infant formula
  submission a new filing date. FDA   submission a new filing date. FDA
  will acknowledge receipt of the     will acknowledge receipt of the
  additional information and, when    additional information within five
  applicable, notify the manufacturer working days and, when applicable,
  of the new filing date, which is    notify the submitter of the new
  the date of receipt by FDA of the   filing date, which is the date of
  information that constitutes the    receipt by FDA of the information
  substantive amendment to the new    that constitutes the substantive
  infant formula submission.          amendment to the new infant formula
                                      submission.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.120(f) If the ~~manufacturer~~ [submitter]{.mark} provides
additional information in support of a new infant formula submission,
the agency will determine whether the additional information is a
substantive amendment to the new infant formula submission. If the
agency determines that the new submission is a substantive amendment,
FDA will assign the new infant formula submission a new filing date. FDA
will acknowledge receipt of the additional information [within five
working days]{.mark} and, when applicable, notify the ~~manufacturer~~
[submitter]{.mark} of the new filing date, which is the date of receipt
by FDA of the information that constitutes the substantive amendment to
the new infant formula submission.

IFC Comment

The IFC suggestion to refer to a \"submitter\" will cover both
manufacturers and responsible parties. The five-day provision reflects
the IFC\'s belief that the Agency must be bound by some reasonable time
requirements, so that manufacturers can plan appropriately.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **106.121 Quality factor          | **106.121 Quality factor          |
| submission.**                     | submission.**                     |
|                                   |                                   |
| To provide assurance that an      | To provide assurance that a new   |
| infant formula meets the quality  | infant formula meets the quality  |
| factor requirements set forth in  | factor requirements set forth in  |
| subpart E of this part, the       | subpart E of this part, the       |
| manufacturer shall submit the     | responsible party shall submit    |
| following data and information:   | the following data and            |
|                                   | information:                      |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

To provide assurance that ~~an~~ [a new]{.mark} infant formula meets the
quality factor requirements set forth in subpart E of this part, the
~~manufacturer~~ [responsible party]{.mark} shall submit the following
data and information:

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer. For
this type of submission any duplication of the responsible party\'s
efforts by co-packers would serve no useful purpose. The IFC has also
suggested adding the word \"new\" to clarify that these two requirements
apply only to new infant formulas as defined in these regulations.

U.S. Infant Formula Manufacturers developed the attached "Decision Tree
for Documentation of Nutritional Adequacy of a New or Changed Infant
Formula" (Attachment K) and "Decision Tree Chart for Documentation of
Nutritional Adequacy of a New or Changed Infant Formula" (Attachment L)
in 2002. These documents discuss various changes to infant formula and
the documentation required for such changes to support nutritional
adequacy.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.121(a) An explanation, in       Acceptable as proposed.
  narrative form, setting forth how   
  all quality factor requirements of  
  subpart E of this part have been    
  met.                                

  106.121(b) Records that contain the Delete.
  information required by proposed    
  Sec. 106.97(a)(1)(i) and (a)(1)(ii) 
  collected during the study for each 
  infant enrolled in the study. The   
  records shall be identified by      
  subject number, age, feeding group, 
  gender, and study day of            
  collection.                         
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.121(b) Records that contain the information required by proposed
Sec. 106.97(a)(1)(i) and (a)(1)(ii) collected during the study for each
infant enrolled in the study. The records shall be identified by subject
number, age, feeding group, gender, and study day of collection.~~

######### IFC Comment

Regarding IFC's recommended deletion of these proposed regulations, see
General Comments on Assessment of Normal Growth. IFC offers comments on
all the following proposed regulations falling under section 106.121(a)
with the caveat that clinical growth studies only should be included in
a premarket notification consistent with the new section 106.120(b)(6)
proposed by IFC. The specifics as to the nature and scope of such a
study, as well as the presentation of resulting data, should be
incorporated into agency Guidance rather than a regulation.

See the IFC\'s comments to 106.97(a)(1). The IFC has no objection to
submitting individual growth data whenever a growth study has been
determined to be the most appropriate demonstration of bioavailable and
sufficient nutrition. However, IFC would like to take this opportunity
to point out some potential pitfalls in interpreting those data.

It is fairly straightforward to carry out statistical analysis of growth
variables for each formula feeding group. However, it is more difficult,
and at times impossible, to draw valid conclusions about an individual
or a small subgroup of individuals within a formula feeding group.
Growth data are expected to be normally distributed; consequently, there
will always be a few infants who will be at the lower or upper end of a
particular growth parameter. By presenting growth data on individuals,
unwarranted attention may be brought to these infants at the extremes of
the data distribution. There may be undue concern that every infant did
not demonstrate *average* growth patterns. There may also be undue
concern that the characteristics of these individuals are representative
of a significant subgroup of the sample.

For these reasons, it would ensure a better focus on the key analysis of
a clinical study if the manufacturer were able to present growth data to
FDA simply as group statistics and not as growth data for individual
study infants. IFC realizes, however, that group statistics alone will
not, as a rule, provide enough detail to satisfy the Agency that no
adverse consequences may be attributable to use of the new formula.
Consequently, we ask that the preamble of the final rule make clear that
it is the group statistics that provide the primary basis for the
manufacturer\'s finding that expected physical growth has been attained,
and that the growth data for individual study infants will be reviewed
by the Agency only as supportive data to demonstrate that there was no
significant subgroup within the sample for which the formula had adverse
effects.

The IFC also suggests that the preamble acknowledge that the \"records\"
contemplated by 106.121(b) need not be the investigator\'s original
records, but may instead be records that contain the necessary
information drawn from the investigators\' original records.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.121(c)(1) Statistical           Delete.
  evaluation for all measurements,    
  including: Group means, group       
  standard deviations, and measures   
  of statistical significance for all 
  measurements for each feeding group 
  at the beginning of the study and   
  at every point where measurements   
  were made throughout the study.     

  106.121(c)(2) Calculation of the    Delete.
  statistical power of the study at   
  its completion.                     
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.121(c)(1) Statistical evaluation for all measurements, including:
Group means, group standard deviations, and measures of statistical
significance for all measurements for each feeding group at the
beginning of the study and at every point where measurements were made
throughout the study.~~

~~106.121(c)(2) Calculation of the statistical power of the study at its
completion.~~

IFC Comment

As would be codified under 106.97(a)(1)(ii)(E) of the proposed
regulations, the need for a power calculation arises *before* a study is
initiated, in order to determine the number of study subjects required
to answer a clinical question. Because subject dropout may be predicted
for most clinical studies, various strategies are employed to achieve
the desired number of subjects at study conclusion such as over
enrollment or replacement of dropouts. In some situations fewer subjects
are available for clinical study or complete a clinical study than
originally anticipated. It is reasonable to expect from a study report
that: a) there was an *a priori* calculation of the power of the study,
b) the number of subjects to be recruited met the needs of the power
calculation, and c) whether the number of subjects who actually
completed the study corresponded to this need.

It is necessary and of unproven value to require a calculation of the
power of a study at its completion. This is clearly a *post-hoc*
analysis. It is also a confounding and burdensome calculation to make,
as there may be several parameters with multiple time points with
differing numbers of subjects for each variable and time point. The IFC
recommends, accordingly, that FDA not require such a calculation in the
context of submission to FDA of clinical study results, since there is
no general scientific consensus that this practice is necessary or
appropriate.

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.121(d) A report on attrition    Delete.
  and on all occurrences of adverse   
  events during the study, which      
  shall include:                      

  106.121(d)(1) Identification of the Delete.
  infant by subject number and        
  feeding group and a complete        
  description of the adverse event,   
  including comparisons of the        
  frequency and nature of occurrence  
  in each feeding group and           
  information on the health of the    
  infant during the course of the     
  study, including the occurrence and 
  duration of any illness;            

  106.121(d)(2) A clinical            Delete.
  assessment, by a health care        
  provider, of the infant\'s health   
  during each suspected adverse       
  event;                              

  106.121(d)(3) A complete listing of Delete.
  all infants who did not complete    
  the study, including the infant\'s  
  subject number and the reason that  
  each infant left the study.         

  106.121(e) The results of the       Delete.
  Protein Efficiency Ratio, in        
  accordance with Sec. 106.97(b).     
  ----------------------------------- -----------------------------------

IFC Redlined Version

~~106.121(d) A report on attrition and on all occurrences of adverse
events during the study, which shall include:~~

~~106.121(d)(1) Identification of the infant by subject number and
feeding group and a complete description of the adverse event, including
comparisons of the frequency and nature of occurrence in each feeding
group and information on the health of the infant during the course of
the study, including the occurrence and duration of any illness;~~

~~106.121(d)(2) A clinical assessment, by a health care provider, of the
infant\'s health during each suspected adverse event;~~

~~106.121(d)(3) A complete listing of all infants who did not complete
the study, including the infant\'s subject number and the reason that
each infant left the study.~~

~~106.121(e) The results of the Protein Efficiency Ratio, in accordance
with Sec. 106.97(b).~~

IFC Comment

The language in section 106.121(d) and its subsections is acceptable,
with the caveat that clinical growth studies only should be included in
a premarket notification consistent with the new section 106.120(b)(6)
proposed by IFC. For the reasons discussed previously, any specifics as
to the nature and scope of such a study, as well as the presentation of
resulting data, should be incorporated into agency Guidance rather than
a regulation.

The effect of the proposed 106.121(d) would be to mandate the submission
of test results for biological quality of the protein 90 days before the
new infant formula is to be marketed. (See proposed 106.121(e)). The IFC
agrees with the requirement for PER or other testing to demonstrate
protein quality and the circumstances in which it is required. However,
the IFC disagrees with the time that the results of this testing are
due.

Under current regulations, protein results need not be submitted at the
time of the 90-day submission, but can be submitted along with the
verification submission that is filed subsequent to the 90-day
submission. (See 106.30(c)(2)). This timing is particularly significant
when new equipment triggers the 90-day premarket requirement. As stated
above, under current regulations, protein testing can be deferred and
can be performed on product that has been produced on the newly
installed equipment. The proposed regulation would instead require
protein test results to be submitted at the time of the 90-day premarket
submission without apparent exception.

Where PER testing is used, requiring protein testing to be submitted
with the 90 day premarket submission effectively accelerates the needed
start of testing by 5 months (three months premarket and two months of
test time). This will force the manufacturer either to delay the
start-up with the new equipment by 5 months or choose to determine and
convince FDA that the research production system is \"close enough\" to
the full scale system to be representative of product produced on the
full scale production equipment.

The timing of submittal of the protein testing results created by the
proposal could delay improvements and add significant additional costs
to infant formula. This will be detrimental to the public and not add
value to infant formula. Therefore, it would be in the best interest of
consumers to allow the results of protein-quality testing to be included
with the verification test results as they are currently without known
adverse events.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.121(f) A statement certifying   106.121(b) A statement of assurance
  that the manufacturer has collected that the manufacturer or
  and considered all information and  responsible party has collected and
  data concerning the ability of the  considered all information and data
  infant formula to meet the quality  concerning the ability of the
  factor requirements, and that the   infant formula to meet the quality
  manufacturer is not aware of any    factor requirements, and that the
  information or data that would show manufacturer or responsible party
  that the formula does not meet the  is not aware of any information or
  quality factors requirements.       data that would show that the
                                      formula does not meet the quality
                                      factors requirements.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.121(~~f~~[b]{.mark}) A statement ~~certifying~~ [of
assurance]{.mark} that the manufacturer [or responsible party]{.mark}
has collected and considered all information and data concerning the
ability of the infant formula to meet the quality factor requirements,
and that the manufacturer [or responsible party]{.mark} is not aware of
any information or data that would show that the formula does not meet
the quality factors requirements.

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer. The
suggested use of \"assurance\" is based on the provisions of the Infant
Formula Act relating to verifications that refer specifically to
\"assurances,\" as opposed to certifications. (See, e.g.,
412(d)(1)(C)&(D).

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **106.130 Verification            | **106.130 Verification            |
| submission.**                     | submission.**                     |
|                                   |                                   |
| 106.130(a) Manufacturers shall,   | 106.130(a) Unless subject to      |
| after the first production and    | 106.120(c) \[proposed by IFC to   |
| before the introduction into      | be moved and become 106.140(d)\], |
| interstate commerce of the new    | manufacturers or responsible      |
| infant formula, verify in a       | parties shall, after the first    |
| written submission to FDA at the  | production and before the         |
| address given in Sec. 106.110(a), | introduction into interstate      |
| that the infant formula complies  | commerce of the new infant        |
| with the requirements of the      | formula, verify in a written      |
| Federal Food, Drug, and Cosmetic  | submission to FDA at the address  |
| Act (the act) and is not          | given in Sec. 106.110(A), that    |
| adulterated. An original and two  | the infant formula complies with  |
| copies of this verification shall | the requirements of the act and   |
| be submitted.                     | is not adulterated. An original   |
|                                   | and two copies of this            |
|                                   | verification shall be submitted.  |
+-----------------------------------+-----------------------------------+

# IFC Redlined Version

106.130(a) [Unless subject to 106.120(c) \[proposed by IFC to be moved
and become 106.140(d)\],]{.mark} ~~M~~manufacturers [or responsible
parties]{.mark} shall, after the first production and before the
introduction into interstate commerce of the new infant formula, verify
in a written submission to FDA at the address given in Sec. 106.110(a),
that the infant formula complies with the requirements of the ~~Federal
Food, Drug, and Cosmetic Act (the~~ act~~)~~ and is not adulterated. An
original and two copies of this verification shall be submitted.

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer. For
this type of submission, any duplication of the responsible party\'s
efforts by co-packers would serve no useful purpose.

See the IFC\'s General Comment concerning Infant Formulas Intended For
Export. The proposed language does not exempt infant formulas intended
for export. Because such formulas are exempt from GMPs and other
requirements of the act, such a submission will serve no purpose.
Therefore, infant formula intended for export only should clearly be
exempt from this section.

**Rest of page left intentionally blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.130(b) The verification       | Acceptable as proposed.           |
| submission shall include the      |                                   |
| following information:            | 106.130(b)(1) The name of the new |
|                                   | infant formula; the filing date   |
| 106.130(b)(1) The name of the new | for the new infant formula        |
| infant formula; the filing date   | submission, in accordance with    |
| for the new infant formula        | Sec. 106.120, for the subject     |
| submission, in accordance with    | formula; and the identification   |
| Sec. 106.120, for the subject     | number assigned by the agency, if |
| formula; and the identification   | available, to the new infant      |
| number assigned by the agency to  | formula submission;               |
| the new infant formula            |                                   |
| submission;                       |                                   |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.130(b)(1) The name of the new infant formula; the filing date for
the new infant formula submission, in accordance with Sec. 106.120, for
the subject formula; and the identification number assigned by the
agency[, if available,]{.mark} to the new infant formula submission;

IFC Comment

This number may not in all cases have been assigned or be available, so
providing the qualifier acknowledges this possibility.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.130(b)(2) A statement that the  106.130(b)(2) A statement that the
  infant formula to be introduced     infant formula to be introduced
  into interstate commerce is the     into interstate commerce is the
  same as the infant formula that was same as the infant formula that was
  the subject of the new infant       the subject of the new infant
  formula notification and for which  formula notification and for which
  the manufacturer provided           the manufacturer or responsible
  assurances in accordance with the   party provided assurances in
  requirements of Sec. 106.120;       accordance with the requirements of
                                      Sec. 106.120;
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.130(b)(2) A statement that the infant formula to be introduced into
interstate commerce is the same as the infant formula that was the
subject of the new infant formula notification and for which the
manufacturer [or responsible party]{.mark} provided assurances in
accordance with the requirements of Sec. 106.120;

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.130(b)(3) A summary of test     Acceptable as proposed.
  results of the level of each        
  nutrient required by §107.100 of    
  this chapter and any nutrient added 
  by the manufacturer in the formula, 
  presented in units per 100          
  kilocalories at the                 
  final‑product‑stage.                

  None.                               106.130(b)(4) If testing for
                                      protein biological quality is
                                      needed, an assurance that the PER
                                      or other test has commenced, and
                                      that the results will be forwarded
                                      to FDA within 10 working days of
                                      their receipt by the manufacturer
                                      or responsible party as a
                                      supplement to the verification
                                      submission.

  106.130(b)(4) A certification that  106.130(b)(5) An assurance by the
  the manufacturer has established    responsible party that all
  current good manufacturing          manufacturers have established
  practices including quality control current good manufacturing
  procedures and in-process controls, practices including quality control
  including testing required by       procedures and in-process controls,
  current good manufacturing          including testing required by
  practice, designed to prevent       current good manufacturing
  adulteration of this formula in     practice, designed to prevent
  accordance with subparts B and C of adulteration of this formula in
  this part.                          accordance with subparts B and C of
                                      this part.
  ----------------------------------- -----------------------------------

IFC Redlined Version

[106.130(b)(4) If testing for protein biological quality is needed, an
assurance that the PER or other test has commenced, and that the results
will be forwarded to FDA within 10 working days of their receipt by the
manufacturer or responsible party as a supplement to the verification
submission.]{.mark}

106.130(b)(~~4~~5) ~~A certification that the manufacturer has~~ [An
assurance by the responsible party that all manufacturers have]{.mark}
established current good manufacturing practices including quality
control procedures and in‑process controls, including testing required
by current good manufacturing practice, designed to prevent adulteration
of this formula in accordance with subparts B and C of this part.

IFC Comment

In reference to section 106.30(b)(3), all nutrients are tested at the
finished product stage of major change batches. A notification
indicating the batch complies is sent to the FDA. If the proposed change
is accepted, additional information will need to be prepared to send to
the FDA.

See the IFC Comment to proposed 106.121(e) for the basis for the
suggested new language regarding protein quality, its comment to 121(f)
for use of the term \"assurance.\"

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.130(c) The submission will not  106.130(c) The submission will not
  constitute written verification     constitute written verification
  under section 412(d)(2) of the act  under section 412(d)(2) of the act
  when any data prescribed in         when any data prescribed in
  paragraph (b) of this section are   paragraph (b) of this section are
  lacking or are not set forth so as  lacking or are not set forth so as
  to be readily understood. In such   to be readily understood. In such
  circumstances the agency will       circumstances the agency will
  notify the submitter that the       notify the submitter within five
  notice is not adequate.             working days that the notice is not
                                      complete.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.130(c) The submission will not constitute written verification under
section 412(d)(2) of the act when any data prescribed in paragraph (b)
of this section are lacking or are not set forth so as to be readily
understood. In such circumstances the agency will notify the submitter
[within five working days]{.mark} that the notice is not ~~adequate~~
[complete]{.mark}.

IFC Comment

FDA should be required to notify manufacturers within five working days
when their verifications are unacceptable. Otherwise, manufacturers will
not be able to market their product with assurance that FDA found the
submission acceptable. The IFC also recommends that the FDA develop a
form for verifications that will help in FDA\'s review of the
sufficiency of the verification.

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **106.140 Submission concerning a | **106.140 Submissions for Minor   |
| change in infant formula that may | Changes in the Infant Formula.**  |
| adulterate the product.**         |                                   |
|                                   | 106.140(a) When a manufacturer    |
| 106.140(a) When a manufacturer    | makes a change in the formulation |
| makes a change in the formulation | or processing of the formula that |
| or processing of the formula that | is determined to be a notifiable  |
| may affect whether the formula is | minor change because the          |
| adulterated under section 412(a)  | manufacturer or responsible party |
| of the Federal Food, Drug, and    | determines it may affect whether  |
| Cosmetic Act (the act), it shall, | the formula is adulterated under  |
| before the first processing of    | section 412(a) of the act, it     |
| such formula, make a submission   | shall, before the first           |
| to the Food and Drug              | processing of such formula, make  |
| Administration at the address     | a submission to the Food and Drug |
| given in Sec. 106.110(a). An      | Administration at the address     |
| original and two copies shall be  | given in Sec. 106.110(a). An      |
| submitted.                        | original and two copies shall be  |
|                                   | submitted.                        |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

**106.140 Submission[s for Minor Changes in the Infant Formula]{.mark}
~~concerning a change in infant formula that may adulterate the
product~~.**

106.140(a) When a manufacturer makes a change in the formulation or
processing of the formula that [is determined to be a notifiable minor
change because the manufacturer or responsible party determines
it]{.mark} may affect whether the formula is adulterated under section
412(a) of the ~~Federal Food, Drug, and Cosmetic Act (the act)~~
[act]{.mark}, it shall, before the first processing of such formula,
make a submission to the Food and Drug Administration at the address
given in Sec. 106.110(a). An original and two copies shall be submitted.

######### IFC Comment

The IFC believes that the suggested wording will help clarify what
conduct constitutes a "major change," and what constitutes a "minor
change."

IFC also requests FDA to clarify that minor changes made to infant
formulas intended solely for export are not subject to the notification
requirements of this provision.

Additionally, FDA's April announcement of the reopening of the comment
period requested comments on the specific changes in current activities
that would be required for companies to comply with proposal. Infant
formula manufacturers currently evaluate all changes to formulation or
processing of an infant formula. In that assessment they determine if
the change will affect the nutrient content of the formulation and if
so, notify the FDA. In the preamble of the proposed GMP's, FDA has
provided examples of changes they would consider notifiable changes
requiring testing at the required intervals. If the manufacturer is now
required to notify all of these types of changes, this will increase the
amount of submissions drastically, and additional personnel will be
needed. (See also 106.3(i)(5))

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.140(b) The submission shall   | Acceptable as proposed.           |
| include:                          |                                   |
|                                   | Acceptable as proposed.           |
| 106.140(b)(1) The name and        |                                   |
| physical form of the infant       |                                   |
| formula (i.e., powder,            |                                   |
| ready‑to‑feed, or concentrate);   |                                   |
+-----------------------------------+-----------------------------------+
| 106.140(b)(2) An explanation of   | 106.140(b)(2) An explanation of   |
| why the change in formulation or  | why the change may affect whether |
| processing may affect whether the | the formula is adulterated and    |
| formula is adulterated;           | assurance that the formula will   |
|                                   | not be introduced into interstate |
|                                   | commerce unless it is not         |
|                                   | adulterated;                      |
+-----------------------------------+-----------------------------------+

#########  IFC Redlined Version

106.140(b)(2) An explanation of why the change ~~in formulation or
processing~~ may affect whether the formula is adulterated [and
assurance that the formula will not be introduced into interstate
commerce unless it is not adulterated]{.mark};

IFC Comment

The addition of the information requested in (ii) will enable FDA to
receive a more complete explanation of the change.

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.140(b)(3) A submission that     Acceptable as proposed.
  complies with §106.120(b)(3),       
  (b)(4), (b)(5), and (b)(6). When    
  appropriate, a statement to the     
  effect that the information         
  required by §106.120(b)(3), (b)(4), 
  (b)(5), or (b)(6) has been provided 
  to the agency previously and has    
  not been affected by the changes    
  that is the subject of this         
  submission, together with the       
  identification number assigned by   
  the agency to the relevant infant   
  formula submission, may be provided 
  in lieu of such submission.         

  106.140(c) The submission will not  106.140(c) The submission will not
  constitute notice under section 412 constitute notice under section 412
  of the act unless it complies fully of the act unless it complies fully
  with paragraph (b) of this section, with paragraph (b) of this section,
  and the information that it         and the information that it
  contains is set forth in a manner   contains is set forth in a manner
  that is readily understandable. The that is readily understandable. The
  agency will notify the submitter if agency will promptly acknowledge
  the notice is not adequate because  receipt and notify the submitter if
  it does not meet the requirements   the notice is not adequate because
  of section 412(d)(3) of the act.    it does not meet the requirements
                                      of section 412(d)(3) of the act.

  None.                               106.140(d) The requirements of
                                      106.140 do not apply to products
                                      legally exported under §801(e) of
                                      the act.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.140(c) The submission will not constitute notice under section 412
of the act unless it complies fully with paragraph (b) of this section,
and the information that it contains is set forth in a manner that is
readily understandable. The agency will [promptly acknowledge receipt
and]{.mark} notify the submitter if the notice is not adequate because
it does not meet the requirements of section 412(d)(3) of the act.

[106.140(d) The requirements of 106.140 do not apply to products legally
exported under §801(e) of the act.]{.mark}

IFC Comment

FDA should be required to notify manufacturers within one week, or
within some other reasonable period of time, of whether their
verifications are acceptable. Otherwise, manufacturers will not be able
to market their product with assurance that FDA found the submission
acceptable.

**Rest of page intentionally left blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **106.150 Notification of an      | **106.150 Notification of an      |
| adulterated or misbranded infant  | adulterated or misbranded infant  |
| formula.**                        | formula.**                        |
|                                   |                                   |
| 106.150(a) A manufacturer shall   | 106.150(a) A manufacturer or      |
| promptly notify FDA in accordance | responsible party shall promptly  |
| with paragraph (b) of this        | notify FDA in accordance with     |
| section, when the manufacturer    | paragraph (b) of this section,    |
| has knowledge (that is, the       | when the manufacturer or          |
| actual knowledge that the         | responsible party has knowledge   |
| manufacturer had, or the          | (that is, the actual knowledge    |
| knowledge which a reasonable      | that the manufacturer or          |
| person would have had under like  | responsible party had, or the     |
| circumstances or which would have | knowledge which a reasonable      |
| been obtained upon the exercise   | person would have had under like  |
| of due care) that reasonably      | circumstances or which would have |
| supports the conclusion that an   | been obtained upon the exercise   |
| infant formula that has been      | of due care) that reasonably      |
| processed by the manufacturer and | supports the conclusion that an   |
| that has left an establishment    | infant formula that has been      |
| subject to the control of the     | processed by the manufacturer or  |
| manufacturer:                     | responsible party and that has    |
|                                   | left an establishment subject to  |
|                                   | the control of the manufacturer   |
|                                   | or responsible party:             |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.150(a) A manufacturer [or responsible party]{.mark} shall promptly
notify FDA in accordance with paragraph (b) of this section, when the
manufacturer [or responsible party]{.mark} has knowledge (that is, the
actual knowledge that the manufacturer [or responsible party]{.mark}
had, or the knowledge which a reasonable person would have had under
like circumstances or which would have been obtained upon the exercise
of due care) that reasonably supports the conclusion that an infant
formula that has been processed by the manufacturer [or responsible
party]{.mark} and that has left an establishment subject to the control
of the manufacturer [or responsible party]{.mark}:

######### IFC Comment

See the IFC General Comment regarding Definition of Manufacturer. For
this type of submission any duplication of the responsible party\'s
efforts by co-packers would serve no useful purpose.

**Rest of page intentionally left blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| 106.150(a)(1) May not provide the | Acceptable as proposed.           |
| nutrients required by section     |                                   |
| 412(i) of the act or by           | 106.150(a)(2) May be otherwise    |
| regulations issued under section  | adulterated or misbranded. In the |
| 412(i)(2); or                     | case of \"adulteration\" based on |
|                                   | a failure to follow GMPs, the     |
| 106.150(a)(2) May be otherwise    | failure must be of such a nature  |
| adulterated or misbranded.        | as to reasonably call into        |
|                                   | question the suitability of the   |
|                                   | formula. Notification shall not   |
|                                   | be required for minor or          |
|                                   | technical misbranding.            |
+-----------------------------------+-----------------------------------+

IFC Redlined Version

106.150(a)(2) May be otherwise adulterated or misbranded. [In the case
of \"adulteration\" based on a failure to follow GMPs, the failure must
be of such a nature as to reasonably call into question the suitability
of the formula. Notification shall not be required for minor or
technical misbranding.]{.mark}

IFC Comment

See the IFC General Comment regarding Notification of Adulteration or
Misbranding.

**Rest of page intentionally left blank**

  ----------------------------------- -----------------------------------
  FDA Proposed Regulation             IFC Suggested Language

  106.150(b) The notification made    106.150(b) The notification made
  according to paragraph (a) of this  according to paragraph (a) of this
  section shall be made by telephone, section shall be made by telephone,
  to the Director of the appropriate  to the Director of the appropriate
  Food and Drug Administration        Food and Drug Administration
  district office. After normal       district office. After normal
  business hours (8 a.m. to 4:30      business hours (8 a.m. to 4:30
  p.m.), FDA\'s emergency number,     p.m.), FDA\'s emergency number,
  202-857-8400, shall be used. The    202-857-8400, shall be used. The
  manufacturer shall send written     manufacturer or responsible party
  confirmation of the notification to shall send written confirmation of
  the Food and Drug Administration,   the notification to the Food and
  Center for Food Safety and Applied  Drug Administration, Center for
  Nutrition, Office of Special        Food Safety and Applied Nutrition,
  Nutritionals, Division of Programs  Office of Special Nutritionals,
  and Policy Enforcement (HFS-455),   Division of Programs and Policy
  Infant Formula Coordinator, 200 C   Enforcement (HFS-455), Infant
  St. SW, Washington, DC 20204, and   Formula Coordinator, 200 C St. SW,
  to the appropriate Food and Drug    Washington, DC 20204, and to the
  Administration district office      appropriate Food and Drug
  specified in Sec. 5.115 of this     Administration district office
  chapter.                            specified in Sec. 5.115 of this
                                      chapter.
  ----------------------------------- -----------------------------------

IFC Redlined Version

106.150(b) The notification made according to paragraph (a) of this
section shall be made by telephone, to the Director of the appropriate
Food and Drug Administration district office. After normal business
hours (8 a.m. to 4:30 p.m.), FDA\'s emergency number, 202‑857‑8400,
shall be used. The manufacturer [or responsible party]{.mark} shall send
written confirmation of the notification to the Food and Drug
Administration, Center for Food Safety and Applied Nutrition, Office of
Special Nutritionals, Division of Programs and Policy Enforcement
(HFS‑455), Infant Formula Coordinator, 200 C St. SW, Washington, DC
20204, and to the appropriate Food and Drug Administration district
office specified in Sec. 5.115 of this chapter.

IFC Comment

See the IFC General Comment regarding Definition of Manufacturer.

**Rest of page intentionally left blank**

+-----------------------------------+-----------------------------------+
| FDA Proposed Regulation           | IFC Suggested Language            |
+-----------------------------------+-----------------------------------+
| **107.1 Status and applicability  | **107.1 Status and applicability  |
| of the regulations in part 107.** | of the regulations in part 107.** |
+-----------------------------------+-----------------------------------+
| 107.1(a) The criteria set forth   | Acceptable as proposed.           |
| in subpart B of this part         |                                   |
| describes the labeling            |                                   |
| requirements applicable to infant |                                   |
| formula under section 403 of the  |                                   |
| Federal Food, Drug, and Cosmetic  |                                   |
| Act (the act). Failure to comply  |                                   |
| with any regulation in subpart B  |                                   |
| of this part will render an       |                                   |
| infant formula misbranded under   |                                   |
| that section of the act.          |                                   |
| Acceptable as proposed.           |                                   |
+-----------------------------------+-----------------------------------+
| 107.1(b) The criteria set forth   | Acceptable as proposed.           |
| in subpart C of this part         |                                   |
| describes the terms and           |                                   |
| conditions for the exemption of   |                                   |
| an infant formula from the        |                                   |
| requirements of section 412(a),   |                                   |
| (b), and (c) of the act. Failure  |                                   |
| to comply with any regulations in |                                   |
| subpart C of this part will       |                                   |
| result in the withdrawal of the   |                                   |
| exemption given under section     |                                   |
| 412(h)(1) of the act.             |                                   |
+-----------------------------------+-----------------------------------+
| 107.1(c) Subpart D of this part   | Acceptable as proposed.           |
| sets forth the nutrient           |                                   |
| requirements for infant formula   |                                   |
| under section 412(i) of the act.  |                                   |
| Failure to comply with any        |                                   |
| regulation in subpart D of this   |                                   |
| part will render an infant        |                                   |
| formula adulterated under section |                                   |
| 412(a)(1) of the act.             |                                   |
+-----------------------------------+-----------------------------------+
| **107.10 Nutrient Information.**  | **107.10 Nutrient Information.**  |
+-----------------------------------+-----------------------------------+
| 107.10(a) \* \* \*                | Acceptable as proposed.           |
|                                   |                                   |
| 107.10(a)(2) A statement of the   |                                   |
| amount, supplied by 100           |                                   |
| kilocalories, of each of the      |                                   |
| following nutrients and of any    |                                   |
| nutrient added by the             |                                   |
| manufacturer:                     |                                   |
+-----------------------------------+-----------------------------------+
| **107.240 Notification            | **107.240 Notification            |
| requirements.**                   | requirements.**                   |
+-----------------------------------+-----------------------------------+
| 107.240(a) Telephone report. When | Acceptable as proposed.           |
| a determination is made that an   |                                   |
| infant formula is to be recalled, |                                   |
| the recalling firm shall          |                                   |
| telephone within 24 hours the     |                                   |
| appropriate Food and Drug         |                                   |
| Administration district office    |                                   |
| listed in §5.115 of this chapter  |                                   |
| and shall provide relevant        |                                   |
| information about the infant      |                                   |
| formula that is to be recalled.   |                                   |
+-----------------------------------+-----------------------------------+

**Rest of page left intentionally blank**

  -----------------------------------------------------------------------
  FDA Proposed Regulation             IFC Suggested Language
  ----------------------------------- -----------------------------------
  107.240(b) Initial written report.  Acceptable as proposed.
  Within 14 days after the recall has 
  begun, the recalling firm shall     
  provide a written report to the     
  appropriate Food and Drug           
  Administration district office. The 
  report shall contain relevant       
  information, including the          
  following cumulative information    
  concerning the infant formula that  
  is being recalled:                  

  107.240(b)(1) Number of consignees  Acceptable as proposed.
  notified of the recall and date and 
  method of notification, including   
  recalls required by §107.200,       
  information about the notice        
  provided for retail display and the 
  request for its display.            

  107.240(b)(2) Number of consignees  Acceptable as proposed.
  responding to the recall            
  communication and quantity of       
  recalled infant formula on hand at  
  the time it was received.           

  107.240(b)(3) Quantity of recalled  Acceptable as proposed.
  infant formula returned or          
  corrected by each consignee         
  contacted and the quantity of       
  recalled infant formula accounted   
  for.                                

  107.240(b)(4) Number and results of Acceptable as proposed.
  effectiveness checks that were      
  made.                               

  107.240(b)(5) Estimated timeframes  Acceptable as proposed.
  for completion of the recall.       

  107.240(c) Status reports. The      Acceptable as proposed.
  recalling firm shall submit to the  
  appropriate Food and Drug           
  Administration district office a    
  written status report on the recall 
  at least every 14 days until the    
  recall is terminated. The status    
  report shall describe the steps     
  taken by the recalling firm to      
  carry out the recall since the last 
  report and the results of these     
  steps.                              

  **107.250 Termination of an infant  **107.250 Termination of an infant
  formula recall**                    formula recall**

  The recalling firm may submit a     Acceptable as proposed.
  recommendation for termination of   
  the recall to the appropriate Food  
  and Drug Administration district    
  office listed in §5.115 of this     
  chapter for transmittal to the      
  Division of Enforcement (HFS‑605),  
  Office of Field Programs, Center    
  for Food Safety and Applied         
  Nutrition, for action. Any such     
  recommendation shall contain        
  information supporting a conclusion 
  that the recall strategy has been   
  effective. The agency will respond  
  within 15 days of receipt by the    
  Division of Enforcement (HFS‑605),  
  Office of Field Programs, Center    
  for Food Safety and Applied         
  Nutrition, of the request for       
  termination. The recalling firm     
  shall continue to implement the     
  recall strategy until it receives   
  final written notification from the 
  agency that the recall has been     
  terminated. The agency will send    
  such notification, unless it has    
  information, from FDA\'s own audits 
  or from other sources demonstrating 
  the recall has not been effective.  
  The agency may conclude that a      
  recall has not been effective if:   
  -----------------------------------------------------------------------

**CONCLUSION**

The International Formula Council appreciates the opportunity to comment
on this proposal. As stated above, if FDA has any questions or requires
clarification of any aspects of this document, it should feel free to
contact Mardi Mountford or Robert Gelardi.

Respectfully submitted,

Robert C. Gelardi Mardi K. Mountford

President Executive Director

International Formula Council International Formula Council

Thomas Ferguson Melanie Fairchild-Dzanis

Director, Regulatory Affairs Director, Regulatory Affairs

Mead Johnson Nutritionals Nutrition Division

Bristol Meyers Squibb Nestlé USA

Pamela Anderson Dennis Heuring

Director, Regulatory Affairs Managing Partner

Ross Products Division Solus Products

Abbott Laboratories

John Wallingford

Assistant Vice President

Regulatory Affairs and Market Compliance

Wyeth Nutrition

RCG/mkm/rs

######### Enclosures: Attachment A: International Formula Council Suggested Language

> Attachment B: FDA Infant Formula GMP Regulation (Redlined against IFC
> Suggested Edits)
>
> Attachment C: IFC's June 20, 2003 letter to Dr. Christine Taylor re
> Industry Proposal on Infant Formula Powder Labeling
>
> Attachment D: IFC's June 27, 2003 letter to Dr. Christine Taylor re
> Proposed Discussion Points on Powdered Infant Formula Good
> Manufacturing Practices
>
> Attachment E: IFC's July 7, 2003 letter to Dr. Christine Taylor re
> Special Products
>
> Attachment F: Douglas L. Archer's July 7, 2003 letter to Robert C.
> Gelardi re Summary of Industry Data re Testing for *E. sakazakii* in
> Powdered Infant Formula -- Submitted to Dr. Christine Taylor on July,
> 7, 2003
>
> Attachment G: "Guidelines Concerning Notification and Testing of
> Infant Formulas" incorporated into section 412(c)(1) of the 1986
> Amendments to the Infant Formula Act (hereinafter "1986 Guidelines")
>
> Attachment H: Russell J. Merritt's November 2002 Slide Presentation to
> FAC
>
> Attachment I: Jon A. Vanderhoof's November 2002 Slide Presentation to
> FAC
>
> Attachment J: Jose M. Saavedra's November 2002 Slide Presentation to
> FAC
>
> Attachment K: IFC's "Decision Tree for Documentation of Nutritional
> Adequacy of a New or Changed Infant Formula" submitted to the FAC in
> November 2002
>
> Attachment L: IFC's "Decision Tree Chart for Documentation of
> Nutritional Adequacy of a New or Changed Infant Formula" submitted to
> FAC in November 2002
>
> Attachment M: IFC's "Sample Clinical Growth Trial Protocol for Healthy
> Term Infants" submitted to the FAC in November 2002
>
> Attachment N: Robert C. Gelardi's Oral Testimony before the FAC, April
> 4, 2002
>
> Attachment O: Nutritional Profiles of Infant Formula provided to FASEB
> by IFC's August 22, 1996 letter

[^1]: International Formula Council members are: Abbott Laboratories,
    Ross Products Division; Bristol-Meyers Squibb Company, Mead Johnson
    Nutritionals; Nestlé USA, Inc., Nutrition Division; Solus Products;
    and Wyeth Nutrition.

[^2]: There are four reports of *E. sakazakii* disease among healthy
    term infants. Monroe and Tift (1979) reported bacteremia in one male
    term infant (birth weight 2600 g) that had been fed formula, but did
    not provide evidence that the formula was causally related to the
    infection. They write, "The epidemiological aspects concerning the
    reservoir and route of transmission of the organism in relationship
    to this case are uncertain."

    Muytjens et al. (1983) reported on 8 infants, one of who was
    described as full term and had a birth weight over 2500 g. *E.
    sakazakii* was isolated several times from prepared formula, a
    stirring spoon and a dish brush; but was not isolated from formula
    powder.

    Biering et al. (1989) reported 3 cases, 2 of which were more than 38
    weeks and above 2500 g, but one had gastrointestinal surgery. The
    other was fed on breast milk and powdered formula. These
    investigators attempted to isolate the organism from the
    environment, including powdered formula. They could not isolate the
    organism from "numerous" cultures of freshly prepared formula, but
    could if reconstituted powder was incubated for 4 hours at 36
    degrees C. They suggest that the reason some infants got sick and
    others fed the same formula did not: "The most likely explanation
    appears to be that the rules pertaining to the handling of the
    formula in the wards were not always adhered to. There is some
    anecdotal evidence that the formula bottles were occasionally kept
    at 35 to 37 C for extended periods of time in bottle heaters, thus
    allowing for multiplication of the organism." This is the strongest
    evidence to date that there may be a risk of disease if formula is
    mishandled. However, there are many forms of mishandling of formula
    that could constitute a risk to the health of infants.

    Finally, Block et al. (2002) conducted a look-back through hospital
    records from 1987 onward for cases of *E. sakazakii* infection.
    Their database, from two hospitals each delivering 3000-3500 infants
    annually, found one case of bacteremia in a term infant that had
    been formula fed, but the formula itself was not analyzed and there
    is no further information about the case.

[^3]: *See* House Committee on Interstate and Foreign Commerce Report:
    The Infant Formula Act, p. 6.

[^4]: *Id.* at p. 5.

[^5]: *See* House Committee on Interstate and Foreign Commerce Report:
    The Infant Formula Act, p. 6.

[^6]: