36154 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

DEPARTMENT OF HEALTH AND

HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 106 and 107

[Docket No. 95N–0309]

RIN 0910–AA04

Current Good Manufacturing Practice,

Quality Control Procedures, Quality

Factors, Notification Requirements,

and Records and Reports, for the

Production of Infant Formula

AGENCY: Food and Drug Administration,

HHS.

ACTION: Proposed rule.

SUMMARY: The Food and Drug

Administration (FDA) is proposing to

revise its infant formula regulations to

establish requirements for quality

factors and current good manufacturing

practice (CGMP); to amend its quality

control procedure, notification, and

records and report requirements for

infant formulas; to require that infant

formulas contain, and be tested for,

required nutrients and for any nutrient

added by the manufacturer throughout

their shelf life, and that they be

produced under strict microbiological

controls; and to require that

manufacturers implement the CGMP

and quality control procedure

requirements by establishing a

production and in-process control

system of their own design. This action

is being taken to improve the protection

of infants that use infant formula

products.

DATES: Comments by October 7, 1996,

except that comments regarding

information collection should be

submitted by August 8, 1996. The

agency proposes that any final rule that

may issue based on this proposal

become effective 120 days after its date

of publication.

ADDRESSES: Submit written comments,

data, or information to the Dockets

Management Branch (HFA–305), Food

and Drug Administration, rm. 1–23,

12420 Parklawn Dr., Rockville, MD

20857. Comments regarding information

collection to the Office of Information

and Regulatory Affairs, OMB, New

Executive Office Bldg., 725 17th St.

NW., rm. 10235, Washington, DC 20503,

ATTN: Desk Officer for FDA.

FOR FURTHER INFORMATION CONTACT:

Carolyn W. Miles, Center for Food

Safety and Applied Nutrition (HFS–

456), Food and Drug Administration,

200 C St. SW., Washington, DC 20204,

202–401–9858.

SUPPLEMENTARY INFORMATION:

I. Background

A. The Infant Formula Act of 1980

In 1978, a major manufacturer of

infant formula reformulated two of its

soy products by discontinuing the

addition of salt. This reformulation

resulted in infant formula products that

contained an inadequate amount of

chloride, an essential nutrient for

growth and development in infants. By

mid-1979, a substantial number of

infants had been diagnosed with

hypochloremic metabolic alkalosis, a

syndrome associated with chloride

deficiency. Development of this

syndrome in these infants was found to

be associated with prolonged exclusive

use of chloride-deficient soy formulas.

After reviewing the matter, Congress

determined that, to improve protection

of infants using infant formula products,

greater regulatory control over the

formulation and production of infant

formula was needed, including

modifications of industry’s and FDA’s

recall procedures. Accordingly,

Congress passed, and the President

signed into law on September 26, 1980,

the Infant Formula Act of 1980 (the

1980 act) (Pub. L. 96–359). This law

amended the act to include section 412

(21 U.S.C. 350a).

In 1982, FDA adopted infant formula

recall procedures, establishing subpart

D of part 107 of its regulations (21 CFR

part 107) (47 FR 18832, April 30, 1982),

and infant formula quality control

procedures (21 CFR part 106 (47 FR

17016, April 20, 1982)). In 1985, FDA

further implemented the 1980 act by

establishing subparts B, C, and D in 21

CFR part 107 regarding the labeling of

infant formula, exempt infant formulas,

and nutrient requirements for infant

formula, respectively (50 FR 1833,

January 14, 1985; 50 FR 48183,

November 22, 1985; and 50 FR 45106,

October 30, 1985).

B. The 1986 Amendments to the Infant

Formula Act

In 1986, Congress, as part of the Drug

Enforcement, Education, and Control

Act of 1986 (the 1986 amendments)

(Pub. L. 99–570) completely revamped

section 412 of the act to address

concerns that had been expressed by

Congress and consumers about the 1980

act and FDA’s implementation of that

statute. These concerns included

whether the quality control testing,

CGMP, recordkeeping, and recall

requirements that FDA had adopted

would prevent children ‘‘from ever

again being threatened by defective baby

formula’’ (Ref. 1). The 1986

amendments: (1) State that an infant

formula is deemed to be adulterated

unless it provides certain required

nutrients, meets the quality factor

requirements established by the

Secretary of Health and Human Services

(the Secretary) (and, by delegation,

FDA), and is manufactured in

accordance with CGMP and quality

control procedures established by the

Secretary; (2) require that the Secretary

issue regulations establishing

requirements for quality factors and

CGMP, including quality control

procedures; (3) require that infant

formula manufacturers regularly audit

their operations to ensure that those

operations comply with CGMP and

quality control procedure regulations;

(4) expand the circumstances in which

manufacturers must make a submission

to the agency to include when a

manufacturer makes major changes in

an infant formula, and when a

manufacturer makes changes that may

affect whether the formula is

adulterated; (5) specify the nutrient

quality control testing that must be done

on each batch of infant formula; (6)

modify the infant formula recall

requirements; and (7) give the Secretary

authority to establish requirements for

retention of records, including records

necessary to demonstrate compliance

with CGMP and quality control

procedures.

In 1989, the agency responded to the

provisions of the 1986 amendments on

recalls (sections 412(f) and (g) of the act)

by establishing subpart E in part 107 (54

FR 4006, January 27, 1989). In 1991, the

agency adopted infant formula record

and record retention requirements that

implemented the 1986 amendments by

revising § 106.100 (56 FR 66566,

December 24, 1991).

Although the agency has adopted

regulations that respond to a number of

the provisions of the 1986 amendments,

it has not issued regulations on infant

formula CGMP and quality factors or

revised the notification procedures and

quality control procedures to reflect the

1986 amendments. Since the passage of

the 1986 amendments, agency

representatives have visited infant

formula plants to observe the

manufacturing practice and quality

control procedures that they employ,

and the agency has solicited and

received recommendations on CGMP

from the Infant Formula Council. In

addition, FDA has contracted with the

Committee on Nutrition of the American

Academy of Pediatrics (CON/AAP) to

obtain expert advice on clinical testing

of infant formulas with respect to the

quality factor requirements. Moreover,

both industry and the agency have
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36155

increased experience with the quantity

and quality of information that should

be submitted to meet the notification

requirements of section 412(c) and (d) of

the act.

This proposal addresses CGMP,

quality control procedures, quality

factors, and notification procedures and

incorporates information resulting from

the interactions between FDA and

industry and between FDA and AAP.

This proposal updates the language in

part 107 to reflect the 1986 amendments

and the November 1992 reorganization

of the Center for Food Safety and

Applied Nutrition (CFSAN).

C. FDA’s Regulations on Nutrient

Requirements

Section 412(i) of the act includes a

table that lists nutrients that every

infant formula must contain. This

section also establishes a minimum

level for each of the listed nutrients and

a maximum level for eight of the listed

nutrients. In addition, section 412(i)(2)

of the act grants the Secretary (and by

delegation FDA) the authority to revise

the list of nutrients in section 412(i),

and the minimum and maximum levels

of those nutrients, by regulation. In the

Federal Register of October 30, 1995,

FDA established the nutrient

requirements for infant formulas in

§ 107.100 (50 FR 45106). For the

purpose of this document, the nutrients

that are required to be in infant formula

under § 107.100 will be referred to as

‘‘required nutrients,’’ and the levels of

these required nutrients established in

§ 107.100 will be referred to as

‘‘required levels.’’

II. The Need for Regulation

Relative to per unit of body weight,

nutrient requirements are generally

greater in infancy than at any other time

during life. During the first year, the rate

of growth is at its maximum, with birth

weight typically doubling by 4 months

of age and tripling by 1 year (Refs. 2 and

3). Moreover, the metabolic rate in

infants is greater, and the turnover of

nutrients is more rapid, than in adults

(Ref. 4). Thus, infants must ingest

adequate nutrients to support a rapid

rate of growth and of developmental

changes and to supply maintenance

needs. Without adequate nutrition,

infants would be unable to achieve their

genetic potential for growth and

development.

These nutritional needs must be met

in early infancy by food in liquid form.

Sucking and involuntary swallow

reflexes are the mechanisms by which

very young infants ingest food until

teeth and motor coordination develop.

Consequently, for infants who are not

fed breast milk, infant formula often

serves as the sole source, or the major

source, of nutrition during this time of

rapid growth and development.

Therefore, the importance of proper

infant formula manufacture,

composition, and nutrient levels cannot

be overstated. Senator Metzenbaum

explained why infant formula needs

more regulation than other foods when

he stated ‘‘there is simply no margin for

error in the production of baby formula.

An infant relies on the formula to

sustain life and provide the proper

nourishment at a time of rapid physical

and mental development’’ (Ref. 1). The

requirements contained in this proposal

are designed to ensure that the formula

fed to American infants fulfills its

important function.

The CGMP and quality control

procedures that FDA is proposing are

designed to prevent the production of

an adulterated infant formula. Defining

CGMP will help to ensure that all of the

required nutrients are included at

appropriate levels in the formula, and

that the formula is not contaminated

with microorganisms or other materials

that may be harmful to the infant.

Quality control procedures are

designed to ensure that an infant

formula contains the nutrients that are

necessary to support growth and

development, at the appropriate levels,

not only when it enters into commerce

but throughout its shelf life. FDA is

proposing that each batch of infant

formula be tested for all required

nutrients and any nutrient added by the

manufacturer, and that finished batches

be periodically sampled and tested for

nutrients throughout the shelf life of the

product.

Quality factors are designed to ensure

that the required nutrients and any

nutrient added by the manufacturer

actually reach the infant in a useable

form. Quality factors ‘‘pertain to the

bioavailability of a nutrient and the

maintenance of level or potency of

nutrients during the expected shelf life

of the product’’ (Ref. 5). The 1986

amendments directed that the Secretary,

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 (section 412(i) of

the act).’’

In 1986, FDA advised Congress that

the technology and science with respect

to quality factors was still evolving, and

that it was only possible to establish a

quality factor for one nutrient. The

agency said that it had already done so.

However, in the 1986 Congressional

Record (Ref. 1), Senator Metzenbaum

stated that ‘‘the legislation contemplates

that the Secretary will move to promptly

develop and issue appropriate quality

factor standards for different nutrients

as the state of the science progresses.’’

Since that time, as stated above, FDA

has contracted with CON/AAP to obtain

expert advice on quality factors; i.e., on

the clinical testing of infant formula

with respect to its nutritional safety and

suitability for term infants.

In 1988, CON/AAP submitted a report

(Ref. 6) under the contract that

identified and discussed the types of

clinical studies that might be considered

for evaluation of the nutritional

suitability of a formula for normal term

infants. FDA has reviewed this report

and the available scientific literature

and has identified quality factors for

protein and for complete infant

formulas. The agency is proposing to

adopt these quality factors as part of

these regulations.

FDA has received numerous inquiries

from industry for specific guidance on

what information must be submitted to

meet the requirements of sections 412(c)

and (d) of the act, which state when a

manufacturer must register with, submit

to, or notify the agency about a new or

changed infant formula, and what must

be in the registration, submission, or

notification. The agency is responding

to these requests in this proposal. The

agency is providing this information not

only in response to these inquiries but

also to facilitate more consistent

registrations, submissions, and

notifications. The lack of consistency in

the format and content of registrations,

submissions, and notifications has

caused inefficiencies and delays in the

agency’s review. Accordingly, the

agency is proposing to establish a

consistent format and content for infant

formula registrations, submissions, and

notifications.

Within the past year, FDA has

investigated a number of instances in

which infant formula manufactured in

the United States has been diverted

from normal distribution channels and

relabeled, sometimes with counterfeit

labels for the same brand of infant

formula but in other instances with

counterfeit labels for different

formulations. Infant formula bearing

counterfeit labels is a potentially serious

public health problem. It could cause

infant formula that is past the use by

date to enter the marketplace if the

counterfeit label bears an incorrect use

by date. The more serious consequence

of this practice, however, is that it could

cause infants that are intolerant to

certain infant formula ingredients to be

fed an incorrect formula, with serious

consequences to the health of the infant,
36156 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

if an infant formula has been relabeled

with an incorrect label (e.g., a milkbased infant formula relabeled to

indicate that it is a soy-based infant

formula). Therefore, as part of this

proposed regulation, the agency is

requesting comments on new or

modified procedures or controls that

could be instituted during the labeling,

packaging, or distribution of infant

formula and that would be effective in

preventing or reducing the potential for

the diversion of infant formula from

normal distribution channels and its

relabeling with counterfeit labels.

III. Scope of this Document

To implement the 1986 amendments,

the agency is proposing to amend its

regulations by adding new subparts B,

D, and E to part 106 and by

redesignating existing subparts B, C, and

D as subparts C, F, and G. Table 1 sets

out the current and proposed subpart

designations.

TABLE 1

Subparts Current regulation Proposed regulation

A .............. General Provisions ........................................................................ General Provisions.

B .............. Quality Control Procedures for Assuring Nutrient Content of Infant Formulas.Current Good Manufacturing Practice.

C .............. Records and Reports .................................................................... Quality Control Procedures.

D .............. Notification Requirements ............................................................. Conduct of Audits.

E .............. None .............................................................................................. Quality Factors for Infant Formulas.

F .............. None .............................................................................................. Records and Reports.

G .............. None .............................................................................................. Registration, Submission, and Notification Requirements.

The proposed regulation adds a new

§ 107.1 and will amend § 107.10(a)(2) by

requiring that ‘‘any nutrient added by

the manufacturer’’ be listed on the label.

The proposed regulation amends

§§ 107.240 and 107.250 by changing the

reference to the Division of Regulatory

Guidance to the Division of

Enforcement to reflect the November

1992 reorganization of CFSAN.

IV. The Proposed Regulations

A. General Provisions

To reflect the expanded scope of the

proposed regulations, FDA is revising

the heading of part 106 to read, ‘‘Infant

Formula-Requirements Pertaining to

Current Good Manufacturing Practice,

Quality Control Procedures, Quality

Factors, Records and Reports, and

Notifications.’’

1. Status and Applicability of the

Regulations in Part 106

Proposed § 106.1 sets out the

authority for each of the proposed

subparts and the consequences under

the act of failure to comply with any of

the regulations in the proposed

subparts. FDA is including proposed

§ 106.1 because it is important for

manufacturers to be aware of the legal

consequences of failure to comply with

these regulations, which are being

issued to implement specific sections of

the act.

2. Definitions

The agency is proposing to amend

§ 106.3 by adding several definitions

that are needed to explain activities that

specifically concern the infant formula

industry. It is important whenever

possible to maintain consistent

terminology throughout the agency’s

regulations. Therefore, as described in

detail below, FDA has relied, where

possible, on existing definitions in 21

CFR parts 105, 110, and 210 in arriving

at these proposed definitions. Other

definitions were derived from specific

provisions in the act.

Proposed § 106.3(a), (g), (h), and (p)

incorporate into part 106 the definitions

for ‘‘batch,’’ ‘‘lot,’’ ‘‘lot number, control

number, or batch number,’’ and

‘‘representative sample’’ derived from

21 CFR 210.3(b)(2), (b)(10), (b)(11), and

(b)(21), respectively. In addition to

promoting consistency in the agency’s

regulations, FDA has tentatively

determined that use of these definitions

in part 106 is appropriate because they

permit the agency to refer to the product

in terms that reflect the fact that it is

produced in bulk rather than on a unitby-unit basis.

Proposed § 106.3(k), (q), and (r)

incorporate into part 106 the definitions

for ‘‘microorganisms,’’ ‘‘shall,’’ and

‘‘should’’ from 21 CFR 110.3(i), (p), and

(q), respectively. In addition to

promoting consistency, these definitions

reflect the generally recognized

scientific or legal meaning of these

terms.

Proposed § 106.3(c), (f), (j), and (n)

incorporate into part 106 the definitions

for ‘‘indicator nutrient,’’ ‘‘in-process

batch,’’ ‘‘manufacturer,’’ and ‘‘nutrient

premix’’ from current § 106.3. The

definition of ‘‘manufacturer’’ in

proposed § 106.3(j) warrants particular

note. In the past there has been some

confusion about who is and who is not

a manufacturer of infant formula. This

definition makes clear that a

manufacturer is not only a person who

combines raw ingredients together to

produce an infant formula but also is a

person who reconstitutes or otherwise

changes the physical or chemical

characteristics of an infant formula or

who packages or labels the product in

a container for distribution. For

example, the agency is aware of a firm

that reconstitutes powdered infant

formulas and puts the reconstituted

formula in bottles to sell to hospitals.

This definition makes clear that this

firm is a ‘‘manufacturer.’’

Proposed § 106.3(d) incorporates into

part 106 the definition for ‘‘infant’’ from

21 CFR 105.3(e).

In addition to the definitions derived

from FDA’s existing regulations, the

agency is proposing to amend § 106.3 by

adding definitions that are derived from

the definitions provided by Congress in

the act.

Proposed § 106.3(e) and (l)

incorporate into part 106 the definitions

for ‘‘infant formula’’ and ‘‘new infant

formula’’ from sections 201(aa) (21

U.S.C. 321(aa)) and 412(c)(2),

respectively.

Proposed § 106.3(e) defines ‘‘infant

formula’’ as a food that 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. The phrase

‘‘solely as a food for infants’’ is

somewhat ambiguous. Where there is an

ambiguity in a statutory provision, it is

appropriate to look to the legislative

history to determine the appropriate

interpretation. In the legislative history

of the Infant Formula Act, whenever the

words ‘‘sole’’ or ‘‘solely’’ are used, they

appear in the context of describing

infant formula as the ‘‘sole’’ or primary

source of nutrition for infants or babies.

For example, in explaining how the
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36157

1980 act would change existing laws,

then-Congressman Gore stated: ‘‘First it

would require that any infant formula

marketed in the United States as the

sole source of nutrition for normal

babies include minimum amounts of all

essential nutrients.’’ (Ref. 7.)

Congressman Mottl stated that the 1980

act ‘‘is concerned with human lives at

their most vulnerable stage. We are

talking about food that may be the sole

source of nourishment for infants.’’ (Ref.

7.) This language and other similar

language in the legislative history

evidence that Congress intended the act

to apply to any food that purports to be

or that is represented as an infant

formula, regardless of whether other

possible uses of the product are

suggested in its labeling. If the law only

applied to foods that are represented

only for use as infant formula, then

manufacturers could easily evade the

requirements of the act for infant

formula by representing their products

for a second purpose. Such an

interpretation would be inconsistent

with the remedial purposes of the infant

formula provisions of the act.

Proposed § 106.3(b) incorporates into

part 106 the definition for ‘‘finalproduct-stage’’ derived from section

412(b)(3)(E) of the act. FDA has

modified the definition, however, by

adding the phrase ‘‘due to processing’’

at the end of the definition to clarify

that the final-product-stage is when the

infant formula ‘‘is homogeneous and is

not subject to further degradation due to

processing’’ and to distinguish the point

in time after which the formula is

subject to further degradation during the

shelf life of the product.

Proposed § 106.3(i) incorporates into

part 106 a definition of ‘‘major change’’

that is derived from section 412(c)(2)(B)

of the act, which states that ‘‘* * * 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’’ (Ref. 8). Proposed § 106.3(i)

defines ‘‘major change’’ as it is defined

in current § 106.30(c)(2). It also provides

a number of examples of infant formulas

deemed to differ fundamentally in

processing or in composition. These

examples are derived from the

guidelines that were issued by the

agency and were incorporated into the

definition of ‘‘major change’’ in section

412(c) of the act by the 1986

amendments.

Proposed § 106.3(m) revises the

definition for ‘‘nutrient’’ in current

§ 106.3(d) to reflect changes to the act

made by the 1986 amendments. As

stated above, the 1986 amendments

moved the nutrient table from section

412(g) to section 412(i)(1) and moved

the provision on promulgation of

standards for nutrients from section

412(a)(2)(A) to section 412(i)(2). The

proposed regulation references the new

section numbers. Proposed § 106.3(m)

also includes the statement that

nutrients are substances determined to

be essential by the Food and Nutrition

Board of the National Research Council

or by FDA. The agency is including this

statement in the proposed definition to

provide consistency with § 107.10(b)(5)

on labeling nutrient information. This

paragraph allows such information to

include any vitamin or mineral in the

formula, provided that the nutrient has

been identified as essential by the

National Academy of Sciences through

its development of a recommended

dietary allowance or an estimated safe

and adequate daily dietary intake range,

or the nutrient has been identified as

essential by FDA through a Federal

Register publication.

Proposed § 106.3(o) defines ‘‘quality

factors.’’ The definition that FDA is

proposing derives from the language of

the act and its legislative history.

Section 412(b)(1) of the act states that

the Secretary shall ‘‘establish

requirements for quality factors for

infant formulas * * *, including quality

factor requirements for the nutrients

required by subsection (i).’’ House

Report 96–936 (Ref. 5) states that quality

factors ‘‘pertain to the bioavailability of

a nutrient and the maintenance of level

or potency of nutrients during the

expected shelf life of the product.’’ The

language of the act and the House report

show that Congress intended that infant

formulas marketed in the United States

should not only be safe, and contain all

of the nutrients required to support

infant growth and health, but should

provide those nutrients in a bioavailable

form that will mean that, throughout its

shelf life, the formula will support

optimal infant growth and health.

Thus, quality factors encompass

something different than the analyzable

nutrient content of the finished infant

formula. Quality factor requirements not

only ensure that the nutrient potency

and biological effectiveness of a

formula, as formulated, are adequate to

support healthy growth, but also that

subsequent processing, ingredient

interactions, and time do not reduce the

biological effectiveness of a formula.

Quality factor requirements also ensure

that unsafe nutrient ‘‘super potencies’’

or by-products are not created from

ingredient breakdowns or interactions

caused by processing or time.

B. CGMP

1. Introduction

The agency is proposing to adopt a

new subpart B to implement the CGMP

requirements in section 412(b)(2) of the

act. Proposed § 106.5 is introductory. It

reflects FDA’s tentative view that the

CGMP requirements set out in subpart B

are the minimum necessary to ensure

that the infant formula that is produced

contains all the requisite nutrients and

is not otherwise adulterated.

To develop the proposed CGMP

regulations, as stated above, agency

representatives visited infant formula

plants to observe the manufacturing

practice that they employ, and the

agency has solicited and received

recommendations on CGMP from the

infant formula industry through the

Infant Formula Council (Ref. 9). The

agency also is relying on its knowledge

of industry manufacturing practices

gained through inspections of infant

formula manufacturing establishments,

review of infant formula submissions

received from industry since 1986, and

monitoring of infant formula recalls.

The proposed CGMP regulations also

are based in part on FDA’s existing

regulations concerning CGMP for foods

(21 CFR part 110) and for drugs (21 CFR

part 211). Because infant formulas are

foods, they should, at a minimum, be

manufactured in a manner that is

consistent with CGMP for all foods

under section 402(a)(4) of the act (21

U.S.C. 342(a)(4)). Moreover, infant

formulas are often the sole source of

nutrition for infants during a period of

rapid growth and development and,

hence, are used during a period of

nutritional vulnerability. Thus, if the

formula is to promote optimal infant

health and growth, each batch of infant

formula must provide the nutrients

prescribed under section 412(i) of the

act at the levels specified in that section,

much like each batch of drugs must

meet compositional requirements for

active ingredients if they are to have

their intended effect. Therefore, FDA

has tentatively concluded that some of

the manufacturing practices required of

drug manufacturers are relevant to

infant formula manufacturers.

2. Production and In-Process Control

System

Section 412(b)(2)(B)(iii) of the act

states that CGMP and quality control

procedures shall include requirements

for ‘‘in-process controls including,

where necessary, testing required by

CGMP designed to prevent adulteration

of each batch of infant formula.’’ In the

past, manufacturers of infant formula

have referred to production and in-
36158 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

process control systems intended to

ensure that required nutrients are

included in the formula and to prevent

adulteration by such terms as ‘‘quality

control plans,’’ ‘‘standard operating

procedures,’’ or ‘‘master manufacturing

procedures.’’ Infant formula

manufacturers also have investigated

adopting a system, known as the

ISO.9000 series, developed by the

International Organization for

Standardization (ISO).

The agency is proposing to establish

a framework in which decisions about

the production of infant formula are left

to the manufacturer but that charges the

manufacturer with incorporating into its

production process measures that are

designed to ensure the safety and

nutritional quality of the formula.

For example, proposed § 106.10(a)

requires that there be 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. This provision is a

performance standard for determining

how many employees are necessary, i.e.,

that there be enough to achieve,

maintain, and document CGMP. FDA is

not proposing to provide the specific

number of employees required, the

specific type of training that they must

have, the specific task they are to

perform, or the specific method by

which records are to be kept.

In another example, proposed

§ 106.35(b)(4) requires that infant

formula manufacturers ensure that

automatic (mechanical or electronic)

systems are validated before their first

use to manufacture commercial product.

However, in this provision, the agency

is not stipulating any standards or

specifications for the validation process

because the extent of the validation that

is necessary is related to the level of risk

that each component of the system

presents. These decisions about the

validation necessary are left to the

infant formula manufacturer to make.

As a third example, proposed

§ 106.91(b) requires that the

manufacturer conduct nutrient stability

testing at the beginning, midpoint, and

end of the shelf life of the infant formula

and with sufficient frequency to ensure

that the formula complies with

§ 107.100 throughout its shelf life.

Because manufacturers have experience

with the nutrient stability of the infant

formula matrices that they produce and

are in a position to determine how

frequently testing is necessary, the

agency is proposing only to require

testing ‘‘with sufficient frequency,’’

instead of specifying what frequency is

required.

Proposed § 106.6(a) requires that

infant formula manufacturers comply

with the requirements of subpart B of

part 106 by implementing a system of

production and in-process controls that

covers all stages of processing, from

receipt and acceptance of raw materials,

ingredients, and components through

storage and distribution of finished

product, and that is designed to ensure

that all requirements of subpart B of part

106 are met.

Infant formula manufacturing requires

a degree of sophistication (e.g., in

research and development, production

equipment and procedures, and

analytical equipment and methodology)

that a vast majority of companies in the

food processing industry do not have. A

manufacturer must maintain constant

control because a seemingly innocuous

change in formulation or in a

preparation method, or exposure to an

unanticipated environmental condition,

could create a health hazard. Moreover,

infant formula manufacturers must be

concerned not only that something is

present in the formula that may

adulterate that formula, such as a

contaminant or a level of a required

nutrient that exceeds the maximum

level allowed by § 107.100, but also that

something is absent from the formula,

such as the lack or unavailability of a

required nutrient. For example, the lack

of a nutrient or the unavailability of an

added nutrient has been responsible for

a number of documented problems that

have occurred in infant formulas (Ref.

1). Thus, FDA has tentatively concluded

that the use of a production and inprocess control system covering all

stages of processing is necessary to

ensure that the infant formula is

manufactured in a manner that will

prevent adulteration of the infant

formula.

Proposed § 106.6(b) requires that the

production and in-process control

system be set out in a written plan, or

set of procedures, that is designed to

ensure that the infant formula is

manufactured in a manner that will

prevent adulteration of the formula.

FDA has tentatively concluded that

requiring that the production and inprocess control system be set out in a

written plan or a set of procedures is

necessary to provide consistency in

production of different batches of infant

formula and to facilitate the preparation

of each batch of infant formula.

Consistency is provided because the

plan means that there is a single set of

procedures established that are to be

followed in producing the formula. The

plan also facilitates preparation of the

formula because, given the

sophistication of the infant formula

manufacturing process, a written plan to

which ready and easy reference can be

had is essential. The importance of a

written plan is well-recognized by

industry. The use of a written plan or

set of procedures for production of a

batch of infant formula is already a

wide-spread practice.

The agency has sought to develop a

basic list of items that a firm would

need to consider in developing its plan

or procedures, but the agency is

reluctant to offer such a list at this stage

of the rulemaking, before it has received

comments on the proposed good

manufacturing practice regulations. The

agency requests comments on whether

such a basic list, over and above the

provisions of Subpart B itself, is

possible or desirable, and if it is, what

such a list should include.

The agency would conceive of such a

list, at a minimum, as consisting of a

number of items. It would need to direct

the manufacturer to establish the

safeguards that it will rely upon to

protect against the foreseeable sources

of adulteration in the production of

infant formula. It would also need to

direct the manufacturer to establish

procedures for ensuring that the

manufacturing process functions

properly. Several of the procedures that

would have to be established to do so

are defined in the proposed regulations,

including: (1) Procedures, in accordance

with proposed § 106.35(b)(2), to

calibrate, inspect, and check hardware;

(2) specifications, in accordance with

proposed § 106.40(d), for the acceptance

or rejection of ingredients, containers,

and closures used in infant formula

manufacture; (3) the master

manufacturing orders in accordance

with proposed § 106.50(a)(1); and (4)

testing procedures, under proposed

§ 106.55(b), to ensure that powdered

infant formula complies with the

microbiological quality standards. Other

items that would also seem to be

appropriately included on such a list

would be procedures for controlling the

release of product, for ensuring its

traceability, and for conducting GMP

audits. However, FDA requests

comments on whether these items

provide an adequate checklist for the

development of the type of written plan

that is necessary under these proposed

regulations.

For now, FDA is leaving the specific

content of the procedures that are in the

written plan to the manufacturer’s

discretion. FDA requests comment on

whether the agency should develop

guidance on the content of any of the
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36159

procedures that are part of the written

plan.

Proposed § 106.6(c) specifies

requirements for a manufacturer’s

handling of any point, step, or stage in

its production process where control of

the process is necessary to prevent

adulteration of the formula. These inprocess control points, steps, or stages

may include retorting or other heating

steps, cooling steps, points where

specific sanitation procedures are

needed, product formulation control

steps, points where cross contamination

may occur, and steps where employee

and environmental hygiene are

necessary to prevent adulteration of the

product.

Proposed § 106.6(c)(1) requires that

infant formula manufacturers establish

standards or specifications to be met at

such points, steps, or stages. These

standards or specifications establish the

boundaries of safety at the point, step,

or stage. Such standards or

specifications may include, for example,

upper and lower limits for parameters

such as temperature, time, pH, visual

appearance, and moisture level as well

as chemical, nutrient, and

microbiological specifications for raw

materials. These standards or

specifications can be set based on

published or unpublished studies, on

regulatory levels established by FDA, or

on consultation with experts in infant

formula production. As discussed in

more detail below, FDA is proposing

(see proposed § 106.100(e)(3)(i)) that

manufacturers make and retain a list of

the standards and specifications that

they establish under proposed

§ 106.6(c)(1) including documentation

of the scientific basis for each standard

or specification. Maintaining such a list

will mean that these standards and

specifications are readily available for

comparison to the actual values

obtained in monitoring (i.e., making a

planned sequence of observations or

measurements) the production and inprocess control system.

Proposed § 106.6(c)(2) requires that

infant formula manufacturers monitor

the points, steps, or stages in their

production process where control is

necessary to prevent adulteration of the

infant formula. Regular monitoring of

these points is necessary to ensure that

the product meets the standards and

specifications set under proposed

§ 106.6(c)(1) and to ensure that any

trend toward loss of control is quickly

identified. Quick identification will

mean that adjustments can be made to

prevent a deviation from occurring, or,

in the event that a deviation does occur,

that effective corrective actions can be

taken to remove adulterated product

from the system.

For many standards or specifications,

continuous monitoring is possible. For

example, temperature and time for a

scheduled thermal process can be

recorded continuously on temperaturerecording charts. When it is not possible

to monitor a particular point, step, or

stage on a continuous basis, monitoring

intervals need to be reliable enough to

permit the manufacturer to determine

whether the production control point is

under control.

Monitoring involves not only making

observations at an appropriate

frequency but also ensuring that the

instruments and equipment, such as

thermometers, temperature-recording

devices, and computer software, that the

manufacturer relies on to make its

observations are accurate and reliable

(see proposed § 106.30(d)).

Proposed § 106.6(c)(3) requires that

infant formula manufacturers establish

corrective action plans for use when a

standard or specification established in

accordance with proposed § 106.6(c)(1)

is not met. FDA has tentatively

concluded that this requirement is

necessary because a manufacturer will

often need to take corrective action

quickly, and the best way to ensure that

a corrective action is appropriate is to

determine the action in advance. The

corrective action plans should provide,

for example, for the disposition of any

infant formula or of any partially

manufactured infant formula that was

produced when a deviation was

occurring.

Proposed § 106.6(c)(4) requires that

infant formula manufacturers review the

results of the monitoring required under

proposed § 106.6(c)(2). This review will

reveal whether the monitoring is

actually being done and being done

correctly, and whether standards and

specifications are being met.

Proposed § 106.6(c)(4) further requires

that infant formula manufacturers

review, and evaluate the public health

significance of, any deviations from

standards or specifications established

in accordance with proposed

§ 106.6(c)(1). This proposed requirement

is necessary to ensure that products that

may have been affected by a deviation

do not enter commerce if they are likely

to be unsafe. It also will ensure that the

disruption of a manufacturer’s business

is minimized when a deviation does

occur. For example, if review of

monitoring records reveals that an

ingredient premix does not contain the

required nutrients at the required levels,

the manufacturer can take steps to

dispose of the premix before it is used

in the manufacture of an infant formula.

If the monitoring records are not

reviewed, a product made with a

deficient premix may be placed on the

market, and a costly and embarrassing

recall may be required.

Proposed § 106.6(c)(4) also requires

that this review be conducted by an

individual qualified by training and

experience to conduct such reviews.

This proposed requirement is necessary

to ensure that the review is conducted

by a person who understands the

production and in-process control

system, understands the significance of

a processing deviation, and knows how

to respond to a deviation. Such

understanding and knowledge will

ensure that the review is appropriately

conducted, and that the response to any

deviation is measured and appropriate.

Proposed § 106.6(c)(5) requires that

infant formula manufacturers establish

recordkeeping procedures, in

accordance with proposed

§ 106.100(e)(3), that ensure that

compliance with the requirements of

proposed § 106.6(c) is documented. As

discussed below in the description of

the proposed revisions to subpart F of

part 106, FDA has authority to require

that these records be made and retained

under section 412(b)(4)(A)(i) of the act.

FDA is proposing to provide a complete

description of all recordkeeping

requirements in subpart F. When

applicable, FDA is including crossreferences to these recordkeeping

requirements in the regulations in

subparts B, C, and D. These records will

allow manufacturers to discern trends or

to pinpoint the onset of a problem if a

standard or specification is not being

met at a point where control is deemed

necessary to prevent adulteration, or if

a batch of infant formula is associated

with an adverse event.

3. Controls to Prevent Adulteration by

Workers

Proposed § 106.10(a) requires that

there be 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. Proposed

§ 106.10(a) is consistent with existing

regulations concerning CGMP for foods

(§ 110.10(c)) and drugs (§ 211.25). In this

provision, FDA is proposing a general

standard for determining how many

employees are necessary, i.e., that there

be enough to achieve, maintain, and

document CGMP. However, FDA is

leaving the determination of the actual

number of employees necessary to the

manufacturer’s discretion.
36160 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

Proposed § 106.10(a) also requires that

such personnel be qualified by training

and experience. Training is necessary to

ensure that employees know how to

correctly and fully perform the

operations in question and to ensure

that employees are competent to

produce a safe and clean infant formula.

The extent and frequency of training is

left to the manufacturer’s discretion.

Proposed § 106.10(b) requires that

personnel working directly with infant

formula, infant formula raw materials,

infant formula packaging, or infant

formula equipment or utensil contact

surfaces practice good personal hygiene

to protect the product against

contamination. Proposed § 106.10(b) is

consistent with existing regulations

concerning CGMP for foods (§ 110.10(b))

and drugs (§ 211.28(a) and (b)). FDA has

tentatively concluded that it is

necessary that these employees practice

good hygiene so that they will not

transmit disease to others in the

workforce, and so that they will not

transmit filth or pathogenic

microorganisms to the infant formula.

In addition, proposed § 106.10(b)

enumerates the basic elements of good

personal hygiene. Proposed

§ 106.10(b)(1) lists clean outer garments

and protective apparel as one element.

To be ‘‘clean,’’ clothing must be free of

filth or microorganisms that may

contaminate the infant formula.

Protective apparel, such as head, face,

hand, and arm coverings, will help to

ensure that the infant formula is

protected from contaminants such as

hair.

Proposed § 106.10(b)(2) states that

good personal hygiene includes workers

washing their 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 hands may become soiled or

contaminated. Filth and pathogenic

microorganisms can be brought into the

processing environment on the

employee’s hands from outside areas,

restrooms, contaminated raw materials,

waste or waste receptacles, and other

insanitary objects (Refs. 10, 11, and 12).

FDA has tentatively concluded that

requiring workers to practice good

personal hygiene by washing their

hands at the times specified will help to

prevent the introduction of this type of

contamination into infant formula.

Proposed § 106.10(c) requires that 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 the formula may be adversely

affected, 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. Proposed § 106.10(c)

is consistent with existing regulations

concerning CGMP for foods (§ 110.10(a))

and drugs (§ 211.28(d)). Employees can

transmit the organisms responsible for

diseases, such as salmonellosis,

shigellosis, and hepatitis, to the infant

formula. Additionally, open sores, boils,

or infected wounds present the potential

for contamination of the infant formula

with such pathogenic microorganisms

as Staphylococcus aureus (Refs. 14 and

15). Thus, proposed § 106.10(c) will

exclude employees who carry potential

microbial contamination that may

adversely affect the safety of the formula

from direct contact with the infant

formula and from direct contact with

materials and surfaces that come in

contact with the infant formula and thus

will minimize the potential for

employees to transmit microorganisms

to the infant formula that may cause the

infant formula to pose a health hazard

to the infant.

4. Controls to Prevent Adulteration

Caused by Facilities

Proposed § 106.20(a) requires that

buildings used in the manufacture,

processing, packing, or holding of infant

formula be maintained in a clean and

sanitary condition. This proposed

requirement is necessary to prevent

contamination of the infant formula. It

is consistent with FDA’s existing

regulations concerning CGMP for foods

(§§ 110.20(b) and 110.35(a)) and drugs

(§ 211.42). Trash, litter, and waste must

be disposed of to avoid creating

conditions that attract and harbor

potentially pathogenic microorganisms

and attract and harbor pests, such as

rodents or insects. Such pests can carry

a variety of human disease agents,

including microorganisms that are

potentially pathogenic in infants, and

introduce them into the manufacturing

environment (Refs. 10 and 12). They are

also sources of feces and hair that can

contaminate infant formula.

Proposed § 106.20(a) also requires that

buildings used in the manufacture of

infant formula 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. If

raw materials are not separated from the

site of product manufacture, there is a

significant possibility that they will be

used in infant formula manufacture

before they have been tested and found

acceptable for use in infant formula.

Therefore, FDA has tentatively

concluded that the separation of

incompatible operations is necessary to

ensure that infant formula is

manufactured in a manner designed to

prevent adulteration. The proposed

requirement that incompatible

operations be separated is consistent

with FDA’s existing regulations

concerning CGMP for foods

(§ 110.20(b)(2)) and drugs (§ 211.42(c))

and is consistent with the

recommendations made to FDA by the

Infant Formula Council (Ref. 9).

Proposed § 106.20(b) requires separate

holding areas to protect against mixups

that could lead to contamination of

infant formula. Failure to separate raw

materials or in-process materials that

have not been released, or that have

been rejected but not disposed of, from

those that have been released creates the

potential for the use of ingredients that

do not meet the applicable

specifications and thereby can lead to

the production of finished infant

formula that is adulterated. Similar

types of problems can develop if final

product that has not been released, or

that has been rejected but not disposed

of, is not separated from final product

that has been released. Proposed

§ 106.20(b) is consistent with FDA’s

existing regulations concerning CGMP

for drugs (§ 211.42(c)).

Proposed § 106.20(c) defines a

standard for adequate lighting and

allows the manufacturer to exercise

discretion in determining the precise

level of lighting that is sufficient to meet

that standard. Adequate lighting is

important. Inadequate lighting may

make it difficult to read a label or an

instrument, and as a result incorrect

ingredients may be used in infant

formula production, or instruments may

be read incorrectly, which increases the

risk of producing an adulterated infant

formula.

Proposed § 106.20(c) also requires that

any lighting fixtures directly over or

adjacent to exposed raw materials, inprocess materials, or bulk (unpackaged)

finished product be protected to prevent

glass from contaminating the product in

the event of breakage. Glass in an infant

formula may be a safety hazard and

would render the formula adulterated

(Ref. 14). Proposed § 106.20(c) is

consistent with FDA’s existing

regulations concerning CGMP’s for food

(§ 110.20(b)(5)) and drugs (§ 211.44).

FDA is proposing a requirement in

§ 106.20(d) for air filtration systems to

improve air quality in production areas
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36161

and thus reduce the potential for

contamination by air-borne sources (Ref.

15). This proposed requirement is

consistent with FDA’s existing

regulations concerning CGMP for drugs

(§ 211.46(c)).

Proposed new requirements in

§ 106.20(e) protect against the

contamination of infant formula by pest

control agents and cleaning agents. The

agency recognizes that these agents are

needed in infant formula facilities.

However, because many of them are

toxic, they must be handled and stored

in a manner that prevents

contamination of the infant formula.

Proposed § 106.20(e) is consistent with

FDA’s existing regulations concerning

CGMP for food (§ 110.35(b)(2)) and

drugs (§ 211.56(c)).

Proposed § 106.20(f)(1) states that

potable water used in the manufacturer

of infant formula must meet the

Environmental Protection Agency’s

(EPA’s) Primary Drinking Water

Regulations (40 CFR part 141) (with the

one exception that the fluoride level be

as low as possible, as discussed below).

This proposed regulation is consistent

with FDA’s existing regulations

concerning CGMP for drugs

(§ 211.48(a)).

The Safe Drinking Water Act gives

EPA the responsibility for establishing

standards for public drinking water.

Therefore, FDA is proposing to use

EPA’s standards for water used in the

production of infant formulas.

Application of these standards will

ensure that the water used in infant

formula is safe. The agency is proposing

to require that water from both

municipal sources and the firm’s own

wells meet these standards.

The safety and sanitary quality of

water from public water systems is

generally ensured through public water

treatment, chlorination, or monitoring

and control by local health authorities.

Private sources of water, however,

particularly surface waters or water

from shallow wells, may be subject to

microbiological, chemical, or

radiological contamination attributable

to the source itself or to surface

contamination at the well head or

intake. Private sources are also

frequently untreated or minimally

treated. Thus, under the proposed

regulation, when a manufacturer uses a

private source of water, it will need to

take steps to ensure that the water is

safe and sanitary. These steps may

include ensuring that the well design

has been approved by the local health

authority, ensuring that the well meets

coliform test standards, performing

periodic inspections of the sanitary

condition of the well head and source

intake, and performing and monitoring

appropriate water treatment procedures,

including filtration, sedimentation, and

chlorination. The type and frequency of

controls exercised by the manufacturer

will be based upon the type of source

water and its historic safety and sanitary

quality.

Proposed § 106.20(f)(1) makes one

exception to the use of EPA standards

for drinking water. On April 2, 1986,

EPA issued a maximum contaminant

level (MCL) for fluoride in drinking

water of 4 milligrams per liter (mg/L)

(51 FR 11396) and reaffirmed this level

on December 29, 1993 (58 FR 68826).

The National Academy of Sciences

(NAS) recommends 0.1 to 0.5 mg/day as

the safe and adequate intake for infants

from 0 to 6 months of age. Mottling of

teeth in children has been observed at

2 to 8 milligrams/kilogram (mg/kg)

concentration of fluoride in diet and

drinking water (Ref. 16). Thus, if 4 mg

of fluoride/L of water was allowed in

the water used in infant formula

manufacture, infants consuming readyto-feed infant formula could receive

enough fluoride to adversely affect their

teeth. Currently, no infant formulas are

manufactured with fluoridated water

(Ref. 17), so that the pediatrician or

other health care provider is able to

decide whether a fluoride supplement is

appropriate for formula-fed infants,

principally by considering whether the

formula was diluted with fluoridated

water (Ref. 18).

NAS has established a safe and

adequate daily dietary intake of fluoride

for infants (Ref. 19). The agency is

considering proposing to revise the

infant formula nutrient requirements in

§ 107.100 to include fluoride and other

nutrients that NAS has determined are

essential for infants. FDA will consider

fluoride levels for infant formulas at that

time. FDA has tentatively concluded

that, until it has revised the levels of

required nutrients, manufacturers

should continue their practice of not

using fluoridated water in the

manufacture of infant formula.

Proposed § 106.20(f)(1) also requires

that the water be supplied under

continuous positive pressure in a

plumbing system that is free of defects

that could contaminate an infant

formula. FDA has tentatively concluded

that this requirement is necessary to

ensure that all potable water coming

into the plant is not adversely affected

by the in-plant plumbing. Contaminated

water can serve as a vehicle for

contamination of infant formula, both

when used as an ingredient in the infant

formula and when allowed to enter the

product indirectly, as can occur, for

example, when water is used to cool the

product after retorting. Thus, FDA

tentatively concludes that it is

appropriate to include this positive

requirement in this regulation.

Proposed § 106.20(f)(2), which sets

forth requirements for testing

representative samples of potable water

used in infant formula manufacturing, is

necessary to provide assurance that the

water used in infant formula

manufacturing meets EPA’s standards.

Proposed § 106.20(f)(3) requires that

manufacturers conduct these tests with

appropriate frequency. The regulation

allows manufacturers some discretion in

determining the testing frequency

necessary to ensure that EPA standards

are met, but it requires a minimum

frequency of testing for certain

contaminants (i.e., chemical

contaminants, radiological

contaminants, and bacteriological

contaminants). FDA is basing these

proposed minimum frequencies on

those adopted by EPA for primary

drinking water. This frequency of

testing is consistent with FDA’s own

regulations concerning processing and

bottling of bottled drinking water

(§ 129.35(a)(3)).

Proposed § 106.20(f)(4) requires that

manufacturers make and retain records

of the frequency and the results of the

testing that they do on the water used

in the production of infant formula.

These records will document that the

manufacturer is complying with the

potable water testing requirements of

§ 106.20(f)(2) and (f)(3), and that the

water complies with EPA standards.

They will identify any trend toward loss

of compliance with these standards, so

that the manufacturer can take

corrective actions before the water

becomes inappropriate for use in infant

formula. As discussed below in the

description of the proposed revisions to

subpart F, FDA has authority to require

the creation and retention of these

records under section 412(b)(4)(A)(i) of

the act.

In proposed § 106.20(g), FDA sets out

requirements regarding piping systems

to prevent a source of contamination

(i.e., waste water) from coming in

contact with the infant formula. Cross

connections could allow back siphonage

into a potable system from a nonpotable

system under negative pressure

conditions and thus could result in the

chemical or microbiological

contamination of the potable water

system (Ref. 20). Proposed § 106.20(g) is

consistent with FDA’s regulations

concerning CGMP for food

(§ 110.37(b)(5)) and drugs (§ 211.48(b)).

Proposed § 106.20(h) requires that

steam that comes in direct contact with

infant formula be safe and free of rust
36162 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

and other particulate matter that could

contaminate the formula. Steam comes

in direct contact with infant formula

when the steam is injected into the head

space of a can of infant formula to create

a vacuum. Thus, this proposed

requirement is necessary to ensure that

the steam does not adulterate the infant

formula.

Proposed § 106.20(h) also requires

that boiler water additives in the steam

meet safety standards set forth in FDA

regulations at 21 CFR 173.310 which

lists boiler water additives that may be

safely used in the preparation of steam

that will contact food and the

conditions for the safe use of those

boiler water additives. This proposed

requirement is necessary because boiler

water additives dissolve in water and

can be carried over as a residue in the

steam. A proposed requirement that

boiler water additives in the steam

comply with § 173.310 will ensure that

any residue is safe to come in contact

with the infant formula.

Proposed § 106.20(i) requires that

each infant formula manufacturing site

provide its employees with readily

accessible toilet and hand washing

facilities. This proposed requirement is

consistent with good sanitary practice

common to all food-processing facilities

and is consistent with FDA’s CGMP

regulations for foods (§ 110.37(d) and

(e)) and drugs (§ 211.52). The

requirement is also a necessary adjunct

to the requirement in proposed

§ 106.10(b)(2) that employees wash their

hands before starting work, after each

absence from the work station, and at

any other time when the hands may

become soiled or contaminated. Handwashing facilities are not likely to be

used in an appropriate manner by

employees if the facilities are not

conveniently located.

Proposed § 106.20(i) also requires that

these facilities be equipped with hot

and cold water, ordinary soap or

detergent, and single-service towels to

ensure that microbiological

contamination does not occur through

the repeated use of the same towel by

several individuals.

In addition, proposed § 106.20(i)

requires that toilet facilities be

maintained in good repair and in a

sanitary condition at all times, and that

these facilities provide for proper

disposal of sewage, so that the

processing environment is protected

against pathogenic microorganisms shed

in fecal material. Restroom floors and

the grounds around the processing

facility can become contaminated with

pathogens if fecal material is not

removed by an adequate sewage system.

Foot traffic over the affected areas can

introduce pathogens into the processing

room and cause product contamination.

Insanitary toilet facilities can also

increase the potential for contamination

of employees’ hands and, ultimately, of

the product itself (Refs. 10 and 11).

Proposed § 106.20(i) further protects

against potential microbiological

contamination by setting forth

requirements for the positioning of toilet

facility doors.

5. Controls to Prevent Adulteration

Caused by Equipment or Utensils

Equipment used in infant formula

manufacture, packaging, or holding that

is of an inappropriate design or an

inadequate size, or that is installed

improperly, can result in a variety of

problems. For example, a mixer for the

blending of powdered ingredients will

not properly perform its function if the

blade is too small relative to the size of

the mixer, or if the mixer blade or auger

is not properly positioned in the inside

of the mixer. Such a mixer may produce

infant formula that is not uniform in

composition throughout a batch and

that is, consequently, adulterated

because the required nutrients are not

provided at the required levels

throughout the batch.

Installing equipment in a manner that

will facilitate its cleaning and

maintenance is also important in

preventing adulteration. Equipment that

is not properly cleaned can be the

source of contaminants that adulterate

the infant formula. Equipment that is

not properly maintained can result in a

variety of problems. For example,

improper maintenance of equipment

such as a mixer may result in

inadequate compositional uniformity in

a batch of formula. Improper

maintenance of equipment used to

measure a parameter such as

temperature may result in the

processing of the infant formula at a

temperature that can adversely affect the

product. In either case, the product

would be adulterated. Design and

installation of equipment also needs to

be checked when the equipment is

modified or repaired to ensure that the

equipment is still designed and

installed to function as intended as part

of the manufacturing process. Thus,

proposed § 106.30(a) requires that

equipment be appropriately designed

and installed. This proposed

requirement is consistent with FDA’s

CGMP regulations for foods (§ 110.40(a))

and drugs (§ 211.63).

If a food-contact surface is

constructed of toxic material, the

product may be directly contaminated

with that material (Ref. 11). Therefore,

FDA is proposing to require in

§ 106.30(b) that equipment and utensils

be made of materials that are not

reactive or absorptive, so that the

equipment and utensil materials do not

contaminate the infant formula and

cause it to be adulterated. Proposed

§ 106.30(b) also requires that such

equipment and utensils be designed to

be easily cleanable because they can be

vehicles for microbial contamination of

both raw and finished products.

Utensils, equipment, and other foodcontact surfaces that are made of

corrosive material, or that contain

breaks, pits, cuts, or grooves, are

difficult to clean because the pores and

crevices shield the microorganisms from

the action of cleaning and sanitizing

agents (Ref. 21). In addition proposed

§ 106.30(b) requires that equipment and

utensils be designed to withstand the

environment in which they are used.

This requirement will ensure that

equipment and utensils are constructed

of materials that will not corrode or

undergo other types of chemical or

physical degeneration resulting from

their use in infant formula production.

Degeneration of the equipment and

utensils may introduce contaminants

into the formula and thereby lead to

adulteration. Surfaces that are not

adequately cleaned and sanitized can be

a source of filth, an attractant for

vermin, and a reservoir for

microorganisms.

Proposed § 106.30(b) requires regular,

effective cleaning and sanitizing of all

food-contact surfaces to minimize the

probability of contamination of the

infant formula (Ref. 21) and prescribes

requirements for effective sanitizing

agents. An effective sanitizing agent is

one that has a good bactericidal effect

on the types of microorganisms

normally present in the plant

environment and that is safe, stable, and

convenient for use (Ref. 22). Sanitizing

agents are indirect food additives and

must be used in accordance with 21

CFR 178.1010, which prescribes their

conditions of safe use. Examples of

sanitizing agents that comply with

§ 178.1010 include hypochlorites,

iodophors, and quaternary ammonium

compounds. However, sanitizers can

achieve their intended effect only if they

are applied to a surface that has been

thoroughly cleaned, and if they are

applied at a proper concentration (Ref.

22).

Thus, it is important that effective

cleaning compounds be used. An

effective cleaning compound is one that

will lower the surface tension of water

so that spills can be lifted and flushed

away (Ref. 23). Ordinary soap has a

limited ability to solubilize fats, oils,

and proteins, and inorganic alkaline
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36163

detergents can dissolve food solids such

as fats and proteins, but mineral

deposits will frequently require the use

of acid cleaners (Ref. 23).

In order to ensure that infant formula

is not contaminated with unsafe

substances that are a part of the

manufacturing process, FDA is

proposing requirements in § 106.30(c)

regarding substances necessary for the

operation of equipment, such as

lubricants or coolants.

Proposed § 106.30(d)(1) sets forth

requirements for maintaining the

accuracy of instruments, since an

instrument that is not easily read, or

that is not properly calibrated, may not

provide accurate measurements. If an

instrument is not properly maintained,

it may not be reliable over time, and the

readings obtained from it may lead to

adulteration of the infant formula

during processing. This proposed

regulation also requires that such

instruments be sufficient in number for

their intended use. For example, if the

temperature of a large piece of

equipment needs to be monitored,

several temperature-indicating devices

may be needed to accurately monitor

the temperature in all parts of the

equipment. Also, instruments and

controls must be tested for accuracy

(i.e., calibrated) against a known

reference standard before first use and at

routine intervals thereafter, as specified

in writing by the manufacturer of the

instrument or control, or as otherwise

deemed necessary to ensure the

accuracy of the instrument. FDA has

tentatively concluded that this

requirement is necessary because

equipment used to manufacture infant

formula must operate properly to ensure

production of a safe, uniform product

with a consistent nutrient content

throughout a lot or a batch.

The accuracy of an instrument is the

degree to which it produces a correct

result. The instruments used to measure

parameters such as temperature or

pressure at points where control is

deemed necessary to prevent

adulteration must reflect the true

measurement so that, for example, a

manufacturer can have confidence that

when a thermometer indicates that the

temperature is 240 °F, the temperature

really is 240 °F. FDA’s experience is that

calibration of the instrument using a

reference standard is the most reliable

method to ensure accuracy. FDA is

proposing to require that this test for

accuracy be done before first use to

provide assurance that the instruments

and controls will perform as intended

and at routine intervals afterward to

ensure that the instruments and controls

continue to perform as intended.

Reliability is the instrument’s

accuracy over time. The reliability of the

instrument will determine the length of

time that it can be used before it begins

to lose accuracy. The manufacturer of

the instrument is in the best position to

establish how frequently recalibration is

needed because that manufacturer is

responsible for putting together the

technology by which the instrument

operates. However, if the infant formula

manufacturer’s experience with the

instrument demonstrates that the

instrument needs to be calibrated more

frequently than the instrument

manufacturer suggests, FDA has

tentatively concluded that the infant

formula manufacturer must act on its

own experience with the instrument

and calibrate it as often as necessary to

ensure the accuracy of the instrument.

Proposed § 106.30(d)(1) further

requires that the known reference

standard be certified for accuracy at

routine intervals specified in writing by

the manufacturer of the instrument, or

as otherwise deemed necessary. Known

reference standard devices are

accompanied by certificates of accuracy,

but these certificates do not preclude

the possibility that these instruments

will go out of calibration. Just as a

calibration routine needs to be

established for the process

instrumentation, a recertification of the

known reference standard needs to be

established in accordance with the

equipment manufacturer’s

recommendations. For example, the

length of time that a certified

thermometer can be considered reliable

will depend on the materials used in its

manufacture, the degree of control

exercised in its manufacture, and its

use, as would be the case for the

indicating thermometer used in the

production line. The accuracy of a

calibrated thermometer is only going to

be as good as the accuracy of the known

reference standard that is used during

its calibration.

Proposed § 106.30(d)(1) also requires

that manufacturers make and retain

records of accuracy checks in

accordance with the provisions of

proposed § 106.100(f)(2). As discussed

below in the description of the proposed

revisions to subpart F of part 106, FDA

has authority to require these records

under section 412(b)(4)(A)(i) of the act.

These records will enable the

manufacturer to establish the historical

performance of the instrument to

determine whether the calibration

schedule is sufficient to ensure the

accuracy of the instrument and will

provide information on when and how

the instruments were calibrated to assist

the manufacturer in identifying the

cause of a problem that may arise with

a batch of infant formula.

Proposed § 106.30(d)(2) requires that

instruments and controls that cannot be

adjusted to agree with the reference

standard be repaired or replaced. FDA is

proposing this requirement because an

instrument or control cannot be trusted

for use in infant formula production if

it cannot be adjusted to agree with the

reference standard. Adjustments made

to reach agreement with a known

accurate or reference standard must also

be done in accordance with any

adjustment range limitations specified

by the vender of the instrument.

Proposed § 106.30(d)(3) provides that

if calibration of an instrument (testing

for accuracy against a known reference

standard) shows that a specification or

standard has not been met at a point

where control is deemed necessary to

prevent adulteration, a written

evaluation must be made of all affected

product and of any actions that need to

be taken. FDA has tentatively concluded

that this written evaluation is necessary

because if an instrument has been giving

inaccurate readings, all infant formula

produced subject to such inaccuracies

must be identified and evaluated for the

possibility that the inaccuracies resulted

in the production of adulterated

formula. If the manufacturer determines

that adulterated formula has been

produced, the firm must decide what

actions, if any, need to be taken to

prevent such formula from reaching

infants.

FDA is also requiring that this written

evaluation needs to be maintained in

the firm’s records. FDA tentatively

concludes that this record is necessary

to demonstrate that the firm has

complied with CGMP. As discussed

below in the description of the proposed

revisions to subpart F of part 106, FDA

has authority to require that these

records be retained under section

412(b)(4)(A)(i) of the act.

Proposed § 106.30(e)(1) requires that

the temperature in cold storage

compartments used to store raw

materials, in-process materials, or final

product, as well as the temperature of

thermal processing equipment used at

points where temperature control is

necessary to prevent adulteration, be

monitored with such frequency as is

necessary to ensure that temperature

control is maintained. The frequency of

the monitoring is left to the

manufacturer to determine. Growth of

microorganisms can occur and cause

spoilage if materials that should be kept

in cold storage compartments are not

maintained at the proper temperature.

Infant formula may also be adulterated

if thermal processing equipment is not
36164 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

operated at the proper temperature, and

the final liquid infant formula product

is not commercially sterile. Therefore,

FDA tentatively concludes that their

requirement is appropriate.

In addition, FDA is proposing that a

temperature of 40 °F (4.4 °C) is

appropriate in cold storage

compartments to minimize the growth

of pathogens (Ref. 24) and the

deterioration of liquid ingredients,

nutrients, and the formulated product

before canning (proposed

§ 106.30(e)(2)).

Proposed § 106.30(e)(3)(i) requires

that cold storage compartments and

thermal processing equipment be

equipped with easily readable, accurate

temperature-indicating devices. These

devices are necessary to ensure that the

manufacturer can monitor the

temperatures where materials are stored

or where product is processed. Proposed

§ 106.30(e)(3)(ii) requires that thermal

processing equipment be equipped with

temperature-recording devices that

reflect the true temperature on a

continuing basis, so that the

manufacturer will be able to determine

whether the product was thermally

processed at a minimum temperature for

an appropriate period of time. Two

factors, temperature and time, are

relevant in ensuring that thermal

processing is conducted in a manner

that will produce commercially sterile

infant formula after retorting. Thus,

recording the temperature that is

maintained during the time period used

will show whether the thermal process

is conducted properly.

Proposed § 106.30(e)(3)(ii) also

requires that cold storage compartments

be equipped with either a temperaturerecording device that will reflect the

true temperature within the

compartment on a continuing basis, or

a high-temperature alarm or a

maximum-indicating thermometer that

has been verified to function properly.

These temperature records will show

whether the materials were stored at an

appropriate temperature to minimize

the growth of pathogens and the

deterioration of ingredients and

formulated product. If the manufacturer

does not wish to equip cold storage

compartments with such temperaturerecording devices, FDA is proposing to

require that it maintain a temperature

log in which the temperature in the

compartment is noted with such

frequency as is necessary to achieve

control. The agency is leaving it to the

manufacturer’s discretion to determine

what frequency of temperature notation

is necessary to achieve control.

The agency has tentatively concluded

that it is not necessary for the

manufacturer to record the temperature

of the cold storage compartment on a

continuous basis as long as the

manufacturer can determine that the

temperature of the cold storage

compartment has gone above 40 °F. A

high-temperature alarm set to go off

when the cold storage compartment

goes above 40 °F will allow the

manufacturer to make this

determination. Likewise, a maximumindicating thermometer will remain at

the highest temperature that it ever

reaches. If the maximum indicating

thermometer indicates a temperature

above 40 °F, the infant formula

manufacturer must assume that the

temperature has been above 40 °F since

the last check of the thermometer. Thus,

FDA has tentatively concluded that

either a high-temperature alarm or a

maximum-indicating thermometer are

acceptable alternatives for determining

whether the cold storage compartment

has gone above 40 °F.

In some cases, the actual location of

the sensors may be an important factor

in ensuring the accurate representation

of temperature. For example, one sensor

located at the end of a large piece of

thermal processing equipment may not

accurately represent the temperature in

the whole piece of equipment. In

addition, these temperature devices

must often be read under less than ideal

plant conditions, so they should be

installed in a location that facilitates

easy reading. Temperature-recording

devices can be easily jarred and

rendered inaccurate. They can be

recalibrated against a reference

temperature-indicating device (e.g., a

thermometer) quite easily, however.

Manufacturers should do so at least at

the beginning and end of each

production day in order to determine

whether the instrument was accurate

throughout the day’s production. For

thermal processing equipment used to

produce commercially sterile liquid

infant formula, the mandatory and

recommended procedures of 21 CFR

part 113 apply.

FDA is also proposing that

manufacturers make and retain records,

in accordance with the provisions of

proposed § 106.100(f)(3), of the

temperatures indicated or recorded by

these devices (see § 106.30(e)(3)). As

discussed below in the description of

the proposed revisions to subpart F of

part 106, FDA has authority to require

these records under section

412(b)(4)(A)(i) of the act. They are

needed to show that the thermal

processing equipment or cold storage

compartments are being maintained at

the correct temperatures to prevent

adulteration of the product. They also

will enable the manufacturer to identify

trends in temperature fluctuations that

can signal the need to perform

nonscheduled maintenance.

Proposed § 106.30(e)(4) requires that

for thermal processing, the temperaturerecording device not read higher than

the calibrated temperature-indicating

device because it is important to ensure

that the infant formula is processed at

a minimum temperature for a continual

period of time. A temperature-recording

device reading higher than the reference

temperature-indicating device for

thermal processing equipment would

show that the product had been

processed at a temperature higher than

the true processing temperature.

Because thermal processing is used to

destroy microorganisms, a temperaturerecording device reading higher than the

true processing temperature may mean

that the product has not been processed

at a temperature that is high enough to

destroy all microorganisms.

For cold storage compartments, the

temperature-recording device must not

read lower than the temperatureindicating device because when raw

materials, in-process materials, or

finished product must be stored at a

cold temperature, it is important to

ensure that the infant formula was not

exposed to a temperature above the

maximum temperature. A temperaturerecording device reading lower than the

reference temperature-indicating device

for cold storage equipment would show

the materials in the compartment as

having been held at a lower temperature

than the true temperature. Because cold

storage is used to prevent

microbiological growth, a temperaturerecording device reading lower than the

reference temperature-indicating device

would mean that the material was

actually being stored at a higher

temperature than the recorded

temperature, and that, as a result,

microbial growth may have occurred.

Proposed § 106.30(f) requires that all

equipment and utensils used in the

manufacture of infant formula be

cleaned, sanitized, and maintained at

regular intervals to prevent adulteration

of the infant formula. Any equipment or

utensil that is not cleaned and

maintained properly can be a source of

contamination. FDA is therefore

proposing to require that cleaning,

sanitizing, and maintaining be done at

regular intervals. The details of

sanitation procedures e.g., equipment

cleaning, can differ from plant to plant

depending upon the type of operation

and other conditions. In one plant, it

may be necessary to disassemble all or

part of the equipment to clean it. In

other plants, breaking down the
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36165

1 ISO is a world-wide federation of national

standards bodies that set quality assurance

guidelines for products that will enter international

commerce. The ISO defines software as an

‘‘intellectual creation comprising the programs,

procedures, rules and any associated

documentation pertaining to the operation of a data

processing system’’ (Ref. 26).

2 IEEE is a trade organization comprised of several

societies. IEEE standards are developed within the

technical committees of the IEEE societies and

represent a consensus opinion of experts from

within IEEE as well as experts who are not members

of IEEE. IEEE defines software as ‘‘computer

programs, procedures, and possibly associated

documentation and data pertaining to the operation

of a computer system’’ (Ref. 27).

equipment may not be necessary.

Likewise, different cleaning compounds

may be needed from one plant to

another to solve specialized problems

such as buildups of mineral deposits.

Each manufacturer should study its own

plant and develop a procedure that is

tailored to that plant’s needs and

circumstances.

FDA considers that cleaning,

sanitizing, and maintaining equipment

and utensils is so important for ensuring

that adulterated infant formula is not

produced that it is proposing to require

that the cleaning, sanitizing, and

maintenance be checked for satisfactory

completion by an individual qualified to

conduct such a review. Such an

individual will understand the

importance of ensuring that cleaning,

sanitizing, and maintenance is properly

done, so that equipment and utensils do

not contribute to the adulteration of the

infant formula. Also, the agency has

tentatively concluded that this

requirement will ensure that there is

accountability for proper performance of

this function.

In addition, proposed § 106.30(f)

requires that manufacturers make and

retain records on equipment cleaning,

sanitizing, and maintenance in

accordance with proposed

§ 106.100(f)(4). As discussed below in

the description of the proposed

revisions to subpart F, FDA has

authority to require these records under

section 412(b)(4)(A)(i) of the act. These

records will document when the

cleaning, sanitizing, and maintenance of

equipment occurs and will allow the

manufacturer to trace all formula that

may be affected if cleaning, sanitizing,

or maintenance is not properly

performed.

In order to ensure that compressed air

or other gases will not contaminate the

infant formula with unlawful indirect

food additives or other chemical,

physical, or microbiological

contaminants, FDA is proposing to

require in § 106.30(g) that they be

appropriately treated. Air or other gases

that are not properly treated and

filtered, or air that is not of the proper

purity, can introduce contaminants into

the infant formula that may render it

adulterated. Also, compressed gases can

be contaminated with oil from the

compressor or with filth or

microbiological contaminants from the

compression, storage, or distribution

equipment. Filtration at the air intake

and after compression, storage, and

distribution is an effective means of

reducing the risk that such

contaminants will enter the gases and,

thereby, the food. Therefore, FDA is also

proposing in § 106.30(g) to require the

use of a filter when compressed gases

are used at product filling machines to

replace air removed from the headspace

of containers. The filter will prevent

contaminants from entering the infant

formula during that operation (Ref. 25).

6. Controls to Prevent Adulteration Due

to Automatic (Mechanical or Electronic)

Equipment

Manufacturers of infant formula are

increasingly relying on automatic

equipment (including mechanical and

electronic equipment) in production

and quality control. In some cases,

manufacturers are replacing manually

initiated processing procedures with

automated process control systems to

ensure proper formulation (addition of

ingredients and premixes), mixing, or

processing of an infant formula or to test

a batch of infant formula. Such

automated process control systems

frequently consist of a computer or

system of computers that controls many

or all stages of production, in-process

sampling, and testing. In other cases,

manufacturers are relying on

programmable equipment (such as an

autoanalyzer) to perform a critical

function, such as testing a batch of

infant formula to ensure that the batch

meets the nutrient requirements of the

act. In all cases, it is important that such

systems and equipment function as

expected to ensure that the infant

formula contains the required nutrients

at the required levels and is

manufactured according to the CGMP

and quality control procedures

prescribed under section 412(b)(2) of the

act and therefore is not adulterated

under section 412(a)(1) or (a)(3) of the

act.

FDA is proposing to define

‘‘hardware,’’ ‘‘software,’’ ‘‘system,’’ and

‘‘validation’’ in § 106.35 because the use

of these terms will simplify the language

of the proposed regulations and will

clarify which sections of the proposed

regulations apply to hardware only, to

software only, or to systems consisting

of both hardware and software.

The definition of ‘‘hardware’’ in

proposed § 106.35(a)(1) is based on

common usage of the term and makes

clear that the regulations in proposed

§ 106.35 apply to all automatic

equipment, whether the equipment is

mechanical or electronic in nature.

Proposed § 106.35(a)(1) also makes clear

that electronic equipment includes, but

is not limited to, computers. This

definition of ‘‘hardware’’ distinguishes

those elements of equipment that have

a physical form from the elements

considered to be intellectual property

that may be encoded on a physical

element such as a diskette, tape, or

microprocessing chip.

Software may be developed by an

infant formula manufacturer, by a

manufacturer of equipment purchased

by the infant formula manufacturer, or

by a third party vendor (such as the

vendor of a computer operating system).

The definition of ‘‘software’’ in

proposed § 106.35(a)(2) derives from the

ISO International Guideline ISO–9000–

3 1 (Ref. 26) and the Institute for

Electrical and Electronics Engineers,

Inc. (IEEE) Standard 610–12–1990 2 (Ref.

27) and is consistent with the definition

of software in FDA’s ‘‘Glossary of

Computerized Systems and Software

Development Terminology (Ref. 28).

FDA is proposing to incorporate this

definition into the agency’s infant

formula regulations because the

definition is derived from

internationally accepted definitions,

includes documentation, applies to the

operation of all types of hardware

(rather than the narrowly defined ‘‘data

processing system’’ or ‘‘computer

system’’ included in the definitions

from the ISO and IEEE, respectively),

and is consistent with current FDA

terminology. Software documentation

consists of the instructions on how to

use the software. FDA has tentatively

concluded that such instructions need

to be included in the definition of

‘‘software’’ to ensure the proper

operation of the software.

The definition of ‘‘system’’ in

proposed § 106.35(a)(3) derives from the

IEEE Standard 610.12–1990 (Ref. 27).

FDA is proposing to incorporate this

definition because many of the

requirements in proposed § 106.35

cannot be related to software or

hardware alone but rather to systems in

which software is used in conjunction

with hardware. For example, testing

software under simulated conditions of

use may be beneficial during the early

and middle stages of software

development, but validation of the

software must be performed in

conjunction with the relevant hardware

in the operational environment it is
36166 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

intended to be used in. Therefore in

proposed § 106.35(b)(4), FDA is

proposing that all systems be validated

‘‘before their first use to manufacture

commercial product.’’

Proposed § 106.35(a)(4) defines

‘‘validation’’ as 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. It is important that a

process control system comply with

specified requirements each time it

operates. The proposed definition is

derived from the ISO International

Guideline ISO–9000–3, (which defines

‘‘validation’’ as ‘‘the process of

evaluating software to ensure

compliance with specified

requirements’’ (Ref. 26)); the IEEE

Standard 610.12–1990, which (defines it

as ‘‘the process of evaluating a system

or component during or at the end of the

development process to determine

whether it satisfies specified

requirements’’ (Ref. 27)); and FDA’s

‘‘Glossary of Computerized System and

Software Development Terminology,’’

which defines it as ‘‘establishing

documented evidence which provides a

high degree of assurance that a specific

process will consistently produce a

product meeting its predetermined

specifications and quality

characteristics’’ (Ref. 28). FDA is

proposing to incorporate these

definitions into its regulations because

they are applicable to the types of

systems used in infant formula

manufacture, are derived from

internationally accepted definitions, are

consistent with existing FDA

terminology, make clear that the process

of evaluation includes the complete

system (i.e., the hardware used in

conjunction with the software), and

include the concept of consistency.

Proposed § 106.35(b)(1) sets forth

requirements for designing, installing,

testing, and maintaining all systems so

that they function as intended. Some

systems may work properly only within

a narrow range of environmental

conditions, such as temperature and

humidity, and some might be

particularly sensitive to electromagnetic

interference. The actual conditions of

use of a system should be considered as

early as possible in its design and

development. Systems need to be

installed in a manner that takes into

account the inherent limitations of the

system, tested under conditions that

reflect actual conditions of use, and

properly maintained to ensure that they

continue to function as expected during

their lifetime.

Proposed § 106.35(b)(2) requires that

the manufacturer ensure that all

hardware is routinely calibrated,

inspected, and checked according to

written procedures. FDA has tentatively

concluded that this provision is

necessary to ensure that any infant

formula manufactured under the control

of automatic equipment meets the

requirements of the act and is

manufactured in a manner designed to

prevent adulteration. For example, a

batch of infant formula may lack the

required levels of nutrients if equipment

used for the automatic dispensing of a

nutrient premix is out of calibration or

has a clogged delivery line. The routine

calibration, inspection, and checking of

hardware will ensure that it continues

to perform as intended, and that its

operation will not result in a process

that deviates from established

specifications. The establishment of

written procedures for the calibration,

inspection, and checking of hardware

will ensure that these procedures are

performed consistently and in an

appropriate way.

The incorporation of software into the

operation of automatic equipment has

not only increased the complexity of

such equipment but also has resulted in

a process that may operate differently

for each execution because a softwarebased control system can be configured

at will by the operator or by the system

itself. Therefore, proposed

§ 106.35(b)(3), (b)(4), and (b)(5) require

that manufacturers exercise appropriate

controls over systems and, in particular,

over the software used in the systems.

Proposed § 106.35(b)(3) prescribes

procedures for ensuring that systems are

checked for input and output errors

resulting from faulty data entry, faulty

programming, or equipment

malfunction. Such errors can result in

serious production or quality control

errors leading to a contaminated or

adulterated infant formula. For example,

a faulty position sensor on a

downstream valve that improperly

indicates that it is closed may result in

a post-sterilization contamination. An

improperly installed (or empty) ink

cartridge in a color printer or multi-pen

recorder may cause portions of a record

to not be printed. FDA has tentatively

concluded that the regulation is

necessary to ensure that the infant

formula produced or analyzed using the

system is not adulterated. However,

proposed § 106.35(b)(3) also provides

that the degree and frequency of input/

output checks are to be based on the

complexity and reliability of the system

and the level of risk associated with the

safe operation of the system.

Proposed § 106.35(b)(4) requires that

manufacturers ensure that all systems

are validated before their first use to

manufacture commercial product. FDA

has tentatively concluded that it is

necessary that software programs that

are used in a process control system to

monitor and control established points

deemed necessary to prevent

adulteration (such as the speed of a

pump, temperature of a heat exchanger,

addition of vital nutrients, and air

overpressure in an aseptic storage tank)

be validated to ensure that use of the

process control system will produce

compliance with the specifications or

standards at each control point. For

example, if a continuous flow process is

designed to heat an in-process batch of

infant formula in a plate-to-plate heat

exchanger to a specification of 271 °F,

as indicated by the temperature at the

end of the hold tube, and the system is

mistakenly programmed to divert the

product to the raw (unsterilized) surge

tank only if the temperature drops

below 261 °F, an in-process batch of

infant formula heated to 261 °F would

not be diverted to the raw surge tank but

rather would be handled by the

computer as if it were adequately

processed. Such an underprocessed

batch of infant formula would likely

pose a foodborne biological hazard.

Thus, FDA has tentatively concluded

that the validation required under

proposed § 106.35(b)(4) is necessary to

ensure that infant formula that is

produced or analyzed using the system

is not adulterated.

The validation of software ordinarily

includes the following elements:

Requirements development, design,

coding, debugging, testing (with the

hardware), and maintenance (Refs. 29,

30, and 31). Software validation also

includes a review for correctness of the

software documentation to ensure that

the instructions prompt the input of the

proper commands or data by the user.

However, depending on the nature of

the software and the hardware that it

controls, some or all of these aspects of

the validation process may be done by

the infant formula manufacturer, by the

manufacturer of equipment that is

purchased by the infant formula

manufacturer, or by a third party

vendor.

Proposed § 106.35(b)(4) leaves the

identity of the person that does the

validation to the discretion of the infant

formula manufacturer but makes clear

that the infant formula manufacturer is

responsible for ensuring that the system

is validated. The proposal does not

stipulate any standards or specifications

for the validation process because the

extent of the validation necessary is
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36167

related to the level of risk that each

component of the system presents.

More emphasis should be placed on

validating portions of the system that

represent major risk than on those that

confer moderate or minor risk. A major

risk is associated with systems that

control or monitor a point where such

control or monitoring is deemed

necessary to prevent adulteration of the

infant formula; for example, systems

that control or monitor nutrient addition

or processing temperature present a

major risk. A moderate risk is associated

with systems that influence, but that do

not control or monitor, a point where

control or monitoring is deemed

necessary to prevent adulteration of the

infant formula. For example, the speed

of computer processing presents a

moderate risk if software that is

designed to be used on a high-speed

computer is used on a slower computer.

A minor risk is associated with systems

that do not involve a point where

control or monitoring is deemed

necessary to prevent adulteration. For

example, systems that control pallet

stacking or product conveying present a

low risk.

Proposed § 106.35(b)(5) requires that

any system that is modified be

revalidated after any modification and

before use of the modified system to

manufacture commercial product. FDA

has tentatively concluded that

revalidation is necessary to ensure that

no errors are introduced into the system

during the modification and to ensure

that a modification in one aspect of a

process control system does not,

unknowingly but adversely, affect other

aspects of the process control system,

particularly those operations that follow

the modified aspect of the system.

Under § 106.35(b)(5), FDA is also

proposing that a specific individual (or

group of individuals) is designated to

modify software to prevent the

indiscriminate modification of software

and to ensure that all modifications are

made consistently. The designated

individual may be employed by the

infant formula manufacturer, the

manufacturer of equipment purchased

by the infant formula manufacturer, or

by a third party. The regulation states,

however, that the infant formula

manufacturer is responsible for ensuring

that modified software is retested or

revalidated regardless of who does the

modification.

Proposed § 106.35(c)requires that

infant formula manufacturers make and

retain records concerning automatic

(mechanical or electronic) equipment.

FDA is proposing this requirement

under the authority of section

412(b)(4)(A)(i) of the act, which requires

the retention of all records necessary to

demonstrate compliance with the CGMP

and quality control procedures

prescribed under section 412(b)(2) of the

act, including the results of all testing

required under section 412(b)(2)(B) of

the act. These records will allow

manufacturers to readily determine

whether this crucial equipment is being

appropriately operated and maintained.

They will allow manufacturers to

troubleshoot and to operate these

systems with a minimum of downtime

when problems occur because the

records will include a copy of all

software used and a backup file of data

entered into the computer or related

system which can be used to reload the

system. The records will also provide

information that the manufacturer can

use in trying to determine why a

problem with the system is occurring or

why the system is not producing an

infant formula that complies with the

manufacturer’s specifications for the

product.

7. Controls to Prevent Adulteration

Caused by Ingredients, Containers, and

Closures

Proposed § 106.40(a) specifies that the

only substances that may be used in

infant formulas are food ingredients that

are generally recognized as safe (GRAS)

for use in infant formula, that are used

in accordance with the agency’s food

additive regulations, or that are

authorized by a prior sanction issued by

FDA. Under section 412(b)(2)(A) of the

act, FDA is to establish CGMP’s that it

determines are necessary to ensure that

the infant formula is manufactured in a

way that is designed to prevent

adulteration of the formula. Unless the

safety of the ingredients of an infant

formula has been established, the

formula is adulterated under section

402(a)(1) and (a)(2)(C) of the act. Thus,

the agency has tentatively concluded

that CGMP requires that the

manufacturer ensure that the

ingredients that it uses in its formula are

safe and suitable.

Proposed § 106.40(b) requires that

infant formula containers and closures

not be reactive or absorptive so as to

affect the safety of the infant formula,

and that all packaging material that

comes in contact with an infant formula

be composed of authorized substances

and be used in accordance with any

prescribed limitations. Various

regulations that authorize the use of a

material in contact with the food

product also set conditions and

limitations on that use. Thus, the agency

proposes to require that the

manufacturer not only use only

materials specified in proposed

§ 106.40(b), but also that the materials

be used as specified in the regulations

authorizing their use. This provision

will ensure that the food contact surface

of containers and closures will not

adulterate the infant formula.

In order for the manufacturer to

maintain a complete record of how each

ingredient, container, or closure was

used and to determine which lots of

infant formula are adulterated if a

problem is ultimately identified with a

particular lot of ingredients, containers,

or closures, FDA is proposing, in

§ 106.40(c), that they be identified with

batch or lot numbers. This batch or lot

number can be used to identify

ingredients, containers, or closures that

have been released for use in infant

formula or rejected for use in infant

formula manufacture. It also can be used

to track the ingredients, containers, or

closures that were used in the

manufacture of each batch of infant

formula.

Proposed § 106.40(d) requires that

infant formula manufacturers develop

written specifications that stipulate the

standards for acceptance or rejection of

ingredients, containers, and closures.

Stipulating the standards for acceptance

or rejection of ingredients used to

supply nutrients is important to ensure

that all the required nutrients are

present in the formula at the required

levels. For example, the level of

endogenous nutrients that a

manufacturer expects will be supplied

by an ingredient should be stipulated as

a standard for acceptance or rejection of

that ingredient. Endogenous nutrients

are nutrients provided as a part of other

nutrients, such as minerals provided as

a part of the protein source. Sodium, for

example, is frequently provided as part

of the protein ingredient ‘‘caseinate.’’

To ensure that the mineral is provided

in the infant formula at at least the

minimal level, and not above the

maximum level, required by § 107.100,

the infant formula manufacturer must

know what amount of a mineral is

provided to the formula by all

ingredients that are sources of the

mineral. Thus, a standard for the level

of the endogenous nutrient that is to be

provided by an ingredient is an

appropriate specification for the

manufacturer to develop. If the level of

the mineral is too high in the ingredient,

it may cause the formula to exceed the

maximum established in § 107.100.

Similarly, if the level is too low, the

formula may not meet the required

minimal level.

Developing standards for acceptance

or rejection of ingredients used in infant

formula manufacture is also important

to ensure that contaminants in the
36168 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

ingredients that may lead to

adulteration of the product are not

present in the formula. Examples of

contaminants that may lead to

adulteration of an infant formula

include certain heavy metals, such as

lead. Infant formula manufacturers are

currently setting standards for the lead

in the ingredients that they use in infant

formula to ensure that the lead level in

infant formulas is at or below the

quantification limit of the method used

for lead determination (Ref. 32).

Stipulating the standards for

acceptance or rejection of containers or

closures used in infant formula

manufacture is important to ensure that

the integrity of the container and of the

closure is maintained to prevent leakage

of the formula and to prevent an infant

formula from becoming adulterated,

which can occur if the container or

closure is not impenetrable to air (which

can cause nutrient degradation), or if the

container or closure allows outside

contaminants to get into the infant

formula.

Proposed § 106.40(d) also requires

that manufacturers establish written

specifications that stipulate the

procedures for determining whether the

ingredients, containers, and closures

meet the standards. Examples of

procedures manufacturers may use to

determine whether they meet the

standards are acceptance of a supplier’s

guarantee or certification and testing

conducted by the infant formula

manufacturer. In some cases,

manufacturers must conduct their own

testing to ensure that the standards for

acceptance or rejection of the ingredient

are met. For example, section

412(b)(3)(B) of the act requires that

manufacturers test each nutrient premix

for each relied-upon nutrient to ensure

that the premix complies with its

specifications or certifications by a

premix supplier, but the act does not

require testing of individual nutrient

ingredients when such nutrients are not

supplied as a nutrient premix. However,

a manufacturer may find through

experience that the best way to ensure

that the final product will meet all

specifications is to test certain nutrient

ingredients for identity, purity, and

potency before using them in the infant

formula.

In addition, manufacturers should

have controls in place to ensure that any

ingredients, containers, or closures that

do not meet any of their specifications

are not used in production of a batch of

infant formula. However, if these

controls fail, and any such ingredients,

containers, or closures are used in a

batch of formula, FDA is proposing

under § 106.40(d) that an individual

qualified by training or experience

conduct an investigation to ensure that

the failure does not lead to release into

the marketplace of an adulterated

product.

Proposed § 106.40(e) requires that

ingredients, containers, and closures be

stored in areas clearly designated for

materials pending release for use,

materials released for use, or materials

rejected for use in infant formula

production in order to prevent mixups

in using materials that are inappropriate

for infant formula manufacturing. FDA

is further proposing to require that any

lot of ingredients, containers, or

closures that does not meet the

manufacturer’s specifications be

rejected and controlled under a

quarantine system designed to prevent

its use in the manufacture of infant

formula. Failure to protect against the

use of these materials would

significantly increase the likelihood that

an adulterated product will be

produced.

Some ingredients used in infant

formula are vulnerable to degradation

when they are exposed to heat or air.

Moreover, containers or closures may be

exposed to air containing dust and dirt

and become contaminated. Thus, the

ingredients, containers, and closures

may need to be reexamined after they

are exposed to air, heat, or other

conditions that may adversely affect

them to ensure that they still meet the

manufacturer’s specifications. Thus,

FDA is proposing, in § 106.40(f), to

require retesting or reexamination after

approved materials have been exposed

to conditions that may adversely affect

them.

Proposed § 106.40(g) requires that

manufacturers make and retain records

on ingredients, containers, and closures

used in the manufacture of infant

formula so that if adulteration of

formula occurs, the manufacturer will

be able to determine the source of the

material, so that its use can be halted.

In addition, the records will show the

basis on which each ingredient,

container, and closure was released for

use in infant formula production, if

questions about such release later arise.

FDA has authority to require these

records, under section 412(b)(4)(A)(i) of

the act.

8. Controls to Prevent Adulteration

During Manufacturing

The infant formula manufacturing

process involves a number of

complicated processes that may cause

adulterated formula to be produced if

the processes are not properly

conducted or monitored. Therefore,

FDA is proposing, under section

§ 106.50, to require that manufacturers

establish controls to minimize the risk

that manufacturing process errors will

produce an adulterated or unsafe

formula. The proposed requirements

reflect many of the practices currently

used by infant formula manufacturers

and manufacturers of other commodities

that require strict production controls to

prevent product adulteration (e.g., Ref. 9

and 21 CFR 211.100 through 211.115).

Proposed § 106.50(a)(1) carries

forward and amends the requirement in

current § 106.25(a) that a master

manufacturing order be prepared and

followed. A master manufacturing order

is necessary to ensure that the

manufacturer will produce each batch of

a particular infant formula the same

way. If the master manufacturing order

is not followed, all necessary

ingredients may not be added to the

formula in the appropriate

concentrations and in the appropriate

manner.

FDA is also proposing that

manufacturers make and retain records

that include complete information

relating to the production and control of

the batch at the time each

manufacturing operation is performed

(see proposed § 106.50(a)(2)). This

proposed requirement will ensure that

the complete history of each batch of

infant formula is available for review in

the event that a problem arises with a

particular batch.

Proposed § 106.50(a)(2) also requires

that an individual qualified by training

or experience conduct an investigation

of any deviations from the master

manufacturing order and any corrective

actions taken. This investigation is

necessary to ensure that any deviations

from the master manufacturing order do

not lead to an adulterated product.

If any changes are made to the master

manufacturing order, proposed

§ 106.50(a)(3) requires that they 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. This process

is necessary to prevent unintended

adverse effects that could result from

changes to the master manufacturing

order made by persons not qualified to

assess their impact. The production of

infant formula is a sophisticated

process, and all organizational units that

are involved in critical formulation and

production steps, such as production,

engineering, research, and regulatory

affairs, should review and approve

changes to the master manufacturing

order. FDA has tentatively concluded,

however, that all changes to the master

manufacturing order need to be
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36169

reviewed by at least one responsible

official, and that this official will need

to evaluate how the change will affect

the nutrient content and the suitability

of the product for infants, to ensure that

the infant formula is not adulterated.

A significant change in the master

manufacturing order without proper

approval may result in the production of

an infant formula that lacks a required

nutrient or that is not manufactured in

an appropriate way. For example,

homogenization of an infant formula is

done to ensure a uniform dispersion

throughout the formula of the lipid

ingredients as well as the fat-soluble

nutrients. If the master manufacturing

order were changed, and the

homogenization process done before the

fat source was added, the fat-soluble

nutrients would not be uniformly

dispersed in the formula, and the

formula would be adulterated. The

system of review and approval required

by proposed § 106.50(a)(3) will

minimize the possibility that a

significant change could result in an

adulterated product.

In order to ensure that the appropriate

ingredients are added during the

manufacturing process, and that the

formula contains all of the nutrients

required by § 107.100 and therefore is

not adulterated, FDA is proposing in

§ 106.50(b) that each raw or in-process

ingredient required by the master

manufacturing order be examined by

one person and checked by a second

person or system. This requirement will

ensure that there will be a check to

prevent mixups in the use of ingredients

and to prevent the use of unapproved

ingredients. Confirmation that the

master manufacturing order is being

followed, and that ingredients are being

properly added, is particularly

important because these matters are

fundamental to ensuring that the

formula is manufactured correctly, and

that it contains the nutrients required by

§ 107.100 but not unapproved

ingredients that might adulterate the

formula.

In proposed § 106.50(c), FDA is

requiring the identification of all

compounding and storage containers,

processing lines, and major equipment

used during the production of a batch of

infant formula. Identification of these

items will enable the manufacturer to

accurately determine the status of all

batches of infant formula during all

stages of the manufacturing process,

will help to prevent mixups in the

addition of ingredients to the formula,

and will facilitate prompt action by the

manufacturer if any problems in

processing are identified. For example,

identifying that a particular storage

container contains a batch of formula

that has not yet had all ingredients

added to it will prevent a manufacturer

from inadvertently final-stage packaging

the product and thus will help to ensure

that adulterated product is not

introduced into interstate commerce.

The presence of the lot or batch number

will help to identify the product if a

problem does occur.

Proposed § 106.50(d) requires that

manufacturers establish controls to

ensure that required nutrient levels are

maintained in the formula, and that the

formula is not contaminated with

microorganisms or other contaminants

and thereby adulterated. In addition, the

agency is proposing to require

establishment of controls for mixing

time, 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. These

parameters are determined by the

manufacturer according to its

experience and knowledge of what will

result in a homogeneous, safe, and

uniform product. It is essential that

controls be established for each of these

parameters, or the likelihood that there

will be inconsistencies in production

from batch to batch will be greatly

increased. For example, if processing

temperatures are not specified, the

formula could be processed at high

temperatures that can destroy vitamins

or other essential nutrients, resulting in

a product that is adulterated because it

does not meet the nutrient requirements

specified in section 412(i) of the act.

Similarly, without established

procedures for mixing time and speed,

the product may be produced using

processing parameters that will not

result in formula that is uniformly

mixed and thus does not contain all

nutrients at the required levels.

FDA is proposing to require that

manufacturers establish controls for the

spray-drying process for powdered

infant formula to prevent microbial and

other contamination (§ 106.50(d)(2)).

Although spray drying involves a heat

treatment, the temperature is not

sufficient to sterilize the formula.

Consequently, powdered infant

formulas are vulnerable to microbial

contamination during the spray-drying

process. Even if the equipment and the

formula are free of microbial and other

forms of contamination initially, the

spray-drying process may permit

contamination of the product as a result

of dust or other air-borne gross

particulates in the intake air. Thus, FDA

has tentatively concluded that it is

important that the manufacturer

establish controls for the spray-drying

process that will ensure that the

powdered formula does not become

contaminated with microorganisms or

other contaminants.

The controls that manufacturers

should consider include: (1) Using

equipment constructed to ensure that

static accumulation of particulate matter

is controlled; (2) using and maintaining

equipment constructed to protect the

product from dust and environmental

contamination; (3) controlling

condensation, moisture, and

temperature conditions throughout the

plant to prevent Salmonella and Listeria

growth in static materials; (4)

controlling condenser cooling water to

prevent potential Salmonella and other

bacterial contamination; (5) controlling

sampling and cleanout ports on the

evaporator for buildup of static material

and avenues for airborne contaminants;

and (6) controlling product flow through

the plant to prevent unnecessary

product movement between areas that

may increase the likelihood of crosscontamination.

As stated above, contaminants may

enter the product in the air introduced

into the spray-drying equipment during

the spray- drying process. Air can

contain free microorganisms or

particulate material that is contaminated

with microorganisms. Controls to

prevent microbial contamination of the

formula by airborne sources must

address not only the presence of

microorganisms themselves but also the

sources of dust, moisture, and other

airborne contaminants that may be

sources of microbial contamination.

Therefore, proposed § 106.50(d)(2)

requires that manufacturers filter the

intake air before heating to remove dust

or other air-borne gross particulates that

can result in the production of

adulterated formula.

FDA is proposing to require that

manufacturers control the removal of air

from finished product containers

(proposed § 106.50(d)(3)) and ensure

that containers of finished products are

properly sealed (proposed

§ 106.50(d)(4)), that visible closure and

seal defects are detected (proposed

§ 106.50(d)(4)(i)), and that destructive

tests are performed to determine closure

strength (proposed § 106.50(d)(4)(ii)).

These requirements are necessary to

prevent oxidation and deterioration of

nutrients in the formula caused by air or

contaminants during the product’s shelf

life. FDA is also proposing that

equipment that is used to prevent

adulteration be monitored, either by

personnel or monitoring equipment, to

alert the manufacturer to malfunctions

(see § 106.50(e)). As a result of such

monitoring, the manufacturer will be
36170 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

able to minimize the amount of product

produced subject to a malfunction that

may develop and to take prompt

corrective actions.

In order to prevent rejected in-process

materials from being inadvertently

commingled with acceptable materials,

FDA is proposing that manufacturers

establish controls that ensure that the

rejected materials are clearly identified

and quarantined, and that reprocessed

materials will not produce adulterated

formula (see § 106.50(f)).

9. Controls to Prevent Adulteration from

Microorganisms

An infant formula that is

contaminated with microorganisms

may, depending on the characteristics of

the microorganisms, raise a safety

concern that would cause the infant

formula to be adulterated under section

402(a)(1) of the act. For example, all

serotypes of the genus Salmonella can

cause illness (often gastrointestinal) in

infants and adults (Refs. 33 and 34) and

the infectious dose is low (Ref. 35).

Moreover, microorganisms that are

generally harmless in older children and

adults can cause serious bacterial

infections in infants because the

immune systems of infants are still

developing (Ref. 36). For example,

newborns and infants are susceptible to

infection with Listeria monocytogenes

that may cause severe illness or death

(Ref. 37) and, as in the case of

Salmonella, the infectious dose is

believed to be low (Ref. 38).

Likewise, Staphylococcus aureus is

harmful to infants because some strains

of this microorganism produce an

enterotoxin that causes acute

gastrointestinal illness (nausea,

vomiting, cramps) soon after the food is

ingested (Ref. 39). Bacillus cereus can

produce diarrhea and vomiting in adult

humans (Ref. 40) when food

contaminated with at least 105 B. cereus

cells is consumed. The infectious dose

of B. cereus for infants is not known;

however, as already noted, infants are

more susceptible to bacterial infections

than are healthy adults and older

children because the immune systems of

infants are not fully developed.

FDA has long held that health

concerns may arise due to the presence

of any detectable Salmonella, Listeria,

or S. aureus bacteria in infant formula

or due to levels of B. cereus that exceed

1,000 ‘‘colony forming units’’ (CFU’s)

per gram (g) of a powdered infant

formula. Such health concerns would

cause the agency to consider an infant

formula that is so contaminated to be

adulterated under section 402(a)(1) of

the act (see 54 FR 3783, Jan. 26, 1989,

and 56 FR 66566, Dec. 24, 1991).

Moreover, the presence of

microorganisms in an infant formula

reflects that the formula was prepared,

packed, or held under insanitary

conditions whereby it may have been

rendered injurious to health and

therefore is adulterated under sections

402(a)(4) and 412 of the act. For

example, the presence of Escherichia

coli in a sample of infant formula is an

indicator of fecal contamination,

implying that the infant formula has

been contaminated by manufacturing

practices conducted under insanitary

conditions and therefore is adulterated

under sections 402(a)(4) and 412 of the

act. In addition, consistent with the

standard adopted by the International

Commission on Microbiological

Specifications for Foods (ICMSF) of the

Food and Agricultural Organization of

the United Nations and the World

Health Organization (WHO) and based

on the results from FDA and Canadian

Surveys (Refs. 41, 42, and 43), an

aerobic plate count (APC) (i.e., the

number of microorganisms that will

grow under certain specified conditions)

that is greater than 10,000 CFU’s per g

of a powdered infant formula evidences

that the formula has been prepared,

packed, or held under insanitary

conditions.

Illnesses from the use of

microbiologically contaminated infant

formulas have occurred (Ref. 33).

Moreover, as recently as May 1993,

infant formula contaminated with

Salmonella bacteria was the subject of a

recall (Ref. 44). Thus, contamination of

infant formula with microorganisms of

public health significance is more than

a theoretical possibility. Therefore, FDA

has tentatively concluded that

manufacturers need to have in place

controls to ensure that formulas are not

microbiologically contaminated at levels

of public health significance, and that,

if they are, those formulas do not enter

interstate commerce. Proposed § 106.55

requires manufacturers to establish such

controls.

Proposed § 106.55(a) requires that

manufacturers of liquid infant formula

comply with the procedures specified in

part 113. These products are thermallyprocessed low-acid foods that are

packaged in hermetically sealed

containers that are heated to achieve

commercial sterility. Therefore, they are

appropriately subject to the

requirements of part 113.

Proposed § 106.55(b) requires that

manufacturers of powdered infant

formula 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

specified in proposed § 106.55(c). This

proposed requirement is necessary

because although powdered infant

formulas are heat treated during

processing, they are not thermally

processed to achieve commercial

sterility. Proposed § 106.55(b) requires

testing at the final product stage because

microbiological contamination can be

inadvertently introduced by ingredients

at any time during production or

through improper processing or holding

procedures (Ref. 45).

Proposed § 106.55(c) establishes that

any powdered infant formula that

contains any microorganism at levels

that exceed the microbiological quality

standards for that microorganism as

listed in this section will be deemed to

be adulterated under sections 402 and

412 of the act. Proposed § 106.55(c)

defines microbiological quality

standards as the maximum allowable

number of microorganisms present in 1

g of dry formula, expressed as CFU/g or

‘‘most probable number’’ (MPN)/g, and

herein designated the ‘‘M value’’ for the

specific microorganism.

The microorganisms for which FDA is

proposing M values are those that are of

known public health significance or that

are indicators that the formula have

been prepared, packed, or held under

insanitary conditions. The

microorganisms and each proposed M

value listed in proposed § 106.55(c) are

adapted from guidelines previously

published and discussed in the

proposed and final rules on infant

formula record and record retention

requirements (see 54 FR 3783, Jan. 26,

1989, and 56 FR 66566, Dec. 24, 1991,

respectively). The agency notes,

however, that microorganisms that must

be tested for in infant formula and the

proposed M values for each

microorganism listed in this proposed

rule represent minimum requirements

for the microbiological quality of an

infant formula based on standards and

methods currently available.

a. Aerobic plate count (APC).

Proposed § 106.55(c) establishes an APC

M value of 10,000 CFU/g as the

maximum level that is consistent with

sanitary conditions in the facility in

which a powdered infant formula is

produced. An APC M value greater than

the proposed standard indicates that the

formula was produced under insanitary

conditions whereby it may have been

rendered injurious to health and thus is

adulterated under sections 402(a)(4) and

412 of the act.

The APC is the number of

microorganisms that will grow on the

APC nutrient medium, incubated at 35

°C for 24 hours in air (Ref. 46).

‘‘Microorganisms’’ (as defined in
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36171

3The calculated MPN value of zero when no

tubes in any dilution produce a positive result is

a recent change that appears in the MPN tables of

the 8th ed. of the BAM. In previous editions of the

BAM, the calculated MPN value when no tubes in

any dilution produce a positive result was ‘‘less

than 3.’’

4The calculated MPN value of 3.01 when a single

tube in the greatest dilution produces a positive

result is a recent change that appears in the MPN

tables of the 8th ed. of the BAM. In previous

editions of the BAM, the calculated MPN value

when a single tube in the greatest dilution produces

a positive result was 3.

5The calculated MPN value of 3.05 when a single

tube in the middle dilution produces a positive

result is a recent change that appears in the MPN

tables of the 8th ed. of the BAM. In previous

editions of the BAM, the calculated MPN value

when a single tube in the middle dilution produces

a positive result was 3.

proposed § 106.3(k)) include yeasts,

molds, bacteria, and viruses. The APC

medium supports the growth of most

microorganisms, including yeasts,

molds, and all bacteria required to be

tested for under proposed § 106.55(c);

however, the APC medium does not

support the growth of viruses. The APC

count is expressed in CFU’s because

multiple microorganisms may adhere

together or attach to the same location

on an agar plate, and microbiologists

cannot determine whether one or

several individual microorganisms

initiated the colony that they detect

growing on the plate.

This M value for the APC proposed in

§ 106.55(c) is consistent with the

standard adopted by the ICMSF and the

WHO and the results from FDA and

Canadian Surveys (Refs. 41, 42, and 43).

The ICMSF based its standards on the

degree of health hazard the

microorganisms present and conditions

of use of the product (Ref. 41).

FDA has tentatively arrived at this

APC M value because the microbial

quality of products consumed by infants

is of primary concern (Ref. 43). When

infant formulas are produced under

good commercial processing, the

available evidence shows that the APC

will be below this M value (Refs. 42 and

43). The agency is notaware of adverse

events occurring in infants who

consumed products with an APC below

this M value.

b. Coliforms, fecal coliforms, and E.

coli. E. colli are bacteria, including some

strains that are pathogenic for infants,

that thrive in the human intestinal tract.

The presence of E. coli in a sample of

powdered infant formula is an indicator

that the infant formula has been

contaminated by manufacturing

practices conducted under insanitary

conditions and therefore is adulterated

under sections 402(a)(4) and 412 of the

act.

E. coli bacteria are a subset of a more

diverse group of bacteria known

collectively as fecal coliforms, which

also thrive in the human intestinal tract

and therefore are also indicators of fecal

contamination. Fecal coliforms are

destroyed by pasteurization, and the

presence of these microorganisms in a

pasteurized product evidences that

there has been post-process

contamination of the formula (Ref. 47).

Fecal coliforms in turn are a subset of

a still further diverse group of bacteria

known as coliforms, which include

bacteria that may or may not be

indicators of fecal contamination.

However, contamination with coliforms

is a reliable indicator of post-process

contamination of the formula, even if

the source of the contamination is not

fecal.

In previously issued guidelines, the

agency recommended that powdered

infant formulas be tested for the

presence of E. coli (54 FR 3783);

however, one comment on this

recommendation suggested that, to

allow greater flexibility and reduce the

cost for manufacturers, the

manufacturer should be given the

option of testing for coliforms, fecal

coliforms, or E. coli. Specific tests for

contamination with E. coli provide the

most definitive evidence of fecal

contamination, but tests for specific

bacteria are more cumbersome than

general tests for a group of bacteria such

as fecal coliforms. Similarly, general

tests for fecal coliforms are more

cumbersome than universal tests for an

even more diverse group of bacteria

such as coliforms.

The agency is proposing in § 106.55(c)

that manufacturers screen their samples

of powdered infant formula for evidence

of contamination with E. coli using

sequential tests for detecting and

enumerating coliforms and fecal

coliforms. Under the proposal,

manufacturers ordinarily would only

perform the simplest test (i.e., the test

for coliforms) using a test sample of the

infant formula. The results of the

coliform test determine whether the

manufacturer needs to followup with a

more specific test for fecal coliforms

using as the test sample cultured

bacteria prepared during the coliform

test. As discussed below, the agency is

not proposing that manufacturers

followup a positive result in the fecal

coliform test with a more specific test

for E. coli but rather is proposing that

a violative sample in the fecal coliforms

test will represent conclusive evidence

that the infant formula is adulterated.

The general test for coliforms is an

example of an MPN test. MPN counts

are estimates of the number of

organisms present in a sample. Methods

resulting in an MPN require inoculation

of multiple tubes of liquid culture

medium with multiple dilutions of the

sample. The method specified in FDA’s

Bacteriological Analytical Manual

(BAM) (Ref. 46) requires inoculation of

3 replicate tubes of culture medium

with each of 3 sample dilutions, for a

total of 9 tubes. The tubes contain

culture medium selective for the

microorganism of interest. After

appropriate incubation (time,

temperature, and atmosphere), each

tube is scored as positive or negative for

the presence of the organism. Examples

of a positive result include the presence

of growth, a biochemical color change,

and the production of gas.

A mathematical formula is used to

calculate the MPN of microorganisms

present based on the number of positive

tubes in each of the three separate

dilutions. Since the calculation in

question involves a repetitious process,

the mathematical formula used to

calculate the MPN has been employed

to create easy-to-use tables that are

available in the BAM and in other books

of statistical tables. Most tables present

both a value for the MPN and

confidence limits for that value. The

calculated table values for the MPN,

using BAM methods, are dependent on

the level of the dilution in which a

positive result is found. The following

table values are based on an inoculation

series of 0.1, 0.01 g, and 0.001 g (or mL)

of the infant formula. When no tubes in

any dilution produce a positive result,

the calculated MPN value is zero.3

When a single tube in the greatest

dilution (least concentrated) produces a

positive result, the calculated MPN

value is equal to 3.01.4 When a single

tube in the middle dilution produces a

positive result, the calculated MPN

value is equal to 3.05.5 In all other

situations in which there is a positive

result in at least one tube (including a

single positive tube in the lowest

dilution (greatest concentration)), the

calculated MPN value is greater than

3.05.

If no tubes in any dilution produce a

positive result in a test for bacterial

contamination of a powdered infant

formula (i.e., if the MPN is zero), such

contamination is unlikely. If a single

tube in any dilution produces a positive

result in a test for bacterial

contamination of the product, such

contamination is a possibility. However,

there are two situations in which a

single positive tube is generally

considered to reflect a false positive test

result: (1) When no tube in the lowest

dilution (greatest concentration)

produces a positive result, but a single

tube in the middle dilution produces a
36172 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

positive result (i.e., the calculated MPN

value is equal to 3.01); or (2) when no

tube in the lowest dilution produces a

positive result, but a single tube in the

greatest dilution (least concentration)

produces a positive result (i.e., the

calculated MPN value is equal to 3.05).

FDA considers that if a sample of a

powdered infant formula produces

positive test results that reflect one of

these two situations, bacterial

contamination also is unlikely.

However, in all other situations (e.g.,

if a single tube in the lowest dilution

(greatest concentration) produces a

positive result, or if two or more tubes

in any dilution produce a positive

result), bacterial contamination of a

powdered infant formula is likely.

Therefore, when the calculated MPN

value in a test for bacterial

contamination is greater than 3.05, that

is if a sample of powdered infant

formula produces positive test results in

which a single tube in the lowest

dilution produces a positive result or in

which two or more tubes in any dilution

produce a positive result, the powdered

infant formula likely is contaminated

with bacteria.

FDA is proposing to use the

calculated MPN values in the BAM as

a means of setting a numerical

specification because these tables are

generally available, represent standard

practice in the industry, and provide a

simple way to classify samples as

violative or nonviolative. Based on the

above discussion of calculated MPN

values, FDA is proposing in § 106.55(c)

that powdered infant formula be

classified as nonviolative for coliforms

in all situations in which the calculated

MPN value is less than or equal to 3.05

and classified as presumptively

violative for coliforms in all situations

in which the calculated MPN value is

greater than 3.05. In other words, FDA

is proposing that an MPN value of 3.05

represents the maximum allowable

number of coliforms present in 1 g of

dry infant formula. This proposal is

consistent with current FDA infant

formula microbiological guidelines. The

agency requests comment on the

specification of 3.05 MPN/g as the

maximum allowable number of

coliforms in dry infant formula.

FDA has stated that infant formula

with a calculated MPN value of greater

than 3.05 in the coliform test is

presumptively violative because, under

proposed § 106.55(c), the manufacturer

may either consider the sample violative

without further testing or may conduct

an additional test, the fecal coliform

test. Although an MPN value of greater

than 3.05 MPN/g is a valid quality

indicator of microbial contamination,

coliform contamination may not be fecal

in origin, and it may not reflect the

presence of infant pathogenic

microorganisms. Therefore, FDA has

tentatively concluded that an infant

formula for which an MPN value of

greater than 3.05 MPN/g is found in the

coliform test need not be considered

violative if a negative result is found in

a more specific test for fecal coliforms.

If the coliform test using powdered

infant formula samples results in an M

value greater than 3.05 MPN/g, the

manufacturer may use the cultured

bacteria from one or more of the tubes

producing the positive result as a

sample inoculum for the fecal coliform

test. A sample inoculum producing an

MPN value in the fecal coliform test of

less than or equal to 3.05 would indicate

that the coliform contamination is not

fecal in origin, because under

incubation conditions that are specific

for fecal coliforms, the bacteria were not

detected. The testing would effectively

screen out coliforms that are not of

concern, which is not possible with the

more general test. Therefore, FDA has

tentatively concluded that an MPN

value less than or equal to 3.05 in the

fecal coliform test be classified as

nonviolative. FDA also has tentatively

concluded that an MPN value greater

than 3.05 in the fecal coliform test is a

valid quality indicator demonstrating

that the formula contains fecal coliforms

such as E. coli and, therefore, is

adulterated under sections 402(a)(4) and

412 of the act. The agency is proposing

that powdered infant formula that

results in an MPN value greater than

3.05 in the fecal coliform test be

classified as violative.

If the E. coli test was performed, the

sample inoculum would be the cultured

bacteria from positive tubes in the fecal

coliforms test. However, the agency is

not proposing to require specific testing

for the presence of E. coli, or to set a

specification for an M value for E. coli,

because the specification of less than or

equal to 3.05 MPN/g in the fecal

coliforms test is sufficient to ensure that

nonviolative samples do not contain E.

coli since E. coli is a type of fecal

coliform. Moreover, FDA has tentatively

concluded that an MPN value greater

than 3.05 in the fecal coliform test is a

sufficient quality indicator of fecal

contamination that the agency need not

propose, as an option, that a

manufacturer may conduct an

additional specific test for the presence

of E. coli. The agency requests

comments on the proposed

requirements for sequential testing for

coliforms and fecal coliforms, with no

testing for E. coli.

c. Salmonella. Tests for the presence

of Salmonella involve the enrichment in

a broth of the entire analytical unit

followed by plating onto culture plates

rather than the culture of a series of

dilutions that is performed in tests for

coliforms. A positive result in a test for

Salmonella is based on the detectable

presence of the microorganism on the

culture plate rather than on the

mathematical calculations that result in

a MPN.

Proposed § 106.55(c) requires that

powdered infant formula be tested for

Salmonella and provides that the

formula is adulterated if any Salmonella

is found. All serotypes of this genus of

bacteria can cause illness (often

gastrointestinal) in infants and adults

(Refs. 33 and 34). The presence of any

Salmonella in infant formula could

render it injurious to an infant who

consumes it because the infectious dose

of these bacteria is low (Ref. 35).

Therefore, FDA has tentatively

concluded that the risk from Salmonella

is of such significance that an M value

of zero (i.e., none detectable) for

Salmonella in infant formula is

necessary to protect the health of

infants.

d. Listeria monocytogenes. Tests for

the presence of L. monocytogenes are

similar to those for Salmonella and a

positive result is based on the detectable

presence of the microorganism on the

culture plate rather than on the

mathematical calculations that result in

a MPN.

Proposed § 106.55(c) requires that

powdered infant formula be tested for L.

monocytogenes and provides that the

formula is adulterated if any L.

monocytogenes is found. Individuals

with immune systems that make them

susceptible to infections, such as

newborns and infants with incompletely

developed immune systems, are

susceptible to infection with L.

monocytogenes which may cause severe

illness or death (Ref. 37). The infectious

dose of this bacterium is believed to be

low (Ref. 38). Because the specific dose

of this bacterium that may cause illness

is not known but is believed to be low,

FDA has tentatively concluded that the

risk from L. moncytogenes is of such

significance that an M value of zero (i.e.,

none detectable) for L. monocytogenes

in powdered infant formula is necessary

to protect the health of infants. The

agency requests comment on this

proposed specification for L.

monocytogenes.

e. Staphylococcus aureus. S. aureus is

harmful to infants because some strains

of this microorganism produce an

enterotoxin that causes acute

gastrointestinal illness (nausea,
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36173

vomiting, cramps) soon after the food is

ingested (Ref. 39). Tests for S. aureus

involve liquid culture of series of

dilutions as was discussed previously in

reference to coliform and fecal coliform

testing and results are calculated as

MPN based on tables in the BAM.

Proposed § 106.55(c) requires that

powdered infant formula be tested for S.

aureus and establishes an M value of

3.05 for this microorganism. FDA has

tentatively concluded that the risk from

S. aureus is of such significance that an

M value of 3.05 is necessary to protect

the health of infants.

f. Bacillus cereus. Tests for B. cereus

involve liquid culture of a series of

dilutions as was discussed previously in

reference to coliform and fecal coliform

testing and results are calculated as

MPN based on tables in the BAM.

Proposed § 106.55(c) requires that

powdered infant formula be tested for B.

cereus when the APC exceeds 100 CFU/

g and establishes an M value for B.

cereus of 100 MPN/g or 100 CFU/g. This

proposed M value for B. cereus is lower

than the M value of 1,000 MPN/g or

1,000 CFU/g in the current

recommended infant formula

microbiological guidelines (54 FR 3783).

B. cereus can produce diarrhea and

vomiting in adult humans (Ref. 40)

when food contaminated with at least

105 B. cereus cells is consumed. The

infectious dose of B. cereus for infants

is not known; however, because the

immune systems of infants are not fully

developed, infants are more susceptible

to bacterial infections than are healthy

adults and older children. In the

absence of data on the dose of B. cereus

capable of causing disease in infants,

the agency is concerned that a safety

standard of 1,000 MPN/g or 1,000 CFU/

g poses a potential risk to infants who

consume rehydrated formula because B.

cereus in rehydrated powdered infant

formula is capable of rapid growth and

can reach 4.9×106 cells/g within 24

hours at 26 °C (Ref. 48), a level

sufficient to cause disease. Therefore,

FDA has tentatively concluded that the

risk from B. cereus is of such

significance that an M valve that is

lower than the current standard of 1,000

MPN/g or 1,000 CFU/g is necessary to

protect the health of infants.

Powdered infant formulas and similar

products (e.g., powdered milk)

produced under CGMP contain less than

100 MPN/g or 100 CFU/g of B. cereus

(Refs. 43 and 48). Additionally, an FDA

survey of different production lots of

milk-, soy-, and protein hydrolysatebased powdered infant formulas (Ref.

49) showed that the maximum APC was

103 CFU/g, and that the proportion of B.

cereus in the samples ranged from 1.2

to 63.9 percent of the APC. Therefore,

FDA has tentatively concluded that an

M value of 100 MPN/g or 100 CFU/g for

B. cereus will adequately protect the

health of infants. Moreover, because this

M value is higher than the B. cereus

levels typically found in infant formula

currently being produced (Refs. 43, 48,

and 49), the proposed M value of 100

MPN/g or 100 CFU/g will not be overly

burdensome.

g. Methods. Proposed § 106.55(c)

states that the agency intends to

determine compliance with the

proposed M values using the methods in

the BAM. These methods provide

reproducible, consistent, and accurate

results at different laboratories. The

agency proposes to incorporate the BAM

by reference in § 106.55(c) in

accordance with 5 U.S.C. 552(a) and 1

CFR part 51. While manufacturers may

use other equivalent methods, a

manufacturer who uses methods that do

not provide results that are consistent

with the results obtained by methods

approved by FDA will bear the risk that

the firm’s product is not in compliance

with the law.

The agency intends to test for

Salmonella using the method described

in Chapter 5, BAM, including the

sample preparation procedures

described in section C, paragraph 1 and

the sampling plan described in Chapter

1, BAM; for L. monocytogenes using the

method described in Chapter 10, BAM

and the sampling plan described in

Chapter 1, BAM; for coliforms, fecal

coliforms, and E. coli using the MPN

method described in Chapter 4, BAM;

for S. aureus using the MPN method

described in Chapter 12, BAM; for B.

cereus using the MPN or plate count

method described in Chapter 14, BAM.

The agency intends to determine the

APC using the method described in

Chapter 3, BAM. All chapter references

are to the 8th ed. BAM. FDA intends to

update the reference to reflect the most

recent edition of the BAM at the time

the final rule based on this proposed

rule is issued.

h. Records. Proposed § 106.55(d)

requires that manufacturers make and

retain records, in accordance with

proposed § 106.100 (e)(5)(ii) and (f)(7)

on the testing of infant formula for

microorganisms. As discussed in the

description of the revisions to proposed

subpart F of part 106, FDA has the

authority to require such records under

section 412(b)(4)(A)(i) of the act. These

records will document whether the

batch of powdered infant formula meets

the microbiological quality standards of

proposed § 106.55(c) and is therefore

not adulterated. Records that describe

the full methodology for testing

powdered infant formula for

microbiological quality will provide

consistency in the testing of the

microbiological quality of the formula,

even if different laboratory personnel

conduct the tests. The accuracy and

reproducibility of microbiological

quality testing depend on the procedure

used to conduct the test. In addition, the

records will provide the manufacturer

with data to evaluate any complaints

received associated with a particular

batch of infant formula by showing

whether microbiological contamination

could have contributed to the adverse

event.

10. Controls to Prevent Adulteration

During Packaging and Labeling of Infant

Formula

Because consumers rely on correct

labels to select a formula to meet their

childrens’ individual needs and to have

proper instructions for the use of the

formula, FDA is proposing § 106.60(a)

which requires manufacturers examine

packaged and labeled infant formula to

ensure that containers and packages

bear the correct labels, use-by dates, and

traceability codes. The proposal also

requires that labels be designed, printed,

and applied so that they remain

attached and legible during processing,

handling, storage, and use (proposed

§ 106.60(b)), and that all formula held in

a single package be the same product

bearing the same traceability code, and

that the package carry the product

name, name of the manufacturer, and

the code (proposed § 106.60(c)).

These proposed requirements will

ensure that infants who have allergies

will not be placed at risk by consuming

formula containing ingredients to which

they are allergic, and that consumers

will be aware of the date when the

product may no longer be appropriate

for use. In addition, the traceability

codes will show the origin of the

product if there were a recall, and the

packaging requirements will make it

more difficult for counterfeit formula, or

formula with counterfeit labels, to be

shipped in interstate commerce. There

have been cases of counterfeit

shipments in which a single package

held more than one product, or held a

single product which bore more than

one code. The proposed regulations are

not only intended to reduce the

incidence of counterfeit activities, but to

ensure that firms that receive the

formula are aware that only one product

should be in the packaging, and that all

containers should be identified with the

code shown on the package. This

requirement will not impose an

additional burden on industry because

manufacturers routinely package a
36174 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

single infant formula product bearing

the same code.

11. Controls on the Release of Finished

Infant Formula

Proposed § 106.70(a) requires that the

manufacturer determine that each batch

of formula meets all of the

manufacturer’s specifications before

releasing the batch for distribution.

Specifically, each batch must meet the

requirements of § 106.55 on

microbiological contamination to ensure

that the infant formula does not contain

microorganisms at levels that may be

injurious to the health of infants and

render the formula adulterated and must

meet the requirements of § 106.91(a) on

quality control procedures to ensure

that the infant formula provides the

required nutrients at the required levels,

and that it provides any nutrient added

by the manufacturer. Proposed

§ 106.70(a) is designed to ensure that

any infant formula that fails to meet the

manufacturer’s specifications, or that is

adulterated for any reason, will not be

introduced into interstate commerce.

Proposed § 106.70(b) requires that

each batch of infant formula that fails to

meet the manufacturer’s specifications

be rejected. Although proposed

§ 106.70(b) recognizes that the formula

may be reprocessed, it requires that the

reprocessed product be shown to meet

the requirements of § 106.70(a) before

the product is released. FDA has

tentatively concluded that this proposed

requirement is necessary to ensure that

any defect that caused a batch of infant

formula to be rejected is corrected

before the formula is released into

commerce.

Proposed § 106.70(c) requires that an

individual qualified by training or

experience conduct an investigation of a

finding that a batch of infant formula

fails to meet any manufacturer’s

specifications. This investigation is

necessary to determine why such a

failure occurred and to assist the

manufacturer in developing controls to

ensure that such a failure does not

reoccur. FDA has proposed to require

that the individual who conducts the

investigation be qualified to ensure that

the investigation is properly conducted.

12. Traceability

Section 412(g)(1) of the act requires

that each manufacturer make and retain

such distribution records as may be

necessary to effect and monitor recalls

of the formula, and section

412(b)(4)(A)(vi) requires that each

manufacturer retain all complaints

concerning infant formulas that may

reveal the possible existence of a hazard

to health. Therefore, infant formulas

must be traceable to permit

identification of the product that is the

subject of a complaint and to make it

possible to determine whether that

batch of infant formula presents a

possible hazard to health. Traceability

of an infant formula is also necessary so

that the recall requirements of the act

can be met.

The agency’s view, based on its

experience, is that coding is the most

effective method for ensuring

traceability. It provides a uniform

system that is able to identify large

numbers of batches of infant formula

with a distinctive code that is easily

understood and that can be used by

manufacturers, retailers, and consumers.

A code also allows a large amount of

information to be presented on the

container of infant formula in a very

small space. Therefore, the agency is

proposing, under sections 412

(b)(4)(A)(vi) and (g)(1) and 701(a) of the

act that batches of infant formula be

identified with a distinctive code that

will allow the traceability of an infant

formula.

Current § 106.90 requires that

manufacturers ensure traceability by

coding all infant formulas in conformity

with the coding requirements in

§ 113.60(c) for thermally processed lowacid foods packaged in hermetically

sealed containers. Section 113.60(c)

requires that the code identify the

establishment where the product is

packed, the product contained therein,

the year packed, the day packed, and

the period during which packed, and

that the packing period code be changed

with sufficient frequency to permit

ready identification of lots during their

sale and distribution. FDA is proposing

to carry the requirement that

manufacturers code their product in

accordance with § 113.60(c) forward in

proposed § 106.80(a).

FDA has tentatively determined that it

is appropriate to code liquid infant

formulas in this manner because they

are thermally processed low-acid foods,

and a batch is produced in a relatively

short period of time, usually a day. It

also may be appropriate for coding some

powdered infant formulas in this

manner if they are processed in a short

enough time to make the day packed

and the period during which packed

meaningful information.

Proposed § 106.80(b) allows for

alternative coding of batches of

powdered infant formula. Powdered

infant formula is usually manufactured

in stages over a longer period of time

than liquid infant formula. Some

powdered infant formulas are dry mixed

in a number of stages over an extended

period of time. In other cases, powdered

infant formula is mixed in liquid form

at one manufacturing facility and

shipped to a second site for spray drying

and packaging. Powdered infant formula

manufacturing is often not completed in

a short enough period of time for coding

based on the date packed or the period

of time in which it was packed to be

meaningful information. Therefore,

under the alternate method that FDA is

proposing, a sequential code would be

assigned so that all the essential

information needed to track any

problems with the infant formula could

be determined.

13. Audits of CGMP

Proposed § 106.90 requires that

manufacturers (or their agents) conduct

regularly scheduled audits to determine

whether they are complying with

CGMP. This provision derives from

section 412(b)(2)(B)(iv) of the act, which

requires that the CGMP include ‘‘the

conduct by the manufacturer of an

infant formula or an agent of such

manufacturer of regularly scheduled

audits to determine that such

manufacturer has complied with the

regulations prescribed under’’ section

412(b)(2)(A) of the act. Section

412(b)(2)(A) requires that the Secretary

(and by delegation FDA) establish

CGMP’s by regulation.

FDA is proposing to require that

regularly scheduled audits be part of

CGMP because such audits are the best

way to ensure overall compliance with

CGMP and to identify recurring

problems that may dictate an alteration

in the master manufacturing order. For

example, regularly scheduled audits of

all deviations from the manufacturer’s

specifications or procedures will

accentuate deviations that occur

repeatedly and will enable the

manufacturer to identify specifications

or procedures that should be reassessed.

Section 412(b)(2)(B)(iv) of the act also

specifies that such audits are to ‘‘be

conducted by appropriately trained

individuals who do not have any direct

responsibility for the manufacture or

production of infant formula.’’ FDA is

therefore proposing that an individual

be knowledgeable in all aspects of infant

formula production perform the audit.

Without such broad knowledge, the

individual conducting the audit will not

be able to adequately evaluate the

manufacturer’s production and inprocess control procedures. In addition,

because the purpose of the audit is to

determine whether the manufacturer is

complying with the CGMP regulations

issued under section 412(b)(2)(A) of the

act, the agency has tentatively

concluded that the person conducting

the audit needs to be knowledgeable in
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36175

these regulations. Without such

knowledge, the person would be unable

to make the determinations that are the

very purpose of the audit.

The requirement that the audit be

performed by an individual who has no

direct responsibility for the matters

being audited is one way to ensure the

objectiveness of the audit process. The

person should be free of any past

involvement in the activities being

audited because the audit is intended to

uncover any problems or shortcomings

in the manufacturer’s procedures. A

person who has been involved may feel

that finding problems will reflect poorly

on his or her work. Therefore, FDA has

tentatively concluded that the audit

must be conducted by someone who has

no direct interest in the outcome of the

audit.

C. Quality Control Procedures

1. Introduction

FDA is proposing to redesignate and

revise subpart B of part 106 as subpart

C of part 106. Under this proposal,

several sections of the current

regulations will be revoked, and several

sections will be redesignated without

change. The latter sections are being

recodified, however, to fit the

organization of the proposed

regulations. Table II describes the

current and proposed regulations as

follows:

TABLE II

Current regulation Proposed regulation

INGREDIENT CONTROL

§ 106.20(a),

§ 106.20(b)(1),

§ 106.20(b)(2).

Changed by

§§ 106.91(a)(1) and

106.40(d).

IN-PROCESS CONTROL

§ 106.25(a) ................ § 106.50(a)(1).

§ 106.25(b)(1) ............ Omitted.

§ 106.25(b)(2) ............ § 106.91(a)(4).

§ 106.25(b)(3) ............ § 106.91(a)(2).

§ 106.25(b)(4) ............ § 106.91(a)(4) with

modification.

§ 106.25(b)(5) ............ § 106.91(a)(3) with

modification.

FINISHED PRODUCT EVALUATION

§ 106.30(a) ................ § 106.91(a).

§ 106.30(b)(1)(i) ......... § 106.91(a)(3).

§ 106.30(b)(1)(ii) ........ § 106.91(a) with

modification.

§ 106.30(b)(2),

§ 106.30(b)(3).

§ 106.91(b) with

modification.

§ 106.30(c)(1) ............ Omitted.

TABLE II—Continued

Current regulation Proposed regulation

§ 106.30(c)(2) ............ § 106.3(i)

§§ 106.91(b)(1) and

106.97(b)(1) with

elimination of the

osmolality and vitamin D assay.

§ 106.30(d) ................ Omitted.

FDA is proposing quality control

procedures under the authority granted

by section 412(b)(2), (b)(3), and (b)(4) of

the act, which direct the Secretary (and

by delegation, FDA) to establish by

regulation the quality control

procedures that he or she determines are

necessary to ensure that an infant

formula provides the required nutrients

at the required levels. In the

Congressional Record of September 27,

1986, Senator Metzenbaum stated: ‘‘The

most important provision of this

amendment is the simple requirement

that each batch of formula must be

tested for each essential nutrient that

must be contained in the formula’’ (Ref.

1). The quality control procedures in

proposed subpart C of part 106 are the

minimum practices that manufacturers

must implement to ensure that the

infant formula that they produce

contains the required nutrients at the

required levels throughout the shelf life

of the product. Under section 412(a)(3)

of the act, an infant formula is deemed

to be adulterated if the processing of the

formula does not comply with quality

control procedures prescribed by the

Secretary.

2. Nutrient Testing

Proposed § 106.91(a) describes the

testing that FDA has tentatively

concluded each manufacturer must

conduct on each batch of infant formula

to ensure that it provides the required

nutrients at the required levels and

provides any nutrient added by the

manufacturer. FDA is proposing these

requirements under the authority of two

sections of the act. Section

412(b)(2)(B)(i) of the act provides that

the quality control procedures shall

include requirements for testing, in

accordance with section 412(b)(3), of

each batch of infant formula for each

required nutrient, before distribution of

such batch. Section 412(b)(3)(D) of the

act states that if the Secretary adds a

required nutrient, the Secretary must

require that the manufacturer of the

infant formula test each batch of such

formula for that nutrient in accordance

with section 412(b)(3)(A), (b)(3)(B), and

(b)(3)(C) of the act.

Current § 106.20(a) and (b)(2), which

FDA is proposing to replace with

§ 106.91(a)(1), do not require that

manufacturers analyze nutrient

premixes if the premixes come with a

supplier’s guarantee or certification.

Proposed § 106.91(a)(1), however,

requires that each nutrient premix used

in the manufacture of an infant formula

be tested by the formula manufacturer

for each nutrient that the manufacturer

is relying on the premix to provide to

ensure that the premix complies with

the manufacturer’s specification. This

change is required by section

412(b)(3)(B) of the act. Section

412(b)(3)(B) was included in the 1986

amendments because infant formula

manufacturers were increasingly relying

on the use of formula premixes, and

Congress felt that relying on a premix

supplier’s written assurance that its

premix product was properly tested was

inadequate (Ref. 1). In 1985, the

Department of Justice sought an

injunction against a premix supplier

because, ‘‘as a result of inadequate

quality control, numerous * * *

vitamin and mineral mixes—used in

infant formula—have been misbranded

and adulterated’’ (Ref. 3). The premix

supplier entered into a consent decree

of permanent injunction that enjoined it

from shipping any of its vitamin/

mineral premixes for use in infant

formulas until it completed a number of

specific acts that were designed to

improve its quality control (Ref. 50).

FDA is proposing to redesignate

current § 106.25(b)(3) as § 106.91(a)(2),

which requires that after the addition of

the premix, or at the final-product stage

but before distribution, each batch of

infant formula be tested to confirm that

the nutrients contained in any nutrient

premix used in such infant formula are

present in each batch of infant formula

in the proper concentration. This

requirement implements section

412(b)(3)(C)(ii) of the act, which

requires that infant formula be tested to

ensure that any nutrient premixes used

by the manufacturer are actually

included in the batch of infant formula

in the proper amount. Without this

check, inadvertent failure to include the

premix could go undetected, and infant

formula that is deficient in the nutrients

that were to be provided by the premix

would be introduced into the market.

Current § 106.30(b)(1)(i) requires that

the manufacturer analyze representative

samples of each batch of finished infant

formula for specific nutrients to assess

process degradation. FDA is carrying

forward a modified version of this

requirement in proposed § 106.91(a)(3),

which requires that each batch of infant

formula be tested for vitamins A, C, and
36176 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

E and thiamin at the final-product stage,

before distribution. This regulation is

proposed under section 412(b)(3)(A) of

the act, which states: ‘‘At the final

product stage, each batch of infant

formula shall be tested for vitamin A,

vitamin B1, vitamin C, and vitamin E

* * *.’’ In the Congressional Record,

Senator Metzenbaum stated that testing

for these vitamins is required at the

final-product stage because they are

vulnerable to degradation (Ref. 1).

Testing at the final-product stage will

ensure that these nutrients are present

in the infant formula at the end of all

the processing steps that may destroy

them.

Proposed § 106.91(a)(4) requires that,

before distribution, each batch of infant

formula be tested for all nutrients

required to be included, and any others

that have been included, but for which

testing to comply with § 106.91(a)(1) or

(a)(3) was not conducted. This proposed

provision takes a markedly different

tack than current § 106.30(b)(1)(ii),

which states that no analyses are needed

for linoleic acid, vitamin D, vitamin K,

choline, inositol, and biotin before

release of a batch of infant formula for

commercial or charitable distribution.

This change in approach is necessary

because section 412(b)(3)(C) of the act,

which was added by the 1986

amendments, states that each batch of

formula must be tested for each nutrient

required by the law to be present in an

infant formula. Also, manufacturers are

adding nutrients not required by

§ 107.100, such as selenium, to infant

formulas. These nutrients meet the

definition for ‘‘nutrient’’ in proposed

§ 106.3(m) because they have been

identified as essential for infants by

NAS through its development of a

Recommended Dietary Allowance or an

Estimated Safe and Adequate Daily

Dietary Intake range. The agency has not

objected to the addition of nutrients not

required by § 107.100 to infant formulas.

However, it is important that the level

of these added nutrients be controlled,

and that the level of the added nutrient

be consistent from batch to batch and be

uniform throughout the batch of infant

formula.

The level of a nutrient needs to be

controlled because some nutrients can

be toxic to an infant if given at too high

a level. Controlling the level of the

added nutrient for consistency from

batch to batch and in a particular batch

of infant formula will ensure that the

infant receives the essential nutrient on

a consistent basis and will also ensure

that the infant does not receive too high,

or too low, a level of the nutrient

because the nutrient was not uniform

throughout the batch of infant formula.

3. Stability Testing

Current § 106.30(c) requires that the

manufacturer, using representative

samples collected from finished product

batches, conduct stability analysis for

selected nutrients with sufficient

frequency to substantiate the

maintenance of nutrient content

throughout the shelf life of the product.

The 1986 amendments added

subsection 412(b)(2)(B)(ii) to the act,

which requires ‘‘regularly scheduled

testing, by the manufacturer of an infant

formula or an agent of such

manufacturer, of samples of infant

formula during the shelf life of such

formula to ensure that such formulas are

in compliance with’’ section 412 of the

act. To implement this section of the

act, the agency is redesignating and

revising current § 106.30(b)(3) as

proposed § 106.91(b), which requires

quarterly collection of samples of infant

formula for stability testing to provide a

check on nutrient stability. This

periodic check will alert the

manufacturer if nutrient stability has

changed in some unpredicted way so

that the formula no longer complies

with section 412 of the act. Quarterly

testing of infant formulas for nutrient

stability is currently conducted by the

industry (Refs. 51 and 52), and the

agency is not aware of any problems

that have resulted from this frequency of

testing. The agency requests comment

on whether this proposed frequency of

sample collection for stability testing is

appropriate.

The agency has tentatively concluded

that this periodic sample collection to

check on nutrient stability must be

performed on a batch of each physical

form (powder, ready-to-feed, or

concentrate) of each infant formula, at

each different manufacturing facility,

because different forms of the product

may contain different ingredients, and

different forms of infant formula are

subjected to different processing

procedures. Therefore, ensuring the

nutrient stability of one form of the

product, such as the powder, will not

answer questions about the nutrient

stability of other forms of the product.

Thus, the agency has tentatively

concluded that each form of the infant

formula must be sampled on a periodic

basis for nutrient stability. Also, the

agency has tentatively concluded that

the sampling of one batch of each

physical form of each infant formula

must be conducted at each

manufacturing facility. This proposed

requirement is necessary because

manufacturers may produce the same

infant formula at more than one facility,

and the manufacturing conditions at one

facility may not be the same as the

conditions at another facility. The

differences in conditions cannot be

allowed to affect the quality of the

formula.

Proposed § 106.91(b) further requires

testing at the beginning, midpoint, and

end of the shelf life of the infant

formula. Testing at the beginning of the

shelf life shows that the formula is in

compliance with the nutrient

requirements of the act when it is

released for distribution. Testing at the

midpoint of the shelf life will alert the

manufacturer if any nutrient is

deteriorating at a rate different from that

predicted, so that the nutrient may not

be in the formula at a level to comply

with the act throughout the formula’s

shelf life. Testing at the end of shelf life

will ensure that the formula contained

all the nutrients needed to comply with

the act throughout its shelf life and will

provide continued justification for the

predicted shelf life.

Additional testing may be necessary

to ensure that a formula complies with

section 412 of the act throughout its

shelf life. Such testing is likely to focus

on a particular nutrient and its stability

within the matrix of the formulation.

This additional testing will ensure that,

if there is a significant deterioration in

the level of the nutrient in the formula,

the manufacturer will be aware of this

fact and will be able to take steps

promptly to have the product removed

from the market, before a significant

number of infants are exposed to a

deficient product.

The agency is not proposing to specify

what frequency is required because

manufacturers have experience with the

nutrient stability of the infant formula

matrices that they produce and are thus

in a position to determine how

frequently testing is necessary. For

example, the manufacturer is in a

position to know whether the nutrient

levels of a milk-based infant formula

need to be tested on a different basis

than that of a soy-based product, or

whether the nutrient levels of an infant

formula that contains hydrolyzed

protein needs to be tested more

frequently than that of an infant formula

that contains non-hydrolyzed protein.

Manufacturers will be able to comply

with section 412(b)(2)(B)(ii) of the act by

testing different nutrients at different

frequencies. For example, unstable

nutrients, such as vitamins, may require

testing on a more frequent basis than

more stable nutrients, such as minerals.

Proposed § 106.91(b) allows the

manufacturers the discretion to

determine the necessary frequency of

testing to ensure that their infant

formula complies with the nutrient
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36177

requirements of the act, as long as the

minimum testing (i.e., at the beginning,

middle, and end of the shelf life)

required by proposed § 106.91(b) is

accomplished.

Proposed § 106.91(b)(1) provides for

an addition to the stability testing

required under § 106.91(b). FDA is

proposing that the first batch of each

form of a new infant formula be

subjected to such testing to ensure that

the product complies with the nutrient

requirements of section 412 of the act

throughout its shelf life.

Proposed § 106.91(b)(2) requires the

sampling of the first batch of an infant

formula in which there has been a

change in formulation or in processing

that could affect whether the formula is

adulterated under section 412(a) of the

act and requires testing of these samples

for each nutrient that has been, or may

have been, affected by the change. The

change in formulation or processing

referred to here would not be a ‘‘major

change’’ because a ‘‘major change’’

would mean that the formula is a ‘‘new

infant formula.’’ Examples of the types

of changes that are subject to proposed

§ 106.91(b)(2) are: (1) Reducing a

‘‘required nutrient’’ in a minor way or

increasing a ‘‘required nutrient’’ that is

subject to maximum limits in § 107.100

in a minor way; (2) replacing one

nutrient form with another form, such

as replacing vitamin A acetate with

vitamin A palmitate or replacing

calcium carbonate with tricalcium

phosphate; (3) changing a timetemperature condition of preheating,

handling, mixing, or sterilizing an inprocess product; or (4) changing the

oxygen content of a packaged product

that might have a minimal effect on the

level of nutrients. Requiring sample

collection for stability testing when a

manufacturer makes changes such as

these in the manufacture of the product

will ensure that the manufacturer can

verify the predicted shelf life of the

changed formula.

Proposed § 106.91(b)(2) requires that

the manufacturer ensure that the infant

formula meets all the nutrient

requirements of section 412 of the act.

This provision is proposed under the

authority of section 412(b)(2)(A) of the

act, which provides for the

establishment of CGMP’s for infant

formulas, including quality control

procedures that are necessary to assure

that the infant formula provides

nutrients in accordance with section

412 (b) and (i) of the act, as well as

section 412(b)(2)(B)(ii). If the

formulation or processing of the infant

formula has been changed, the

manufacturer must consider what

nutrients may have been affected by the

change and test for each of these

nutrients in the final-product stage of

the first batch of the changed formula.

For example, if the manufacturer makes

a change in the amount of a protein

source used in the infant formula, the

firm must test the formula for protein

content and for any nutrients provided

endogenously to the formula by the

protein, such as minerals like calcium

and phosphorus. The manufacturer is

aware of how much of each mineral it

is relying on the protein source to

provide to the formula. When the

amount of the protein source used in the

formula is changed, the manufacturer

must test for the level of all nutrients it

relies on the protein source to provide

to the formula to ensure that all

nutrients in the formula meet the

requirement of § 107.100.

4. Quality Control Records

Proposed § 106.91(c) requires that

manufacturers make and retain records

of the results of all testing performed on

the batch of infant formula in

accordance with proposed

§ 106.100(e)(5)(i) and a full description

of the methodology used in accordance

with proposed § 106.100(f)(7). As

discussed in the description of the

proposed revisions to subpart F of part

106, FDA has authority to require these

records under section 412(b)(4)(A)(i) of

the act. Providing a record of the results

of quality control testing will verify that

each nutrient required by § 107.100 is

present in each batch of infant formula

at the required level, and that any

nutrients added by the manufacturer are

present at the appropriate level. These

records will show the levels of nutrients

in the formula and will provide data

needed to evaluate a batch of infant

formula if problems, such as adverse

events in infants, occur later with that

particular batch. Records that describe

the full methodology used to conduct

the quality control testing will provide

consistency in the procedure that the

manufacturer is using to test for the

nutrients in each batch of infant

formula, even when different laboratory

personnel are conducting the testing.

The accuracy and reproducibility of

quality control testing depend on the

procedure used to conduct the test.

5. Audits of Quality Control Procedures

Proposed § 106.92 requires that the

manufacturer of an infant formula, or an

agent of such a manufacturer, conduct

regularly scheduled quality control

audits to ensure that an infant formula

provides required nutrients and has

been manufactured in a manner

designed to prevent adulteration.

Proposed § 106.92 derives from section

412(b)(2)(B)(iv) of the act, which

requires that the quality control

procedures prescribed by the Secretary

include ‘‘the conduct by the

manufacturer of an infant formula or an

agent of such manufacturer of regularly

scheduled audits to determine that such

manufacturer has complied with the

regulations prescribed under’’ section

412(b)(2)(A) of the act (stating that the

Secretary (and FDA by delegation)

establish by regulation ‘‘quality control

procedures that the Secretary

determines are necessary to assure that

an infant formula provides nutrients in

accordance with’’ section 412 (b) and (i)

and ‘‘is manufactured in a manner

designed to prevent adulteration of the

formula’’. FDA is proposing to require

that regularly scheduled audits be part

of quality control procedures because

such audits will document compliance

with the quality control procedures and

will identify recurring problems that

may dictate an alteration in the master

manufacturing order. For example,

regularly scheduled audits of the results

of tests of nutrient levels in infant

formulas and of any deviations from the

manufacturer’s specifications or

procedures for acceptable nutrient

levels will reveal deviations that occur

on a repeated basis and will enable the

manufacturer to identify specifications

or procedures that should be reassessed.

Proposed § 106.92 further requires

that the audits 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

responsibilities for the matters being

audited. The legal authority for this

provision, the importance of the

responsible individual’s knowledge in

all aspects of infant formula production

and the agency’s regulations, and the

need for the audit to be performed by an

individual who has no direct

responsibility for the matters being

audited were discussed previously

under the proposed CGMP regulations

in § 106.90.

By proposing different regulations

(proposed §§ 106.90 and 106.92) that

require audits of CGMP and of quality

control procedures, the agency is not

suggesting that it will require that

separate audits be conducted. These

regulations are being proposed

separately to make clear that the

regularly scheduled audits required by

section 412(b)(2)(B)(iv) of the act are an

aspect both of CGMP and of quality

control procedures. The agency would

have no objection to a combined audit
36178 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

of CGMP and of quality control

procedures.

6. Revocation of the Requirement for

Determination of Vitamin D by the Rat

Bioassay Method

FDA is proposing to revoke the

requirement in current § 106.30(c)(2) for

the determination of vitamin D by a rat

bioassay method. This rat bioassay for

vitamin D is no longer a viable assay

because appropriate animals for

conducting this test are difficult to

acquire (Ref. 53), and an alternate

analytical method for the determination

of vitamin D in infant formulas has been

approved by the Association of Official

Analytical Chemists (Ref. 54).

D. Conduct of Audits

Section 412(b)(2)(B)(iv) of the act

provides that CGMP and quality control

procedures include regularly scheduled

audits to determine whether the

manufacturer is complying with CGMP,

including following the quality control

procedures that are necessary to ensure

that an infant formula provides the

required nutrients at the required levels,

and whether it is operating in a manner

designed to prevent adulteration of the

formula. FDA is proposing to require in

§ 106.94(a) that manufacturers develop

and follow a written audit plan that is

available at the manufacturing facility

for FDA inspection. A written audit

plan is necessary to provide consistency

in how audits are conducted and to

ensure that the auditor can determine

whether the facility is operating in

compliance with the applicable

procedures.

Proposed § 106.94(b) requires that the

audit plan include the procedures that

the manufacturer uses to determine

whether the facility is operating in

accordance with CGMP, with the

applicable quality control procedures,

and in a manner designed to prevent

adulteration of the infant formula it

produces. This proposed requirement

derives from current § 106.100(j), which

defines audit procedures as the methods

used to review the manufacturing and

quality control procedures and is

intended to direct the manufacturer’s

attention to the fundamental goals of the

manufacturing process in formulating

its audit plan.

Proposed § 106.94(c) sets out the

minimum requirements for the audit

procedures that are to be employed by

manufacturers. Under proposed

§ 106.94(c)(1) these procedures are to

include a review of how the production

and in-process control system

established under § 106.6(b) is

operating. In particular, proposed

§ 106.94(c)(1)(i) specifies that the

evaluation of the production and inprocess control system include

observation of the production of infant

formula and a comparison of the

observed process to the written

production and in-process control plan

required under proposed § 106.6(b).

FDA has tentatively concluded that

such observations will show whether

the production and in-process control

system is being followed appropriately,

and, if not, they will identify any

deviations from the production and inprocess control system, so that the

manufacturer can take corrective actions

to ensure that infant formula is

produced in compliance with the

production and in-process control

system.

Proposed § 106.94(c)(1)(ii) requires

that the evaluation of the production

and in-process control system include a

review of records of the monitoring of

points, steps, or stages where control is

deemed necessary to prevent

adulteration. As discussed below,

proposed § 106.100(e)(3) requires that

the batch production and control

records document the monitoring of all

points where control is deemed

necessary to prevent adulteration in the

manufacturing of the batch. FDA has

tentatively concluded that proposed

§ 106.94(c)(1)(ii) is necessary because

the auditor can observe the production

of only a limited number of batches of

infant formula. A review of the

production and in-process control

records of all batches produced in a

given period of time will ensure that the

production and in-process control

system is working appropriately on a

continuous basis, will identify any point

that monitoring reveals is out of control

on a recurring basis, and will identify

where the production and in-process

control system needs improvement.

Proposed § 106.94(c)(1)(iii) requires

that the evaluation of the production

and in-process control system include a

review of records of how deviations

from any standard or specification at

points, steps, or stages where control is

deemed necessary to prevent

adulteration were handled. As

discussed below, proposed

§ 106.100(e)(4)(iii) requires that the

batch records include the conclusions

and followup of an investigation of the

failure to meet any specification or

standard at any point where control is

deemed necessary to prevent

adulteration. A review of these records

as a part of the audit will identify

failures that occur on a repeated basis

and will show how these failures are

handled by the manufacturer. The

auditor will be able to evaluate whether

the conclusions and followup of these

investigations are appropriate for each

failure to meet the specification or

standard.

Proposed § 106.94(c)(2) requires that

the audit procedures include a review of

a representative sample of all records

maintained in accordance with

proposed § 106.100 (e) and (f). As

discussed below, proposed § 106.100(e)

sets out the requirements for the batch

production and control records, and

proposed § 106.100(f) sets out the

requirements for records related to

observance of CGMP. A review of a

representative sample of these records

will show the auditor whether there has

been compliance with the appropriate

regulations in producing the batches of

product so that the formula is not

adulterated. Section 412(b)(2)(B)(iv) of

the act states that the audit is conducted

to determine whether the manufacturer

has complied with the regulations

establishing CGMP for infant formulas,

including quality control procedures.

FDA has tentatively concluded that

review of a representative sample of the

records maintained in accordance with

§ 106.100 (e) and (f) is necessary to

determine whether the manufacturer is

complying with these regulations.

E. Quality Factors for Infant Formulas

1. What Are Quality Factors?

The agency is proposing to create a

new subpart E to implement the quality

factor requirements of sections 412

(a)(2) and (b)(1) of the act. Section

412(a)(2) of the act states that an infant

formula is adulterated unless it meets

the quality factor requirements that are

established under section 412(b)(1).

Section 412(b)(1) of the act states that

the Secretary shall by regulation

establish requirements for quality

factors, including quality factor

requirements for required nutrients for

infant formulas to the extent possible

consistent with current scientific

knowledge. Therefore, it is incumbent

on manufacturers to establish that the

infant formula that they produce meets

the minimum quality factor

requirements that FDA adopts.

What Congress meant by ‘‘quality

factors’’ is discussed in the report of the

House Committee on Interstate and

Foreign Commerce that accompanied

the 1980 act. The report states that

quality factors ‘‘pertain to the

bioavailability of a nutrient and the

maintenance of levels or potency of

nutrients during the expected shelf life

of the product’’ (Ref. 5). FDA, in

proposed § 106.3(o), has defined

‘‘quality factors’’ in a manner that

encompasses several basic concepts,

including the concepts of
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36179

‘‘bioavailability’’ and of ‘‘healthy

growth.’’

The concept of ‘‘healthy growth’’ was

discussed in the report of the House

Committee on Interstate and Foreign

Commerce that accompanied the 1980

act. The report states that infant

formulas are often the sole source of

nutrition for infants, and 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’’ (Ref. 5). FDA

considers the concept of ‘‘healthy

growth’’ to be broad, encompassing all

aspects of physical growth and normal

maturational development, including

maturation of organ systems and

achievement of normal functional

development of motor, neurocognitive,

and immune systems. All of these

growth and maturational developmental

processes are major determinants of an

infant’s ability to achieve his/her

biological potential, and all can be

affected by the nutritional status of an

infant.

‘‘Bioavailability’’ of a nutrient for an

infant means that the nutrient is

physiologically available in sufficient

quantities to perform its metabolic

functions (Ref. 55). In a formula

product, bioavailability of individual

nutrients is affected by the net effect of

the formulation and processing of the

product on the chemical form of the

nutrient. These processes are influenced

by such factors as the chemical form of

the nutrient in the ingredient source, the

chemical form of the nutrient after

processing, and the net effect of various

inhibitors and enhancers in a food or

meal on the chemical form of the

nutrient and its ability to be absorbed

and utilized by the infant. In the infant,

the bioavailability of a nutrient is

determined by the net effect of the

amount of nutrient that is converted

during digestion to an absorbable form,

the proportion of the nutrient that is

absorbed into the bloodstream, the

proportion of the absorbed nutrient that

is converted to its biologically useful

form, and the proportion that is lost

through excretory processes (Ref. 55).

Bioavailability varies among nutrients

within a given food product and, for a

given nutrient, among foods. The factors

affecting nutrient bioavailability are

complex and can be difficult to predict

based on analyzed nutrient values

alone.

Bioavailability issues are particularly

critical for infants during the first few

months of life, where a single food

(infant formula) serves as the sole

source of all nutrients at a period when

rapid physical growth and development

and maturation of various organ systems

makes the infant particularly vulnerable

to harm by nutritional insults. Unlike

the mixed diet of persons beyond

infancy where poor bioavailability in

one food can be compensated for by

other foods in the diet, a problem with

bioavailability in an infant formula

affects the total amount of nutrient

available to that infant for several

months after birth. Furthermore,

requirements for nutrients are higher

per kilogram body weight during early

infancy than at any other time during

the life cycle. Because numerous critical

developmental milestones (e.g.,

neurocognitive or immune functions)

must be achieved by young infants, a

nutrient insufficiency during infancy

can quickly develop into serious, and in

some cases, permanent adverse effects

on a range of developmental processes,

including physical growth and organ

maturation. Thus, a problem with

bioavailability is far more critical for a

food such as infant formula than it is for

foods that are used as part of a mixed

diet by the general population.

Furthermore, the rapidly changing

and increasingly complex physical,

chemical, and biologically significant

characteristics of ingredients used in

new and reformulated infant formulas

make it important to continually ensure

that quality factor requirements are met.

Changes in formulation of infant

formulas are made by manufacturers for

a variety of reasons, including

enhancing the functional characteristics

of the formula (e.g., to prevent

separation of ingredients or to prevent

clumping that will plug nipples on

bottles), to enhance digestibility of the

formula (e.g., different sources or blends

of fats), or to improve the nutritional

quality (e.g., a different source of

protein or of a vitamin or mineral, or

adding a nonrequired nutrient such as

selenium). For example, in some

formulas, novel sources of vegetable oils

(e.g., fractions of plant oils that are

particularly rich in certain types of fatty

acids) have partially or fully replaced

cow’s milk fat as the fat source (Refs. 56

and 57). Whey proteins or highly

processed proteins (e.g., hydrolyzed

proteins) are now frequently used as

partial or complete replacements for

more traditional cow’s milk protein

sources. In other cases, nutrient/nutrient

interactions (e.g., high iron inhibiting

absorption of zinc) or nutrient/

ingredient interactions (e.g., phytates

from soy protein isolates inhibiting

absorption of zinc, or the replacing of

the milk sugar (lactose) that enhances

absorption of calcium with a sugar

source that does not have this ability)

can adversely affect nutrient

availability.

New processing methods may also

have unintended consequences when

used with established ingredients or

formulations. For example, a new

processing method that subjects the

formula to conditions that are less

denaturing to cow’s milk proteins than

traditional heat treatments could

produce a formula that is less digestible

and that causes reactivity of the

gastrointestinal wall, such as has been

seen with whole cow’s milk (Ref. 58).

In summary, consideration of quality

factors goes beyond analytical measures

of the presence or absence of a nutrient

in the formula product and is needed to

provide assurance that adverse effects

on the nutritional value of the formula

for the infant do not unintentionally or

unknowingly occur as a result of the

formulation or the processing of an

infant formula. Chemical analysis of the

formula product to define its nutrient

composition often overestimates the

amount of nutrient that is bioavailable

for physiological use by the infant. The

quality factors, therefore, provide a

means of evaluating whether a nutrient

has become less bioavailable than

would be expected, so that it is not

sufficiently effective to meet its normal

nutritive functions, or whether its

bioavailability has been enhanced to a

level that raises safety concerns.

Quality factor requirements are

distinctly different from quality control

procedures. While ‘‘quality control

procedures are intended to insure that

the safety and nutritional potency of a

formula is built into the manufacturing

process’’ (Ref. 5), quality factors are

intended to ensure that an infant

formula contains an adequate amount of

each nutrient in a form that can be

digested, absorbed, and utilized so that

the infant’s physiological needs for

these nutrients will be met (Ref. 5).

Changes in ingredient sources and

processing can affect the chemical forms

of nutrients in the formula product.

Such changes can affect the digestion

and absorption of food nutrients such

that: (1) Absorption is incomplete, (2)

absorbed nutrients are not in a form that

allows use by metabolic pathways, or (3)

the nutrient may interact with other

dietary substances to cause excessive

excretion. Thus, the amount of nutrients

(i.e., the analyzable amounts) in

formulas must generally be higher than

the physiological requirements of

infants (i.e., the amounts of nutrients

needed by the body to meet metabolic

and growth needs of infants). Although

these inefficiencies are generally taken

into account when recommending

nutrient levels for infant formulas, there
36180 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

is always the potential for affecting

nutrient bioavailabilities in unexpected

ways.

In summary, a demonstration that

both the quantitative and quality factor

requirements for essential nutrients in

an infant formula are met is necessary

to ensure that the infant formula is

likely to meet all of the known

physiological nutritional needs of

infants and to ensure that healthy

growth and nutritional well-being will

be achieved by an infant consuming the

infant formula as the sole source of

nutrition.

2. Identification of Quality Factors

In testimony before the passage of the

1986 amendments, the agency 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. (Although

the testimony to the Senate does not

specify the identity of the nutrient for

which there was a basis for a quality

factor, the quality factor was the protein

efficiency ratio used for assessing

protein quality (Ref. 1).) Senator

Metzenbaum stressed that the

amendments contemplated that

additional quality factors would emerge,

and that the Secretary should

implement requirements for such factors

as quickly as scientific advances would

allow.

The agency subsequently took a major

step toward establishing quality factors

through a contract in 1986 with the

CON/AAP. The AAP earlier had

published recommendations regarding

the quantities of nutrients needed in

infant formulas (Ref. 59). These

recommendations were relied upon

during the development of the nutrient

specifications of the act (Ref. 60). In its

report to FDA, ‘‘Clinical Testing of

Infant Formulas with Respect to

Nutritional Suitability for Term Infants’’

(Ref. 6), the CON/AAP identified those

conditions in which changes in formula

composition warranted clinical testing.

The CON/AAP stated that ‘‘clinical

testing is primarily useful for

determining (1) acceptability of the

formula, (2) ability of the formula to

support normal growth, and (3)

availability of selected nutrients.’’ The

CON/AAP also discussed the limitations

of the available measurements,

providing an assessment of the limits of

scientific knowledge.

The agency has considered the CON/

AAP report carefully and has also

considered new scientific information

published since the release of that

report to determine what quality factors

are appropriate for nutrients in infant

formula. Based on its consideration,

FDA is proposing to adopt § 106.96.

This section, if adopted, will require

that all infant formula be of sufficient

quality that it meets the nutritional

requirements of infants for healthy

growth when fed as the sole source of

nutrition, as indicated by a general

quality factor for physical growth,

assessed using anthropometric measures

of infants consuming the formula, and

by a nutrient-specific quality factor for

protein biological quality, assessed by

an animal bioassay using the formula.

The agency is not proposing to require

that manufacturers measure,

individually, the absorption,

metabolism, metabolic transformation,

or utilization of any of the other

essential nutrients. These measures are

often technically difficult or

unavailable, difficult to interpret, or

invasive, thus causing unnecessary

testing of infants without potential for

providing meaningful results. Rather,

the agency has tentatively concluded

that current scientific knowledge and

ethical and practical considerations are

supportive only of requiring two quality

factor measures: (1) Physical growth of

infants consuming the formula as an

integrative indicator of the net effect of

the overall nutritional quality of the

formula, and (2) a rat bioassay of protein

quality in the formula product to ensure

that the infant’s needs for individual

amino acids will be met.

The agency has tentatively

determined that these are minimum

requirements. The agency recognizes

that, on a case-by-case basis as

warranted by the formulation and

intended use of a particular infant

formula, demonstration of additional

quality factors may be necessary. For

example, a formula intended for use by

premature infants who are at a

particularly vulnerable developmental

stage relative to nutritional needs to

support neurocognitive development

may need to be subject to testing that

includes measurement of this endpoint

to ensure that the formula supports

healthy growth. In addition, a formula

in which a novel fatty acid has been

added to enhance the formula’s ability

to meet nutritional needs for supporting

visual development may need to be

evaluated to determine whether it has

adverse nutritional effects on other

aspects of healthy growth (e.g., on

development of immune function).

3. The Regulation

Proposed § 106.96(a) sets forth quality

factor requirements that reflect the

minimum measures needed to evaluate

the nutritional quality of an infant

formula product, taking into account

current scientific knowledge and the

usefulness of the outcome measures for

evaluating quality factors, while

minimizing unnecessary testing of

infants serving as subjects in clinical

trials. Infant formula is defined in the

act as a complete or partial substitute for

human milk (section 201(aa) of the act).

Obviously, the greatest need for a

nutritionally complete formula that

meets all quality factors is when the

formula is used as a complete substitute

for human milk. When no other form of

nutriture is available to the infant, the

formula must provide all of the

nutrients needed for the healthy growth

of the infant. There is no room for error

or miscalculation. The absence or an

inadequate level of an essential nutrient

will be evidenced by growth failure and

other signs or symptoms resulting from

nutritional insufficiencies. FDA has

tentatively concluded, therefore, that an

evaluation of the ability of a formula to

support healthy growth must be made

under its most demanding conditions of

use, i.e., when it is used as the sole

source of nutrition, because other foods

may mask or compensate for

deficiencies in the formula that would

occur if the formula were used as a

complete substitute for human milk,

which would produce results that

cannot be meaningfully interpreted.

Proposed § 106.96(b) identifies

‘‘normal physical growth’’ as a quality

factor. This quality factor reflects the

CON/AAP recommendation that the

determination of physical growth rate is

the most valuable component of the

clinical evaluation of an infant formula

(Ref. 6). Physical measures of growth

such as weight gain are the most widely

accepted and used markers of a young

infant’s overall ability to digest and

utilize those nutrients provided by the

formula. The very rapid rate of growth

in early infancy means that

abnormalities in growth rate can be

detected in a few months, providing an

easily measured and sensitive, although

nonspecific, indication of nutritional

insufficiencies (Ref. 4). Physical

measures of growth rate are easily done,

are familiar to both parents and health

professionals, and are a normal part of

routine office visits. They are

noninvasive and pose little or no risk to

infants and provide meaningful results

for evaluating the ability of an infant

formula to support physical growth in

very young infants. Thus, the agency

has tentatively concluded that the

ability of the formula, when fed as a sole

source of nutrition, to meet the

nutritional requirements of young

infants for normal physical growth is a
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36181

necessary indicator of the overall

nutritional quality of the formula.

Proposed § 106.96(c) requires that the

protein in infant formulas be of

sufficient biological quality to meet the

protein nutritional requirements of

infants. Protein, while generally

discussed as a single nutrient, depends

for its nutritive value on the inclusion

of all essential amino acids at levels and

relative proportions needed to support

healthy growth. The protein

requirement is really the sum of

different requirements for 10 essential

amino acids that occur at different

levels and proportions in various food

protein sources. Protein quality is also

affected by differences in digestibility of

different protein sources, by factors that

modify digestion, and by chemical

reactions that affect the ability of

enzymes in the infant’s gastrointestinal

tract to digest and absorb the amino

acids in the protein source. Once

absorbed, the relative proportions of the

amino acids can affect their uptake by

body tissues because of competition for

receptors and transport systems. Thus,

protein quality depends on a number of

complex interactions and conditions

that can be difficult to predict.

Chemical analysis of foods generally

only measures the amount of total

protein present and does not identify

specific amino acids or their ability to

meet the physiological needs of infants

for the essential amino acids. Chemical

analysis alone, therefore, is not capable

of predicting whether adequate amounts

of all essential amino acids are present,

or whether the amino acids present are

able to support healthy growth in

infants. Yet ensuring that the protein in

an infant formula’s is of high biological

value is critical to an infant’s health. For

example, during the first year of life, the

protein content of an infant’s body

increases from 11 to 15 percent at the

same time that the infant’s body weight

increases by 7 kg. The average increase

in body protein is about 3.5 g/day for

the first 4 months of life and about 3.1

g/day for the next 8 months. These

protein requirements must be met by a

formula that not only contains adequate

protein but also contains protein of high

biological quality in a form that can be

utilized by the infant. Because

biological quality varies among protein

sources and may be adversely affected

by processing methods and other

constituents present in the formula, the

agency has tentatively concluded that

the biological quality of the protein in

an infant formula is a necessary quality

factor. This quality factor will require an

evaluation of whether the formula

contains the essential amino acids and

total nitrogen in the amounts and

proportions necessary to permit normal

tissue and organ growth and

development. As discussed later in this

document, the agency is proposing in

§ 106.97(b) that the biological quality of

the test protein be measured by the

Protein Efficiency Ratio (PER) rat

bioassay and be comparable to the

biological quality of the milk protein

casein.

Proposed § 106.96 does not include

quality factor requirements for all

nutrients required by infants because

methods to determine whether these

requirements are met are not available

or are not practical for most nutrients

(e.g., results cannot be meaningfully

interpreted, or methods are invasive,

thus causing unnecessary testing of

infants). Nonetheless, FDA has

tentatively concluded that, as the

science evolves, establishing quality

factor requirements for other nutrients

needed by infants would provide

assurance, beyond that provided by the

general quality factor of physical growth

in proposed § 106.96(b) and the specific

protein quality factor in § 106.96(c), that

a formula will meet the overall

nutritional needs of infants. As the

science evolves, FDA anticipates being

able to progress beyond generalized,

nonspecific indicators of overall

nutritional intakes (e.g., measures of

physical growth), to more specific and

sensitive measures of biochemical and

functional nutritional status. FDA also

has tentatively concluded that, on a

case-by-case basis, additional quality

factors may be needed for a specific

formula product if formulation or

processing concerns raise sufficient

quality factor questions such that

additional measures are necessary to

adequately ensure that the nutritional

quality of the formula supports healthy

growth. FDA asks for comment on

criteria as to when such measures are

required.

4. Request for Comment on Need for

Establishing Requirements for Other

Quality Factors

Proposed § 106.96(b) and (c) set forth

minimum requirements for quality

factors (physical growth and protein

quality) that all infant formulas should

meet. FDA has tentatively concluded

that these quality factors are consistent

with current state-of- the-art science and

provide significant information on the

nutritional quality of the infant formula

without requiring unnecessary or

meaningless testing of infant enrollees

in studies.

As discussed above, the 1986

amendments contemplated that when

scientific research identified criteria

that could be used to establish quality

factors for specific nutrients in infant

formula, the agency would establish

quality factor requirements for those

nutrients. Proposed § 106.96 will

establish two quality factors (physical

growth and protein quality) because the

agency has tentatively concluded that

there is sufficient scientific evidence of

the importance of these quality factors,

and because adequate methods exist to

meaningfully and ethically measure

these factors.

However, the CON/AAP report

discussed other nutrients necessary for

healthy growth of infants and for which

the report recommended establishing

quality factor requirements (Ref. 6). The

agency has studied the evidence

supporting the establishment of quality

factor requirements for these other

nutrients, and the methods available for

determining whether an infant formula

meets quality factor requirements for

these nutrients. FDA has tentatively

concluded that establishing quality

factor requirements for the three

additional nutrients recommended by

CON/AAP (i.e., (a) fat, as measured by

fat balance; (b) calcium and phosphorus,

as measured by calcium and

phosphorus balance; and (c) iron as

measured by iron bioavailability) is not

warranted at this time. FDA, however,

solicits additional information that it

will consider before reaching a final

decision on whether the scientific

evidence and usefulness of results are

sufficient to support establishing these

additional quality factor requirements.

Therefore, the agency requests

comments and information on: (1) The

scientific evidence on the importance of

the amount, type, and sources of fat,

calcium and phosphorus, and iron in

infant formula, and (2) the appropriate

methods and interpretative criteria to

determine whether an infant formula

meets the nutritional requirements for

fat, calcium and phosphorus, and iron

of infants consuming the formula as the

sole source of nutrition. The basis upon

which the agency is considering

establishing quality factor requirements

for these nutrients is discussed below.

a. Fat. The agency requests comment

on a quality factor for fat balance that

would require that all infant formulas be

formulated and manufactured to

provide fat in a manner that allows the

fat to be absorbed and retained by

infants at a level that the energy and

other nutritional requirements of the

infant are not adversely affected (Ref. 6).

Normal, healthy, full-term infants fed

various mixtures of the fats traditionally

used in infant formulas in the United

States rarely excrete more than 15

percent of their fat intake (Ref. 6). This

level of fat excretion is an indication
36182 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

that the fat is highly digestible. The use

of a fat with lower digestibility would

adversely affect energy balance, could

reduce the absorption of fat-soluble

vitamins and other nutrients, and could

have a negative impact on healthy

growth of the infants.

b. Iron. The agency solicits comment

on a quality factor that would require

that all infant formula be formulated

and manufactured such that the iron

used is bioavailable and meets the iron

requirements of the growing infant. The

maintenance of adequate iron status in

the infant is important because iron is

required to transport oxygen in the red

blood cells to body tissues (as a

component of hemoglobin), to supply

oxygen to muscle tissue (as a

component of myoglobin), and to

support normal mental development.

Full-term infants are generally born

with adequate iron stores to meet their

iron needs for the first few months of

life, but the iron needs of premature

infants and older infants must be met by

the diet.

Iron bioavailability from infant

formulas is low compared to the iron

bioavailability from human milk (Refs.

61 and 62).

Nutrient sources and other

ingredients, such as protein sources, can

affect the chemical form of iron, thus

interfering with its potential for

absorption (Ref. 63). Furthermore,

factors that enhance iron bioavailability

from human breast milk are poorly

understood and currently are not

present in commercial formulas.

Consequently, infant formulas are

fortified with up to 10 times the amount

of iron found in human milk. If,

however, the bioavailability of the iron

in the infant formula is substantially

improved by a change in the

formulation or processing of the

formula, then reductions in the amounts

of iron added to the infant formula may

be necessary to prevent the infant from

absorbing excessive amounts of iron

which could be unsafe because high

dietary intakes of iron can adversely

interfere with the bioavailabilities of

other nutrients (59 FR 51030, October 6,

1994). If, however, the iron was bound

to another ingredient such that it

interfered with absorption, the infant’s

physiological needs for iron might not

be met. Infant formula iron levels and

iron bioavailability, thus, represent a

delicate balance between effectiveness

and safety that cannot be adequately

predicted by chemical analysis of the

iron content of the formula, but can best

be assessed by measurement of clinical

indicators of iron status.

Early changes in iron nutritional

status are not likely to be detected by

the general quality factor of physical

growth. Therefore, a quality factor

requirement for an infant formula to

meet the iron requirements of infants,

and to contain sufficient bioavailable

iron for this purpose, may be needed.

The agency, however, is concerned that

clinical studies, as described in

proposed § 106.97(a), in which selection

criteria include requirements that

enrollees be healthy, full-term infants

aged 0 to 4 and 5 months, may not be

sensitive enough to detect significant

differences in iron bioavailability of a

formula product. Healthy, full-term

infants are usually born with adequate

iron stores to maintain normal iron

status for the first 3 to 4 months of life—

the period of time that a clinical trial

would be conducted. Without assurance

that the test results are meaningful, the

agency has tentatively decided not to

require a specific quality factor for iron

bioavailability.

c. Calcium and phosphorus. The

agency also requests comment on a

quality factor that would require that all

infant formulas be formulated and

manufactured such that the calcium and

phosphorus are bioavailable and meet

the calcium and phosphorus needs of

infants. Calcium and phosphorus are

essential for healthy bone

mineralization and growth in infants.

Calcium bioavailability is of particular

concern because inadequate intakes of

calcium impair bone mineralization and

can cause rickets in severe cases (Refs.

64 and 65).

Interactions with other ingredients

and manufacturing processes can reduce

calcium and phosphorus bioavailability.

High concentrations of calcium and

phosphorus can interact to form

insoluble complexes that may be

unavailable (Ref. 66). Calcium can

interact with free fatty acids and form

soaps that are not absorbed (Ref. 66).

Lactose-free formulas have been found

to have lower calcium absorption than

formulas containing this sugar (Refs. 67

and 68).

Some phosphorus compounds, such

as the phytates found in plant protein

sources, may not be readily digested and

absorbed by infants (Ref. 69). Inadequate

dietary phosphorus can cause a loss of

calcium from the body as a result of

bone resorption (i.e., loss of bone mass)

(Ref. 70). Formulation or processing

changes that affect other formula

ingredients that influence calcium and

phosphorus absorption require careful

consideration of their potential effects

on calcium and phosphorus

bioavailability and the calcium and

phosphorus status of the infant.

A dietary insufficiency of calcium and

phosphorus of a magnitude that

decreases bone formation may not be

detected by physical measures of growth

(Ref. 71). Therefore, a quality factor

requirement for an infant formula to

ensure that it meets the calcium and

phosphorous requirements of infants,

and to ensure that it contains sufficient

bioavailable calcium and phosphorus

for this purpose, may be needed. FDA

is concerned, however, that meaningful

measures for assessing the

bioavailability of calcium and

phosphorus may not be available.

d. Summary. FDA has tentatively

concluded that the clinical and

nutritional sciences have not reached a

state where specific tests are available

that would permit manufacturers to

establish that they meet quality factors

for each of the essential nutrients listed

in § 107.100, except for protein.

Therefore, except for the quality factor

requirements for physical growth and

protein quality discussed above and set

forth in proposed § 106.96 (b) and (c),

the agency has tentatively concluded

that it is not useful to propose quality

factor requirements for specific

nutrients at this time.

Thus, to meet the nutritional needs of

infants consuming formula,

manufacturers must use forms or

sources of essential nutrients that are

bioavailable. The agency is concerned

that manufacturers could

unintentionally or unknowingly use

forms of nutrients that have a relatively

low bioavailability or ingredients or

processing methods that will produce

interactions that adversely affect the

bioavailability of nutrients, thereby

adulterating the formula because it no

longer meets the nutritional needs of the

infant. However, at this time, FDA is not

aware of a means to systematically

identify those circumstances that could

adversely affect all nutrient

bioavailabilities. FDA does not believe

that it is ethical to unnecessarily subject

infants to testing protocols when

meaningful results cannot be assured.

However, because of the potential

seriousness of the public health impact

of not meeting quality factors, FDA also

believes that it is desirable to establish

additional quality factors, as soon as

they are warranted by evolving

scientific knowledge, to ensure adequate

nutrient bioavailability.

FDA, therefore, requests comment on

the: (a) Need for routine testing of

quality factors, in addition to measures

of physical growth and protein quality;

(b) criteria to be used in determining

that such a need can be meaningfully

implemented, and (c) if a need is

established, the type of qualitative and

quantitative measurements that could be

used by manufacturers to demonstrate
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36183

that an infant formula meets with those

quality factors. If FDA receives

information demonstrating the need for

additional quality factors, it will

consider including them in any final

rule that results from this proceeding.

5. Assurances for Quality Factors

a. Quality factor—physical growth of

infants. Proposed § 106.97(a)(1) requires

that the manufacturer conduct an

adequate and well-controlled clinical

study to determine whether the formula

supports normal physical growth in

infants when it is fed as the sole source

of nutrition. The CON/AAP Task Force

on Clinical Testing of Infant Formulas

(Ref. 6) concluded that the capability to

support physical growth is the most

widely accepted and used measurement

available of the nutritional adequacy of

an infant formula. Gains in weight and

length of young infants reflect the longterm, integrative physiological processes

that can only be achieved if the infant’s

nutritional needs are met.

A randomized, controlled study

represents the most sensitive type of

study to measure the nutritional

adequacy of infant formula. The use of

concurrent treatment and control groups

is in agreement with the CON/AAP Task

Force recommendations (Ref. 6) and

with the agency’s recommendations for

human bioavailability studies of drugs

(21 CFR 320.25). Although comparisons

to historical controls (e.g., population

reference standards) have been used by

some investigators to evaluate growth of

infants consuming a particular formula

product, this type of study lends itself

to misleading results because

population reference standards are

generally for the total population of

infants (regardless of birth weight,

health status, socioeconomic status, or

other factors that can affect growth

unrelated to nutritional components). In

a study to evaluate the nutritional

adequacy of a formula, on the other

hand, selection criteria are usually used

to limit enrollment to healthy, full-term

infants. Thus, differences or similarities

in growth between study infants and

population reference standards cannot

be meaningfully interpreted. Therefore,

the agency is proposing to require that

adequate and well-controlled clinical

studies be conducted to collect the data

needed to determine whether a formula

satisfies the quality factor requirements

for physical growth. To assist

manufacturers in understanding the

general principles for adequate and

well-controlled clinical studies, FDA

has prepared the ‘‘Guideline for the

Format and Content of the Clinical and

Statistical Sections of New Drug

Applications,’’ U.S. Department of

Health and Human Services, July, 1988

(Ref. 72).

FDA has tentatively concluded that it

is necessary to enroll infants into a

clinical study shortly after birth, and

that the studies be at least 4 months in

duration (see proposed

§ 106.97(a)(1)(i)(A)), to ensure that the

study focuses on the period during

which infant formula generally serves as

the sole source of nutrition, and, thus,

the infant is most vulnerable to a

problem with a formula since the infant

is not consuming other foods that could

mask or compensate for a deficiency in

the formula. Also, the sensitivity of

growth studies for identifying

nutritional problems with an infant

formula is highest during early infancy.

Young infants, those less than 4 to 5

months, allocate a substantially higher

percentage of the intakes of energy,

protein, and other nutrients for growth

than do older infants. After this early

period of rapid growth, the rate of

physical growth slows, and the

allocation of nutrient intakes for growth

is lower. Thus, early infancy is the

period of greatest nutritional risk and is

the age associated with the most

sensitive growth phase.

Because of the rapid rate of growth in

infants less than 4 months of age,

adverse nutritional impacts that affect

growth rate can be detected within a few

months (Ref. 4). Growth studies in older

infants, where growth rates are of

smaller magnitude and where solid

foods are also consumed, are not

sensitive enough to provide a

meaningful evaluation of the ability of

the formula to support healthy growth.

The CON/AAP Task Force (Ref. 6)

also recommended that clinical studies

be conducted for a period of 3 to 4

months, and that growth be examined at

least during the first 8 weeks of life,

because nutrient requirements per kg

body weight are greatest during this

period. It also pointed out that such a

study will cover a period when the

infant is not consuming solid foods, and

the infant formula is fed as a sole source

of nutrition.

Therefore, FDA has tentatively

concluded that a clinical trial that lasts

at least 4 months will be long enough

to detect adverse effects of nutritional

inadequacies on growth rate. FDA also

has tentatively concluded that a clinical

trial must be conducted with infants

less than 1 month of age at the time of

their entry into the study (see proposed

§ 106.97(a)(1)(i)(A)) to ensure that the

formula is tested during the period of

time when growth rate and nutrient

requirements are proportionately

greatest, and when the infant formula

serves as the sole source of nutrition.

These requirements are intended to

ensure that the study assesses the

nutritional adequacy of the formula for

supporting normal physical growth in

the young infant.

Under proposed § 106.97(a)(1)(i)(B),

the manufacturer will be required to

collect and maintain individual and

group summary data on anthropometric

measures of physical growth and plot

the data on National Center for Health

Statistics (NCHS) reference percentile

body weight and body length curves,

which are standard measurements of

infant physical growth (Refs. 73, 74, and

75) and provide the most widely

accepted assessment of infant growth

(Ref. 6).

Plotting each infant’s anthropometric

data on NCHS reference percentile body

weight and body length curves, and

providing individual data on increments

of weight gain, provide a means to make

a quantitative assessment of the growth

pattern over the 4 months duration of

the study for individual infants. There

is normally wide variation in body

weights and lengths among healthy

infants, with some being smaller than

average and others average or above

average. Single point measures of

weight or length are difficult to interpret

relative to a given infant because one

does not know whether, for example, a

smaller than average weight is

attributable to inadequate nutrition or to

a healthy and thriving infant whose

body size is smaller than average.

Over time, young infants tend to

individualize their track within a given

percentile on population reference

growth standards. An infant at the 25th

percentile level for weight shortly after

birth tends to stay at or near the 25th

percentile for weight throughout the

first few months of life. When multiple

longitudinal measures of weight (or

length) of an infant are plotted on a

weight-for-age reference chart, a

reviewer can make a quick assessment

as to whether an infant’s pattern of

weight or length gain is similar to that

expected for healthy infants of the same

age, taking into account the range of

normal individual variation in body

weights and lengths and that infant’s

percentile track. Similar comparisons

can be made with a given infant’s

weight or length incremental gain data

relative to population reference

standards. These data allow for

identification of infants with unusually

slow or rapid growth, an observation

that is masked by grouped data.

Thus, plots of changes in individual

infant’s weight and length in

conjunction with comparisons of

increments per unit time of weight or

length gains against population
36184 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

reference standards allow researchers

and reviewers to identify those infants

whose growth is not following expected

longitudinal patterns and, therefore, for

whom a more thorough review of their

medical and dietary histories is

necessary to assess the possibility that

the infant formula is responsible for

reduced growth rates in a subgroup of

infants. This careful review of

individual infant growth patterns in

addition to group summary data is

particularly important because studies,

while adequate to evaluate differences

in group means between test and control

formulas, often lack the statistical power

to detect subgroups of infants whose

growth patterns deviate from normal.

These data will also provide useful

information on possible trends towards

failure to thrive or obesity, or on

catchup growth in infants who

experienced transient adverse effects

relative to expected growth rates.

FDA has tentatively concluded that a

comparison of a manufacturer’s data to

well-established population reference

standards can provide the basis for an

evaluation of the growth patterns of

individual infants to identify, and to

provide the basis for an investigation of,

possible causes of unusually slow or fast

rates of gain. Thus, the agency is

proposing that the NCHS growth charts

for individuals and for grouped data be

incorporated by reference into the

regulation (proposed

§ 106.97(a)(1)(i)(B)).

Proposed § 106.97(a)(1)(i)(C) requires

that the manufacturer collect the

anthropometric measurements at the

beginning of the clinical study, at 2

weeks and at 4 weeks of the study, at

least monthly thereafter, and at the

conclusion of the study. These

measurements will permit the

calculation of incremental gains in the

different measurements. Incremental

gains, such as weight gain per unit of

time, are generally considered the most

sensitive indicator of the ability of a

formula to support the physical growth

of individual infants over time (Ref. 4).

Also, because growth rate and

nutritional requirements are curvilinear

rather than linear during early infancy,

multiple measurements help in

assessing whether the formula meets the

nutritional needs throughout the period

of the clinical study and aids in more

accurately placing infants in their

‘‘correct’’ reference percentile tract,

particularly since age of enrollment

varies somewhat among infants

(although, if adopted, this regulation

should serve to minimize that

variation). Additionally, measures of an

infant’s body weight, the most critical

anthropometric measure, are subject to

a number of measurement errors

unrelated to the nutritional value of the

formula (e.g., timing of weighing of

infant relative to feeding or defecation

or urination).

For these reasons, multiple measures

over a relatively long period (e.g., 4

months) provide a more accurate picture

of the pattern of growth of infants than

do one or two point measures. The

agency has tentatively concluded that

the requirement of four measurements

taken 1 month apart will provide a

sufficient number of measurements to

permit evaluation of whether the

formula meets the nutritional needs for

physical growth of the infant throughout

the study period. However, the agency

requests comment, supported by data,

on which measurements are needed to

provide evidence that the formula meets

the nutritional needs for physical

growth of infants.

FDA has tentatively concluded that

more frequent measurements are needed

during the early stages of the study

because variations in measured body

weight that are a result of factors

unrelated to the nutritional quality of

the formula can be particularly serious

in early infancy. For example, during

the first week of life, there is a normal

loss of body weight by the infant

because of fluid loss that may reach 6

to 10 percent of body weight (Ref. 76).

This weight loss will reduce the

apparent growth of the infant as

measured by body weight. This

reduction may affect the ability to

evaluate and interpret the weight gain

data collected early in the study. FDA

has tentatively concluded that requiring

more frequent anthropometric

measurements, especially for weight,

early in the study, increases the ability

to accurately place individual infants in

the correct percentile track for

monitoring their growth patterns in

relation to the population reference

curves and for monitoring physical

growth during the most sensitive part of

their growth phase.

To minimize the burdens of this

regulation, FDA has not proposed to

require that blood samples obtained

from infants during the time period of

their enrollment in the clinical study, or

at completion of the study, be analyzed

for biochemical and clinical indicators

of nutritional and growth status.

However, the CON/AAP Task Force

(Ref. 6) recommended that some blood

tests be conducted at the conclusion of

required clinical studies to provide a

more comprehensive evaluation of the

nutritional adequacy of a formula. Thus,

the agency requests comments on

whether it would be useful for the

manufacturer to collect and maintain

data on standard laboratory measures,

including complete blood count (white

blood cell count and red blood cell

count), hemoglobin concentration or

hematocrit percentage, and serum or

plasma concentrations of albumin, urea

nitrogen, electrolytes (sodium,

potassium, and chloride), alkaline

phosphatase, and creatinine. These

measurements are standard practice

when infants are seen clinically and can

be made with very small quantities of

blood. The maintenance of these

indicators within normal limits at the

end of the study provides additional

assurance over and above measures of

physical growth that the infant’s general

state of well-being is healthy and

‘‘normal,’’ particularly because changes

in biochemical measures may occur

before detectable differences in physical

growth are identified or may not be

detected by measures of physical

growth. General anthropometric

measurements of physical growth

provide indirect, although very

important, evidence that the formula is

able to help the infant maintain overall

good health, but they are not as specific,

and may not be as sensitive, as are

biochemical indicators of health.

FDA also requests comment on

whether requiring some, or all, of the

biochemical and clinical tests described

above would provide useful and

necessary information for determining

whether a formula causes adverse

consequences that may not be reflected

in the quality factor requirements for

measurements of physical growth in

proposed § 106.97(a)(1)(i).

The identification of deviations from

expected values for these biochemical

and clinical measurements, throughout

the duration of the clinical study, could

serve as an early warning of unexpected

risk to infants enrolled in the study and,

therefore, result in early actions to

prevent undue risk to infant enrollees in

the study. Conversely, collection of

blood samples throughout the study

could discourage parents from

continuing their infants in the study,

thus causing a high attrition rate and

producing final study results that are

difficult to interpret.

Proposed § 106.97(a)(1)(ii) sets forth

guidelines for the design of clinical

study protocols. A comprehensive

clinical study protocol will ensure that

individual investigators understand and

follow generally accepted scientific

principles for the design and conduct of

clinical trials, thus enhancing the

likelihood of interpretable results while

maintaining minimal or no risk to

infants enrolled in the studies. In the

conduct of all studies, manufacturers

should use the general principles,
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36185

described in § 314.126 (21 CFR 314.126)

for adequate and well-controlled

clinical studies to ensure that the design

and conduct of the study are adequate

to permit scientific review and

interpretation of the study’s results.

Studies that cannot produce meaningful

results because of poor or inadequate

study design and conduct mean that

infants will be subjected to unnecessary

testing. Such a situation places infant

enrollees at undue risk and is clearly

unethical.

In this section, FDA is not

establishing mandatory elements for

inclusion in a protocol, nor requiring

that manufacturers provide the agency

with the protocol used for a study

intended to provide data to show that an

infant formula meets the quality factor

requirements. However, as discussed

above, a protocol is an essential part of

the design and execution of a wellcontrolled scientific study. Furthermore,

a protocol often provides invaluable

information that assists in the analysis

and interpretation of the study data.

Consequently, the agency strongly

encourages manufacturers to develop

and use protocols that incorporate the

specific elements in proposed

§ 106.97(a)(1)(ii) in all research studies

using infants because these elements

will ensure that the study is designed

and conducted in a manner that will

produce results that will permit

meaningful evaluation of the usefulness

of the infant formula.

The steps outlined in proposed

§ 106.97(a)(1)(ii)(A) represent standard

practice in the design and conduct of

clinical studies (Ref. 72). Proposed

§ 106.97(a)(1)(ii)(B) states that the

clinical study protocol should describe

the necessary qualifications and

experience of the investigators. It is

essential that clinical studies be

conducted by personnel with sufficient

experience and training to ensure that

their work will yield interpretable and

meaningful results. If a study is

conducted by an investigator who is not

qualified, it increases the likelihood that

the study will have to be redone, and

that more infants will be exposed to

risk. Therefore, it is important that in

the protocol, the manufacturer define

the requisite qualifications to conduct

the study it is designing.

Proposed § 106.97(a)(1)(ii)(C) states

that the protocol should be reviewed

and approved by an Institutional

Review Board (IRB) in accordance with

part 56 (21 CFR part 56), and that the

manufacturer should establish

procedures to obtain written informed

consent from the parents or legal

representatives of the infants enrolled in

the study in accordance with part 50 (21

CFR part 50). These steps are necessary

to protect the rights and safety of

subjects involved in the studies.

Proposed § 106.97(a)(1)(ii)(D) states

that the clinical study protocol should

explain how the study population

represents the population for which the

new infant formula is intended. FDA

has tentatively concluded that such an

explanation is necessary so that if

questions about the relevance of the

study population arise, the answer is

readily available and free of any taint

that it is a post hoc rationalization. For

example, FDA has recently had

questions about a study that involved

hospitalized infants that were offered to

support use of the product on postdischarge infants. If there had been the

type of explanation available that FDA

is proposing in this guideline, it would

have greatly minimized the questions

about this product.

Proposed § 106.97(a)(1)(ii)(D) also

states that the clinical study protocol

should explain how the study addresses

the intended conditions of use of the

formula. FDA has tentatively concluded

that, by having manufacturers consider

this question before the study is

conducted, this guideline will prevent

clinical studies that are conducted

under conditions of use that do not

accurately reflect the proposed

conditions of use. For example, a

clinical study protocol for testing a

formula designed to be used by

premature infants throughout infancy

should explain how the study design

will provide information to support the

claim that the formula supports healthy

growth under these conditions.

Proposed § 106.97(a)(1)(ii)(E) states

that the clinical study protocol should

describe the sample size calculations

and the power calculations and the

basis for selecting the sample size and

study design. This information is

necessary to establish the likelihood

that the study will not fail to detect a

real difference, should there be a

difference for the measurements of

interest, between the infant formula

being tested and the control. For

example, a study might not find a

difference in incremental rate of weight

gain between infants consuming two

formulas because too few infants were

enrolled in the study to provide

sufficient statistical power to detect this

difference. Inadequate statistical power

could mask the nutritional inferiority of

a product and could result in the

marketing of a formula that does not

meet the quality factor requirements

and, therefore, is not safe for its

intended use. Therefore, FDA has

tentatively concluded that this guideline

is needed to ensure that manufacturers

design their growth studies to be

capable of detecting biologically

meaningful differences for the

endpoints of interest between the two

formulas. Identification of differences

would raise safety concerns or serious

questions of nutritional quality of the

test formula product.

Proposed § 106.97(a)(1)(ii)(F) states

that the clinical study protocol should

include a plan to identify and evaluate

any adverse events. This proposed

guideline is necessary to document that

appropriate attention is given to the

systematic evaluation and recording of

any adverse events that may occur

during the course of the study.

Inadequate planning for and conduct of

the monitoring of adverse events may

result in an erroneous conclusion that

the formula is safe and suitable, when

in fact the formula is not safe and

suitable for infants under intended

conditions of use.

Proposed § 106.97(a)(1)(ii)(G) states

that the clinical study protocol should

describe the quality control procedures

that the investigator will use to ensure

the validity and reliability of the

measurements collected. This proposed

guideline represents standard practice

in the design and conduct of clinical

studies and is necessary to allow a

meaningful interpretation of study

results. Data obtained with unreliable

measures, or with indicators that do not

accurately or meaningfully measure

identified endpoints, may produce

misleading study results that are

uninterpretable and that suggest that a

formula is safe and suitable, when more

valid or reliable measures would not

have supported this conclusion. The

institution of adequate quality control

procedures before beginning a study

provides a mechanism for

manufacturers to ensure that the data

collected are reliable, and that the study

provides interpretable results.

Proposed § 106.97(a)(1)(ii)(H) states

that the clinical study protocol should

describe and compare the composition

of the control and test formulas. These

descriptions of the control and the test

formulas are necessary to establish that

the formula used as the control provides

an adequate comparison for evaluating

the quality factors of the test formula. If

the control formula is not comparable to

(i.e., bioequivalent to) formulas in

current use, differences between the test

and control formulas have no meaning.

They cannot be generalized to projected

conditions of use. For example,

comparable or enhanced physical

growth in infants consuming a test

formula as compared to infants

consuming a control formula when the

control formula does not meet
36186 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

requirements in § 107.100 for nutrients,

or is not bioequivalent relative to

quality factors to currently marketed

formulas in the United States, cannot be

interpreted as supporting healthy

growth because it is not possible to

determine whether the apparent ‘‘equal’’

or ‘‘enhanced’’ physical growth is

attributable to the fact that the formula

is nutritionally adequate, or whether the

formula looks adequate because it is

being compared to a nutritionally

inadequate formula. The nature of the

differences between control and test

formulas will also affect sample size and

measurement (endpoint) considerations.

FDA’s experience in reviewing

clinical data submitted with 90-day

notifications has been that the absence

of information on control formulas is

not uncommon. Thus, FDA has

tentatively concluded that a guideline

on the information that needs to be

considered in selecting a control

formula is necessary to ensure that

study results are meaningful and

interpretable.

If the test formula used in a study is

not identical to the formula that is

intended to be marketed in the United

States, proposed § 106.97(a)(1)(ii)(I)

states that the clinical protocol should

describe the basis upon which the

manufacturer has decided that the test

formula is appropriate for use in the

study. This proposed guideline is

necessary to ensure that the

manufacturer considers such factors as

the bioequivalence of the studied (test)

formula relative to the formula that is to

be marketed in this country and can

document why its choice of test

formulas is appropriate. Without this

documentation, it would not be possible

to determine whether the marketed

formula meets the quality factor

requirement in proposed § 106.96(b).

FDA has had experience under the

1986 amendments in which

manufacturers have submitted data on

test formulas that were significantly

different (e.g., in calorie levels) from the

formula that they intended to market as

evidence of the safety and suitability of

the latter formula. In these instances,

the agency has had considerable

difficulty in interpreting study results.

Therefore, if the guidance in proposed

§ 106.97(a)(1)(ii)(I) is followed, this

significant study design issue will be

critically reviewed by manufacturers

before they initiate their studies, and, as

a result, they will be more likely to

design and conduct a study that will

produce data that can be meaningfully

interpreted as evidence that an infant

formula is safe, and that it supports

healthy growth.

As provided in proposed

§ 106.97(a)(2), however, FDA

recognizes, that while changes in

ingredients or in the processes used in

the manufacture of infant formulas can

have a significant adverse impact on the

levels or availability of nutrients that

affect healthy growth of infants, other

changes may not be likely to do so. In

the latter circumstances, it may be

possible to demonstrate that the quality

factor requirements are met by means of

measures or data that do not involve the

use of clinical trials. If such assurances

can be provided without clinical trials,

then infants will not be subjected to

unnecessary testing. Therefore, FDA sets

out in proposed § 106.97(a)(2), the

circumstances in which a manufacturer

can request an exemption from the

clinical study requirement.

Proposed § 106.97(a)(2)(i) provides for

an exemption if the manufacturer can

cite experience that shows that the

ingredient, ingredient mixture, or

processing method has been used to

make an infant formula that meets the

quality factor requirements in proposed

§ 106.96(a). For example, if the

manufacturer has previously submitted

information to FDA in response to the

quality factor requirements of the act

that showed that an infant formula that

contains the ingredient or ingredient

mixture, or that was produced by the

processing method, in question

supported adequate physical growth,

this information could form the basis on

which the new infant formula could

qualify for an exemption from this

quality factor requirement. Under this

provision, FDA will evaluate the

experience cited in support of an

exemption on a case-by-case basis. FDA

requests comment on this proposed

provision.

Proposed § 106.97(a)(2)(ii) provides

for an exemption if a manufacturer that

markets a formulation in more than one

form (such as liquid and powdered

forms) can demonstrate that the quality

factor requirements are met by the form

of the formula that is processed using

the method that has the greater potential

for adversely affecting the formula’s

nutrient content and bioavailability. For

example, the temperatures used to retort

liquid formulas during processing can

cause a loss of protein quality compared

to powdered forms processed at lower

temperatures (Refs. 77 and 78). Thus, if

the liquid formula is tested and shown

to meet the quality factors requirements,

it will provide reasonable assurance that

the powdered form of the formula, that

is, the less processed form is of

appropriate nutritional quality. Thus,

FDA tentatively concludes that it would

be unnecessary to test the less processed

form.

Proposed § 106.97(a)(2)(iii) provides

for an exemption if the manufacturer

can demonstrate that the requirements

of proposed § 106.97(a)(1) are not

appropriate for the formula, and an

alternative method or study design for

showing that the formula supports

healthy growth in infants fed the

formula as a sole source of nutrition is

available. As stated above, doubleblind, well-controlled, clinical studies

are generally the most powerful and

sensitive method for demonstrating that

an infant formula will support physical

growth. Nonetheless, the agency

anticipates that there will be

circumstances in which a clinical study

of a new infant formula would not be

appropriate. For example, double-blind

clinical studies would not be

appropriate in situations such as those

involving some exempt infant formulas

in which they would cause withholding

of conventional treatment and,

therefore, would be unethical. Other

situations that may not be amenable to

double-blind clinical trials are those in

which it would be difficult to enroll an

adequate number of infants (e.g., for

exempt infant formulas where the

formula is intended for a rare disease).

Alternative study designs may also be

appropriate in situations in which a

manufacturer has access to extensive

reference data, such as a database on

many similarly conducted clinical

studies using infants from the same

potential study population, provided

that the manufacturer can demonstrate

that the reference data apply to the new

infant formula, its intended use, and its

study population. FDA has tentatively

concluded that such an exemption will

permit flexibility in the design of

suitable experimental protocols but still

provide reasonable and documentable

assurance that the study design can

demonstrate the safety and suitability of

the infant formula.

b. Specific quality factors. Proposed

§ 106.97(b) establishes requirements for

demonstrating that a formula meets the

protein quality factor requirement in

proposed § 106.96(c) and requires that

the manufacturer 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 by

demonstrating that the protein source

supports adequate growth using the PER

rat bioassay, which the agency proposes

to incorporate by reference. The PER

provides an estimate of the

bioavailability and relative proportion

of the essential amino acids in the

protein-containing ingredient.
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36187

A chemical analysis of the protein can

identify the amino acids contained in a

protein source but does not measure

their bioavailability. A protein source

may contain the necessary amino acids,

but they may be in a form that the infant

cannot digest and absorb. Furthermore,

processing methods may alter the

chemical nature of the protein source,

possibly making the protein more

resistant to digestion by the infant. FDA

has tentatively concluded that the rat

bioassay is necessary to establish that

the amino acids in a protein source are

present, and that adequate amounts and

proportions of all essential amino acids

are capable of being digested by an

infant. Such a showing is particularly

important when a manufacturer is using

a novel protein source (e.g., a

hydrolyzed protein), a new protein

mixture, a new processing method that

could affect the chemical form or

bonding of amino acids, or a

formulation that provides an amount of

protein near the minimum required

level (<2.0 g/100 kilocalorie (kcal))

specified in § 107.100.

Proposed § 106.97(b)(1) also provides

that if the manufacturer is unable to

conduct a PER rat bioassay, it must

demonstrate that the amino acid

composition of the protein meets the

known amino acid requirements of

infants for whom the formula is

intended. For example, FDA is aware

that a PER would not provide useful

data for an exempt infant formula

intended for use in infants that cannot

metabolize a specific amino acid and

from which that amino acid has been

purposefully omitted or is limited to a

level inadequate to support healthy

growth. The lack of that amino acid is

necessary for the dietary management of

the intended infant population but

would result in an incomplete protein

and would reduce the growth rate of the

rat, invalidating the conditions upon

which the PER rat bioassay is based.

FDA is not aware of alternative methods

for ensuring bioavailability of such a

protein source. In these circumstances,

proposed § 106.97(b)(1) will provide an

alternate means of evaluating whether

the protein at least contains adequate

amounts of essential amino acids to

meet the known amino acid

requirements of the infant, even though

the bioavailability of these amino acids

cannot be assured using available

methods.

Proposed § 106.97(b)(2) establishes

the circumstances in which a

manufacturer may request an exemption

from the requirements of proposed

§ 106.97(b)(1). Proposed § 106.97(b)(2)(i)

provides that if the protein source

(including the processing method used

to produce it) is already used in another

of the infant formulas marketed by its

manufacturer in the United States, the

manufacturer may request an exemption

if it can demonstrate that such other

infant formula meets the quality factor

requirements prescribed in

§ 106.96(b)(1). The purpose of the PER

or amino acid analyses is to estimate the

quality of the protein in the proposed

formula. Once a manufacturer has

established standard sources and

processing of protein in a formula, and

has demonstrated that the technology is

effective, in its hands, in producing a

formula that meets the quality factor

requirement for protein, other

formulation changes would not be

expected to markedly affect protein

quality. Thus, the quality of the

processed protein would be retained in

other formulas. However, under

proposed 106.97(b)(2)(i), it will be

incumbent on the manufacturer to

demonstrate that the quality of the

protein is not affected.

Proposed § 106.97(b)(2)(ii) provides

for an exemption if the protein source,

or the processing method used to

produce the protein source, in the infant

formula does not constitute a major

change from the infant formula that it

replaces, and the manufacturer can

demonstrate that the infant formula that

it replaces meets the quality factor

requirements prescribed in § 106.96(b).

FDA is proposing to allow this

exemption because it is unlikely that the

methods for assessing protein quality

prescribed are sensitive enough to

measure any change in protein quality

that is not a major change.

Because FDA has, as a matter of

policy, been requesting that infant

formula manufacturers submit data from

a PER or amino acid analysis as part of

their submission 90 days prior to

marketing infant formula, many infant

formulas that are on the market have

been shown to meet the proposed

quality factor requirement for protein.

Therefore, if the proposed exemption

criteria in § 106.97(b)(2) are adopted,

those formulas that contain protein

sources, or proteins which were

produced using processing methods,

that were the subject of a submission to

FDA in response to the quality factor

requirements of the act may qualify for

an exemption.

6. Request for Comment on Establishing

Assurances for Other Quality Factors

As discussed above, FDA has solicited

comment on whether to establish

quality factor requirements for fat, iron,

and calcium and phosphorus. If such

quality factors are adopted, appropriate

methods will be needed to provide

assurance that an infant formula meets

these nutrient-specific quality factors.

Therefore, FDA discusses below

measurements of fat balance and of

calcium and phosphorus balance, as

well as measurements that reflect iron

bioavailability. The agency requests

comments and information on these or

other methods for these three quality

factors:

a. Apparent fat absorption. Apparent

digestibility and apparent absorption

measure the amount of fat that was able

to be digested and absorbed by the

infant. Apparent digestibility is

expressed as a percentage of intake,

while apparent absorption is expressed

in units of fat (e.g., g) absorbed per day.

If a quality factor for fat were

established, manufacturers would be

required to collect and maintain data

establishing that the apparent

digestibility or apparent absorption by

the infant of the fat in an infant formula

is adequate to meet the infant’s energy

requirements. These data would be

necessary because fat represents the

major dietary source of energy for the

infant and must be readily digested and

absorbed if the formula is to support

healthy growth.

The CON/AAP Task Force (Ref. 6)

recommended that studies that are

conducted to determine whether a

formula meets the quality factor for fat

should use a cross-over experimental

design. This type of study requires that

the manufacturer compare apparent fat

absorption of infants fed the test

formula at one time and a currently

marketed formula at another time. An

experiment using this design would

enable a manufacturer to make

measurements of apparent fat

absorption using a small number of

infants, since the variance in fat

excretion of infants fed most fat sources

currently available is less than 5

percent. Furthermore, the method is

noninvasive, is easily implemented, and

does not require costly or sophisticated

equipment to conduct. Other

experimental designs could be used but

would require larger numbers of infants

and would be more expensive. Thus,

FDA asks for comments on whether

there should be a specific requirement

that manufacturers measure apparent fat

absorption using cross-over studies.

The CON/AAP Task Force (Ref. 6)

recommended that studies that are

conducted to determine the apparent

absorption of fat be conducted such that

measurements are made using infants

fed each formula for at least 72 hours.

The Task Force report suggested that

measurements of apparent fat

absorption for this length of time would

accurately reflect the apparent
36188 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

absorption of the fat in the formula

being tested. FDA is considering

requiring that a study of at least 72

hours for each formula tested be

conducted and requests comment on

what duration would be appropriate.

FDA also is considering whether to

require that the manufacturer document

the method that it used to analyze for

fat and explain the reason for choosing

that method. The agency believes that

this information is important because

the method used to analyze the excreted

fat must be appropriate for the specific

type of fat in the formula.

FDA also is considering whether

circumstances exist that would justify

establishing an exemption from the

requirements to measure fat balance.

FDA has tentatively concluded that the

reasons and justification for such an

exemption are essentially those set forth

above in the discussion of proposed

§ 106.97(b)(2). FDA requests comment

on whether, if the agency adopts a

quality factor for fat, it should provide

for exemptions from testing, to show

that the formula meets that quality

factor, such as those set forth in

proposed § 106.97(b)(2), and to allow

manufacturers to assure the agency that

their products meet that quality factor

requirement without subjecting infants

to unnecessary testing.

b. Calcium and phosphorus balance.

If FDA were to establish a quality factor

for calcium and phosphorus,

manufacturers would be required to

collect and maintain data from clinical

studies conducted in infants to show

that the calcium and phosphorus

contained in the infant formula are

sufficient to meet the infant’s

requirements. There are currently no

satisfactory clinical laboratory

measurements that are practical for

directly assessing calcium and

phosphorus nutritional status in infants

(Ref. 79). Furthermore, there are no

accurate indirect measurements that

could be made on the infant formula

itself that would be useful in predicting

how effective the amount and the

sources of calcium and phosphorus in

the formula would be in meeting the

needs of infants consuming that

formula. Therefore, FDA is considering

requiring that manufacturers implement

the recommendations of the CON/AAP

Task Force and make a measurement

that provides a reasonable estimate of

the amount of calcium and phosphorus

that is capable of being absorbed and

retained for use by infants (i.e., calcium

and phosphorus balance) from the

formula.

FDA asks for comment concerning the

appropriateness and usefulness of a

measurement of calcium and

phosphorus balance as one that reflects

both the bioavailability of the calcium

and phosphorus in the formula and how

well the diet meets the metabolic

requirements for these two minerals. As

discussed above with regard to the

conduct of trials to measure apparent fat

absorption, FDA requests comment on

whether it is necessary to require that a

cross-over study design be used for

clinical studies to measure calcium and

phosphorus balance.

FDA also requests comment on what

would be an appropriate duration for

studies to measure calcium and

phosphorus balance. The CON/AAP

task force suggested that calcium and

phosphorus balance studies be

conducted for a 72-hour balance period

after an 11-day adaptation period. FDA

requests comment on whether these

time periods are appropriate, both to

minimize the effects of previous dietary

intake on the availability of calcium

from the formula being tested (Ref. 6)

and to ensure that the results of the

balance study are reliable and

interpretable, and on whether they

provide a meaningful basis on which to

determine that a formula meets the

quality factor requirement for calcium

and phosphorus.

FDA is considering requiring that the

formula used as the control in any

clinical studies to measure calcium and

phosphorus balance contain

approximately the same calcium and

phosphorus levels as the test formula

because the absolute amounts of these

nutrients absorbed and retained by

infants may be different between

formulas with different calcium and

phosphorus levels. FDA is asking for

comment on requirements for

appropriate control formulas for

calcium and phosphorus balance

studies.

Amounts of calcium and phosphorus

in urine and feces, along with calculated

amounts absorbed and retained

expressed in milligrams per kilogram

and as percentages of intake, provide

evidence of the rates of absorption and

retention of these nutrients but do not

specifically measure the ability of the

formula to provide adequate calcium

and phosphorus for proper bone

mineralization, the most important need

for these minerals in the infant. FDA is

considering requiring that serum

alkaline phosphatase be measured in

situations in which calcium and

phosphorus balance studies are required

in order to assess the adequacy of

formula minerals to support normal

bone mineralization. Alkaline

phosphatase is an enzyme involved in

bone remodeling and in maintaining

serum calcium concentration (Ref. 64).

Increased serum alkaline phosphatase

activity may be a marker of reduced

bone mineralization (Ref. 80) and

therefore may be useful in determining

whether a formula meets a quality factor

requirement for calcium and

phosphorus.

Because of the limits of metabolic

balance studies, including short

duration, dependence on previous diet,

and expense, the agency is considering

the appropriateness of alternative

methods for the assessment of bone

mineral accretion. The agency is aware

that sophisticated instruments, such as

single-photon absorptiometry and dualenergy x-ray absorptiometry, have been

tested for measuring bone mineral

content in infants (Refs. 81 through 84),

and that some authorities recommend

them for determining bone

mineralization in infants (Ref. 85).

These types of measurements have the

potential to provide an accurate

measure of bone mineral accretion over

the duration of use of the formula, while

at the same time reducing many sources

of variation inherent in balance studies.

The agency is concerned, however, that

these methods have not been adequately

validated in infants, and that reference

standards for mineralization in infants

have not been established to support a

requirement for manufacturers to

measure bone mineralization in order to

provide assurance that a formula

satisfies a quality factor requirement for

calcium and phosphorus. The agency

asks for comment on the usefulness of

these methods of analysis of bone

mineral accretion in infants, and on

whether they should be used in lieu of

calcium and phosphorus balance

studies as measurements of whether an

infant formula meets the quality factor

requirements for calcium and

phosphorus assuming that the agency

adopts such a quality factor. The agency

also asks for comment on the criteria

that it should use, on a case-by-case

basis, in deciding whether to require

these types of measures when there is

particular reason to be concerned that

calcium and phosphorus bioavailability

may be problematic.

FDA also is considering whether

circumstances exist that would justify

establishing an exemption from a

requirement to measure calcium and

phosphorus balance. FDA has

tentatively concluded that the reasons

and justification for such an exemption

are essentially those set forth above in

the discussion of proposed

§ 106.97(b)(2), and requests comment on

whether, if it adopts a quality factor for

calcium and phosphorus, it should

provide for exemptions from testing to

show that the formula meets the quality
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36189

factor similar to those in proposed

§ 106.97(b)(2) and allow manufacturers

to assure the agency that their products

meet that requirement without requiring

redundant testing.

c. Iron status. If FDA were to adopt a

quality factor for iron, manufacturers

would be required to collect and

maintain data that establish that the iron

in an infant formula is bioavailable and

maintains the iron status of infants that

consume the formula. These data would

be necessary to demonstrate that an

infant formula provides enough iron to

prevent iron deficiency and anemia.

Alterations in a number of

biochemical measurements are useful

signs associated with inadequate iron

intake or the development of iron

deficiency. Early signs of inadequate

iron intake, which reflect the depletion

of iron storage sites, are reductions in

serum ferritin concentration and

transferrin saturation (Ref. 86). If the

dietary intake of iron remains

inadequate, impaired erythropoiesis

(i.e., the process whereby the body

produces new red blood cells) may be

reflected in alterations in erythrocyte

maturation and increases in erythrocyte

size, erythrocyte protoporphyrin

concentration, or serum transferrin

receptor levels. If the period of

inadequate iron intake continues,

erythropoiesis is further impaired, and

hemoglobin concentration, hematocrit,

and mean corpuscular volume decrease.

Iron deficiency without anemia

should be considered to be a risk factor

for iron-deficiency anemia, which may

be associated with long-lasting, adverse

effects in infants (Ref. 86). Therefore,

FDA is considering requiring one

measurement of iron status that is

sensitive to each of the three stages of

inadequate iron intake (stage 1,

decreased stores, normal erythropoiesis;

stage 2, decreased stores and early stage

impaired erythropoiesis; and stage 3,

decreased stores and late stage impaired

erythropoiesis). For example, FDA is

considering requiring that

manufacturers measure: (1) Serum

ferritin concentration, because such a

measurement is sensitive to decreased

iron stores and normal erythropoiesis;

(2) transferrin saturation or erythrocyte

protoporphyrin concentration, because

such measures are sensitive to

decreased iron stores and early stage

impaired erythropoiesis; and (3)

hematocrit percentage, hemoglobin

concentration, or mean corpuscular

volume, because such measurements are

sensitive to decreased iron stores and

late stage impaired erythropoiesis. This

approach would be consistent with the

recommendations of the CON/AAP Task

Force (Ref. 6). It would also provide

reasonable assurance that low iron

availability in an infant formula would

be detected, and that an infant formula

that does not provide sufficient iron to

meet the infant’s requirement, and

thereby does not meet the quality factor

requirement for iron, will not be

marketed.

FDA also is considering whether

circumstances exist that would justify

establishing an exemption from the

requirements to determine iron status.

FDA has tentatively concluded that the

reasons and justification for such an

exemption are essentially those set forth

above in the discussion of proposed

§ 106.97(b)(2). FDA requests comment

on whether, if it adopts a quality factor

for iron, it should provide for

exemptions from testing similar to those

set forth in proposed § 106.97(b)(2) to

show that the formula meets that factor

and allow manufacturers to assure the

agency that their products meet that

quality factor requirement without

requiring redundant testing.

F. Records and Reports

1. Introduction

Under subpart C of part 106, FDA is

proposing to revise the requirements on

the records that must be made and

retained. FDA is proposing

requirements on batch records; records

on CGMP and quality control

procedures; maintenance of distribution

records on formulas for export only;

audits; and notifications to FDA. These

proposed changes to current § 106.100

are outlined in Table III below:

TABLE III

Current Regulation Proposed Regulation

§ 106.100(a) .............. No Change.

§ 106.100(b) .............. No Change.

§ 106.100(c) ............... No Change.

§ 106.100(d) .............. No Change.

§ 106.100(e), (f), and

(h).

Current § 106.100(e),

(f), and (h) will be

incorporated into

proposed

§ 106.100(e).

New § 106.100(f) will

codify the records

required for the

CGMP regulations

found in proposed

subpart B.

§ 106.100(g) .............. Current § 106.100(g)

with modification.

§ 106.100(h) .............. Current § 106.100(h)

is incorporated into

§ 106.100(e).

§ 106.100(h) Reserved.

§ 106.100(i) ................ No Change.

§ 106.100(j) ................ Current § 106.100(j)

with modification.

TABLE III—Continued

Current Regulation Proposed Regulation

§ 106.100(k) ............... Current § 106.100(k)

with modification.

§ 106.100(l) ................ No Change.

§ 106.100(m) ............. No Change.

§ 106.100(n) .............. No Change.

§ 106.100(o) .............. No Change.

2. Batch Production and Control

Records

Proposed § 106.100(e) requires that

manufacturers make and retain records

(hereafter referred to as ‘‘batch records’’)

that include complete information

relating to the production and control of

each batch of infant formula. Section

412(b)(4)(A)(i) of the act requires the

establishment, by regulation, of

requirements for the retention of all

records, including records containing

the results of all testing required under

section 412(b)(2)(B) of the act, necessary

to demonstrate compliance with the

CGMP requirements and quality control

procedures prescribed under section

412(b)(2). In proposed § 106.100(e) FDA

is proposing to require that

manufacturers prepare and maintain

records that include complete

information relating to the production

and control of the batch to ensure that

the complete history of each batch of

infant formula is available for review in

the event that a problem arises with a

particular batch.

Proposed § 106.100(e)(1) requires that

the batch records include the

appropriate master manufacturing order.

As discussed above, proposed

§ 106.50(a) requires that manufacturers

produce each infant formula in

accordance with a master manufacturing

order that has been approved by a

responsible official of the company. The

master manufacturing order thus

provides fundamental information about

the batch. Having all the information

concerning the production of a batch of

infant formula, including the master

manufacturing order, in one place as a

part of a batch record will ensure that

there is a document available that makes

readily apparent whether a batch was

properly produced. It will also ensure

that all the information needed to

evaluate the cause of any problem that

may develop with a batch of infant

formula is readily available. Thus, FDA

has tentatively concluded that the

master manufacturing order is an

essential part of the batch record.

Proposed § 106.100(e)(1)(i) requires

that the master manufacturing order

include the significant steps in the

production of the batch of infant

formula and the date on which each
36190 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

significant step occurred. Thus, the

master manufacturing order will include

a list of the significant steps for the

production of each infant formula and a

space to write in the date the step was

performed. Thus, it will provide both a

check that the step was performed and

a record of when it was performed. FDA

has tentatively concluded that this

information is necessary because all

production activities for a specific batch

of infant formula may not be

accomplished in one day but may occur

over a number of days, and people who

begin work the second day will know

what work has been completed, and

what has not been. Moreover, each date

is needed so that a batch of formula can

be traced if, at a later date, a problem

that may adversely affect an infant

formula is identified at a specific

production stage. Having the date

available will allow the manufacturer to

identify all batches that may have been

affected by the problem.

Proposed § 106.100(e)(1)(ii) requires

that, if the manufacturer has more than

one line or set of equipment in the plant

in which the formula is made, the

master manufacturing order include the

identity of equipment and processing

lines used in producing the batch of

infant formula. This information will

allow the manufacturer to ensure that

the equipment on which the formula

was produced met the requirements of

§ 106.30. This information also will

facilitate the identification of all batches

of formula that may be affected by

equipment malfunctions or that were

produced on the same equipment as a

batch that is discovered to be

microbiologically contaminated.

Proposed § 106.100(e)(1)(iii) requires

that the master manufacturing order

include the identity of each batch or lot

of ingredients, containers, and closures

used in producing the batch of infant

formula. All materials used in infant

formula will have to meet the

specifications of proposed § 106.40(d)

and be identified by a batch or lot

number as specified in proposed

§ 106.40(c). FDA has tentatively

concluded that it is necessary to

propose that the identity of each batch

or lot of ingredients, containers, and

closures used in producing the batch of

infant formula be recorded in the master

manufacturing order to enable the

manufacturer to ensure that all of those

materials met the requirements of

§ 106.40, particularly the standards for

acceptance or rejection of the materials.

Recording this information also will

allow the manufacturer to evaluate the

contribution of specific ingredients,

containers, and closures to any problem

with a batch of infant formula that may

develop.

FDA is not proposing to require that

the batch records contain the results of

any tests conducted on ingredients,

containers, and closures in accordance

with proposed § 106.40(d) because the

same lot of raw materials may be used

in multiple batches. The identification

of the batch or lot of all ingredients,

containers, and closures in the master

manufacturing order should be

sufficient to allow the manufacturer to

locate and review relevant test results if

problems arise with a particular batch of

infant formula.

Proposed § 106.100(e)(1)(iv) requires

that the master manufacturing order

include the amount of each ingredient

to be added to the batch of infant

formula and a check (verification) that

the correct amount was added. As

discussed above, proposed § 106.50(b)

requires that the manufacturer establish

controls to ensure that raw and inprocess ingredients required by the

master manufacturing order are

examined by one person and checked by

a second person or system to ensure that

the correct weight or measure of the

ingredient is added to the batch. The

agency has tentatively concluded that

recording in the master manufacturing

order the amount of each ingredient

added to the batch of formula, and a

check (verification) that the correct

amount was added, are appropriate

controls to ensure that the correct

weight or measure of the ingredient is

added to the batch. This proposed

requirement is necessary to ensure that

there is compliance with proposed

§ 106.50(b), to provide a record that the

batch of infant formula includes all of

the ingredients in the amounts specified

in the master manufacturing order, and

to provide assurance that the product

contains all of the required nutrients.

Proposed § 106.100(e)(1)(v) requires

that the master manufacturing order

include copies of all labeling used and

the results of the examinations

conducted during the finishing

operations to ensure that containers and

packages in the batch are correctly

labeled. (The importance of ensuring

that containers are correctly labeled was

discussed in conjunction with proposed

§ 106.60(b).) The inclusion in the batch

records of copies of the labeling used on

each batch of infant formula will

provide a record of such labeling and

will document that the finishing

operation examinations, required by

proposed § 106.60(b), are conducted.

Proposed § 106.100(e)(2) requires that

the batch record include any deviations

from the master manufacturing order

and any corrective actions taken. While

the manufacturer’s goal should be to

produce the infant formula in

accordance with the master

manufacturing order, on occasion

deviations may occur. On these

occasions, the deviations, and any

corrective actions taken because of the

deviations, should become a part of the

batch record. For example, if a batch of

liquid infant formula was thermally

processed at a different temperature

than the temperature specified in the

master manufacturing order, the batch

record would state the actual processing

temperature. The record would also

state any corrective actions taken

because of this processing temperature,

such as a change in processing time. A

record of deviations from the master

manufacturing order and of the

corrective actions taken by the

manufacturer will allow the

manufacturer to quickly determine

whether all deviations have been

appropriately addressed, and if they

have not been, whether the actions

needed to correct the deviations have

been identified. It will also provide

relevant information if a problem arises

with that batch of infant formula.

Proposed § 106.100(e)(3) requires that

the batch records include

documentation of the monitoring at any

production and in-process control point,

step, or stage where control is deemed

necessary to prevent adulteration. As

discussed above, proposed § 106.6(c)(2)

requires this monitoring. FDA is

proposing that the documentation that

the monitoring required by proposed

§ 106.6(c)(2) is occurring be included in

the batch records to ensure that a

measurement or observation made at

one particular point in time can be

related to a particular batch. The linkage

of the record to the batch is especially

important when a standard or

specification is not met. It will enable

the manufacturer to determine what

batches may have been affected by a

deviation and to take appropriate action,

such as withholding a batch from

distribution.

Proposed § 106.100(e)(3)(i) requires

that the batch records include a list of

the standards or specifications

established at each point, step, or stage

in the production process where control

is deemed necessary to prevent

adulteration, and that it include

documentation of the scientific basis for

each standard or specification. As

discussed above, proposed § 106.6(c)(1)

requires the establishment of such

standards or specifications. The agency

has tentatively concluded that a list of

these standards or specifications must

be a part of the batch record so that the

manufacturer will have them readily
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36191

available to compare to the actual values

obtained during the monitoring

operation of the production and inprocess control system. Also, the

documentation of the scientific basis for

each standard or specification will

verify that each was established by

trained and experienced sources. Such

documentation will summarize the

work performed to establish the

standard or specification and will

establish the source used. If changes to

the standard or specification become

necessary, this documentation of the

scientific basis for each standard or

specification will assist the

manufacturer in making such changes.

Proposed § 106.100(e)(3)(ii) requires

that the batch records include the actual

values obtained during the monitoring

(such as the actual temperatures and

actual times that the measurements

were taken), any deviations from the

established standards or specifications,

and any corrective actions taken. For

example, notations that refrigeration

temperatures are satisfactory or

unsatisfactory, without a record of the

actual temperatures, are subject to

varying interpretation and thus will not

ensure that preventive controls are

working. It is important that the actual

values be recorded. In addition, actual

values are necessary to discern trends or

to pinpoint the onset of a problem. The

record of any corrective actions taken

will show what the manufacturer did

when a standard or specification was

violated, and how the manufacturer is

ensuring that the infant formula is not

adulterated. Entry of information on the

records at the time of the monitoring

ensures that the record does not rely on

the memory of the observer and thus is

as accurate and valid as possible.

Proposed § 106.100(e)(3)(iii) requires

that the batch records identify the

person monitoring each point where

control is deemed necessary to prevent

adulteration. FDA has tentatively

concluded that it is important that the

responsible individuals be identified in

the batch record so that the

manufacturer can check that a qualified

person is actually monitoring the point,

step, or stage where control is deemed

necessary to prevent adulteration, and

so that such individual can be contacted

if a problem with a batch of infant

formula is identified at a later date.

These individuals are in the best

position to know of any other

information that may not have seemed

pertinent at the time but, in retrospect,

could be important in identifying the

cause of the problem and initiating

actions to prevent it from recurring.

Proposed § 106.100(e)(4) requires that

the batch records include the

conclusions and followup, along with

the identity, of the qualified individual

who investigated any deviations, or

failures to meet specifications, that

occurred during the production of the

batch. Under these proposed

regulations, individuals qualified by

training or experience must conduct an

investigation of any deviation from the

master manufacturing order and of the

corrective actions taken (§ 106.50(a)(2));

conduct an investigation of a finding

that a batch or any of its ingredients

failed to meet any manufacturer’s

specifications (§§ 106.40(d) and

106.70(c)); and conduct an investigation

of a failure to meet any specification or

standard at any point where control is

deemed necessary to prevent

adulteration (§ 106.6(c)(4)).

FDA has tentatively concluded that

the record of the conclusions and

followup of these investigations is

necessary to enable the manufacturer to

ensure that it has complied with

proposed §§ 106.6(c)(4), 106.40(d),

106.50(a)(2), and 106.70(c). Such

records will provide information on

how the production of the batch of

infant formula deviated from

established standards or specifications

and on the cause of any problem with

the formula, if infants are reported to

have been adversely affected by the

product at a later date. Identification of

the qualified individual who conducted

the investigations will ensure that there

is responsibility and accountability for

the investigation and will allow the

responsible individuals to be contacted,

if necessary. These individuals will be

in the best position to provide

information if additional details about

the record are needed.

Proposed § 106.100(e)(5) requires that

the batch records include 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.

Section 412(b)(2)(B) of the act requires

that manufacturers conduct such

testing. FDA has tentatively concluded

that the assembly of such records in one

place will enable the manufacturer to

ensure that the batch of infant formula

complies with proposed §§ 106.55 and

106.91 and will facilitate the review of

the test results in the event that a

problem arises with the batch.

Proposed § 106.100(e)(5)(i) states that

the batch records are to include the

results of any quality control testing

conducted, in accordance with

proposed § 106.91(a) and (b), to verify

that each nutrient required by § 107.100

is present at the required level, and that

any nutrient added by the manufacturer

is present at the appropriate level.

Including the results of this testing in

the batch records will provide data

needed to evaluate compliance of the

batch of infant formula with proposed

§ 106.91, and provide data needed to

evaluate a batch of infant formula if

problems, such as adverse events in

infants, occur later with that particular

batch. These records will show the

levels of nutrients in the formula and

will provide information to help the

manufacturer determine whether any

problems associated with the formula

are attributable to the nutrient levels in

the product.

Proposed § 106.100(e)(5)(i)(A)

requires that manufacturers maintain a

summary table in the batch record that

identifies the stages of the

manufacturing process at which the

nutrient analysis is conducted for each

nutrient, in accordance with proposed

§ 106.91(a). As discussed above,

proposed § 106.91(a) provides flexibility

in the stage at which many of the

nutrients are tested. A summary table

will facilitate the manufacturer’s

compliance with quality control

procedures because it will allow a

manufacturer to quickly verify that it

has tested for all the nutrients required

by § 107.100 during the production of

the infant formula.

Proposed § 106.100(e)(5)(i)(B) requires

that the quality control records in the

batch record include a summary table

on the stability testing program,

conducted in accordance with proposed

§ 106.91(b), including the nutrients

tested and the frequency of testing of

nutrients throughout the shelf life of the

product. As discussed above, proposed

§ 106.91(b) requires that manufacturers

test infant formula at the beginning,

midpoint, and end of the shelf life, and

with sufficient frequency to ensure that

the manufacturer is aware if there is a

significant deterioration in the required

level of a nutrient. Therefore, proposed

§ 106.91(b) provides flexibility in the

testing frequency, depending on the

shelf life and the characteristics of the

product. A summary table will facilitate

the manufacturer’s compliance with

quality control procedures because it

will allow a manufacturer to quickly

determine whether it has tested for all

the nutrients required by § 107.100 with

sufficient frequency to verify that the

‘‘use by’’ date on the formula is

appropriate.

Proposed § 106.100(e)(5)(ii) requires

that the batch records for powdered

infant formula include the results of any

testing conducted in accordance with

proposed § 106.55(b) to document that

the tests were done and to verify

compliance with the microbiological
36192 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

quality standards in proposed

§ 106.55(c). As discussed above,

proposed § 106.55(b) requires that

manufacturers test representative

samples of each batch of powdered

infant formula to ensure that the batch

meets the microbiological quality

standards in proposed § 106.55(c) and

therefore is not adulterated. This record

will also provide the manufacturer with

data to evaluate adverse events that

infants may have experienced after

consuming this batch of infant formula

by showing whether microbiological

contamination could have contributed

to the adverse event.

3. CGMP Records

Proposed § 106.100(f) identifies the

records that manufacturers must make

and retain pertaining to CGMP

described in proposed subpart B of part

106. Section 412(b)(4)(A)(i) of the act

requires the establishment by regulation

of requirements for the retention of all

records necessary to demonstrate

compliance with the CGMP, including

testing designed to prevent the

adulteration of infant formula. FDA has

already discussed proposed regulations

(proposed § 106.100(e)) respecting the

retention of records relating to each

batch of infant formula. FDA also is

proposing regulations respecting the

retention of records relating to the

overall operation of the plant and the

maintenance of equipment, because

these records are necessary to

demonstrate that the infant formula was

manufactured in a manner designed to

prevent adulteration. Maintenance of

these records will help manufacturers

identify trends in the processing of the

infant formula, in particular trends that

show when the process is breaking

down in a way that will lead to the

production of adulterated product.

These records also will provide

information to assist the manufacturer

in tracking the cause of adverse events

to a formula, if such events are reported.

Proposed § 106.100(f)(1) requires that

manufacturers make and retain records

of the frequency and results of the

testing of water used in the production

of infant formula. These records will

show if problems are starting to develop

with the water supply so that

manufacturers can take corrective

actions before the water is inappropriate

for use in infant formula.

Proposed § 106.100(f)(2) requires that

manufacturers make and retain records,

in accordance with § 106.30(d), of

accuracy checks on instruments and

controls. Under this proposal, these

records must include a certification of

the accuracy of any known reference

standard used and a history of its

recertification. As discussed previously,

the accuracy of the reference standard

must be ensured before it can be used

to ensure that the production

instruments are properly calibrated.

These records also will provide

information to assist the manufacturer

in tracing the source of a problem, if one

arises, with a batch of infant formula.

For example, if infants have adverse

events to a batch of infant formula,

records containing a certification of

accuracy of the reference standards used

and a history of their recertification

would assist the manufacturer in

determining whether the problem was

created because a production

instrument was calibrated with an

inaccurate reference instrument.

FDA is proposing to require that, at a

minimum, the records 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.

These records will enable the

manufacturer to determine, based on the

performance of the instrument, whether

the calibration schedule is sufficient to

ensure the accuracy of the instrument.

These records also will provide

information on when and how the

instruments were calibrated to assist the

manufacturer in identifying the cause of

a problem, if one arises, with a batch of

infant formula.

Including the date of the accuracy

check in the record will permit a

determination of the accuracy of the

instrument or control over time;

including the standard used will allow

the manufacturer to verify that the

standard was properly calibrated; and

including the calibration method used

will ensure that the instrument is being

calibrated free from the variability that

can occur when different laboratory

personnel perform the same calibration.

The results of the accuracy check in the

record will show whether the

instrument or control is accurate, or

whether a correction was necessary.

Documenting the actions taken if the

instrument is found to be out of

calibration will enable the manufacturer

to ensure that a correction was made.

Requiring that the individual

performing the test note his or her

initials or name in the record will

document who was last responsible for

ensuring the accuracy of the instrument

or control and will allow the

manufacturer to discuss questions that

may arise about the record with the

person in the best position to know

additional, but unrecorded, details

about the record.

If calibration of an instrument 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 of any actions that

need to be taken with respect to that

product, needs to be made. For example,

if the manufacturer is monitoring

temperature to ensure that a

specification or standard of 250 °F is

maintained as a minimum temperature,

and calibration of the temperature

indicating instruments against a

reference standard reveals that it was

reading a true temperature of 248 °F, an

evaluation of the health hazard

significance of this temperature

deviation must be made. This proposed

requirement is necessary because, if an

instrument is found to have been giving

inaccurate readings, all infant formula

produced subject to such inaccuracies

must be identified and evaluated for the

possibility that the inaccuracies caused

the formula to be adulterated. In

identifying the affected product to

ensure that the health of potentially

affected infants is fully protected, in the

absence of evidence to the contrary,

such evaluation would cover all product

manufactured since the last time the

instrument was calibrated and found to

be accurate.

Proposed § 106.100(f)(3) requires that

manufacturers make and retain records,

in accordance with proposed

§ 106.30(e)(3)(ii), of the temperatures

monitored for cold storage

compartments and thermal processing

equipment. These records are needed to

show that the thermal processing

equipment or cold storage

compartments are being maintained at

the correct temperatures to prevent

adulteration of the product. The records

of these temperatures will enable the

manufacturer to identify trends in

temperature fluctuations that can signal

the need to perform nonscheduled

maintenance.

FDA is proposing in § 106.100(f)(4)

that equipment cleaning, sanitizing, and

maintenance records, showing the date

and time of maintenance, as well as the

lot number of each batch of infant

formula processed between equipment

startup and shutdown for cleaning,

sanitizing, and maintenance, be made

and maintained. These records will

allow the manufacturer to ensure that

equipment and utensils are being

cleaned and maintained regularly and to

check that the frequency of such

cleaning, sanitizing, and maintenance is

appropriate in light of the actual, as
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36193

opposed to planned, use of the

equipment. For example, a

manufacturer may need to increase the

frequency of cleaning, sanitizing, and

maintenance if actual rate of production

consistently exceeds the predicted rate

of production. These records also will

allow the manufacturer to trace all

formula that may be affected if evidence

becomes available that a particular

cleaning, sanitizing, or maintenance was

improperly performed.

Proposed § 106.100(f)(4) also requires

that the person performing and checking

the cleaning, sanitizing, or maintenance

date and sign or initial the record

indicating that the work was performed.

Identification of the person performing

and checking the cleaning, sanitizing, or

maintenance will allow the

manufacturer to ensure that a qualified

person is doing these tasks and to

discuss questions that may arise about

the record with the person in the best

position to know additional, but

unrecorded, details about the record.

Proposed § 106.100(f)(5) requires that

manufacturers make and retain records,

in accordance with § 106.35(c), on all

automatic (mechanical or electronic)

equipment used in the production or

quality control of infant formula.

Proposed § 106.100(f)(5)(i) requires that

the automatic equipment records

include a list of all systems used, with

a description of computer files and of

the inherent limitations of each system.

The manufacturer cannot effectively

operate the system, and correct

problems that arise, if it does not

understand the system. It is not always

possible for the individuals who

developed and best understand the

system to be present when the system is

operating. Therefore, these records will

enable the manufacturer to operate and

troubleshoot the systems even when the

individuals who best know the system

are not available.

Proposed § 106.100(f)(5)(ii) requires

that the automatic equipment records

include a copy of all software used.

Having a copy of all software used will

minimize the manufacturer’s down time

if problems occur, and parts of the

software are lost from the system. For

example, if a computer virus is found in

the software used to run the processing

lines, having a copy of the software to

reload into the hardware will minimize

the time lost. Likewise, if there is a

problem with the software used to

perform quality control testing, having

copies of this software will ensure that

the testing can continue with a

minimum amount of time lost.

Proposed § 106.100(f)(5)(iii) further

requires that the automatic equipment

records document installation,

calibration, testing or validation, and

maintenance of the systems used. These

requirements are necessary for

compliance with section 412(b)(4)(A)(i)

of the act. As discussed more fully

above with respect to proposed § 106.35

(b)(1), (b)(2), and (b)(4) CGMP requires

that all systems be installed, calibrated,

and maintained in a manner necessary

to ensure that they are capable of

performing their intended function and

of producing or analyzing infant

formula as intended, and that all

systems be validated before their first

use to manufacture commercial product.

In addition to documenting that the

manufacturer is complying with CGMP,

records documenting installation,

calibration, testing or validation, and

maintenance of systems are necessary to

provide information if the manufacturer

later tries to determine why a problem

with the system is occurring or tries to

determine why the system is not

producing an infant formula that

complies with the manufacturer’s

specifications for the product.

Proposed § 106.100(f)(5)(iv) requires

that the automatic equipment records

include a list of all persons authorized

to create or modify software. This record

will help to minimize delays when the

name of a person with those skills is

needed quickly.

Proposed § 106.100(f)(5)(v) requires

that the automatic equipment records

document modifications to software,

including the identity of the person who

modified it. This documentation will

ensure that the manufacturer is aware of

any changes made to the software, and

that it has a record of how the changed

system works, so that it can continue to

operate the system even in the absence

of the responsible individual who made

the modification to the system. A record

of the identity of the person who

modified the software will show who

was responsible for modifying the

software if problems arise with the

operation of the system and will

identify the person in the best position

to know additional, but unrecorded,

details about the software modification

to help in troubleshooting the software

problems.

Proposed § 106.100(f)(5)(vi) requires

that the automatic equipment records

include documentation of retesting or

revalidation of modified systems. This

proposed requirement is necessary for

compliance with section 412(b)(4)(A)(i)

of the act. As discussed more fully

above in the section on proposed

§ 106.35(b)(5), CGMP requires that all

modifications to software be made by a

designated individual, and that all

systems be revalidated after any

modification to ensure that infant

formula produced or analyzed using the

modified software complies with

subparts B and C. FDA has tentatively

concluded that records on retesting or

revalidation of the modified systems,

just like records on the initial testing or

validation of the system

(§ 106.100(f)(5)(iii)), are necessary to

document that the work has been done

properly and to provide information if

the manufacturer later tries to determine

why a problem with the system is

occurring or tries to determine why the

system isnot producing an infant

formula that complies with the

manufacturer’s specifications for the

product.

Proposed § 106.100(f)(5)(vii) requires

that the manufacturer make and retain

a backup file of data entered into a

computer or related system. It also

requires that this backup file 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. This

proposed requirement is necessary to

ensure compliance with CGMP because

computer files can be easily altered or

erased. Backup files of data will allow

the manufacturer to readily reload the

files of data if problems occur in the

operation of the computer or related

system, so that the manufacturer’s down

time is minimized, and so that the data

entered into the system will be an exact

copy of the data previously used in the

system.

Proposed § 106.100(f)(6) requires that

manufacturers make and retain records

on ingredients, containers, and closures,

including the identity and quantity of

each lot, the name of the supplier, the

supplier’s lot number, the name and

location of the manufacturer (if different

from the supplier), the date of receipt,

and the receiving code as specified

(proposed § 106.100(f)(6) (i) through

(vi)). These records will enable the

manufacturer to document that it is

complying with proposed § 106.40(g).

Moreover, this information is needed to

enable the manufacturer to track the

source of each ingredient, container, or

closure used in infant formula if a

problem arises. If an ingredient,

container, or closure is found to cause

adulteration of the formula, it is

important to be able to determine the

source of the material, so that use of

such materials can be halted and

prevented in the future.

Proposed § 106.100(f)(6)(vii) requires

that the records on ingredients,

containers, and closures include the

results and conclusions of any test or

examination, including retesting and
36194 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

reexamination, performed on them and

their disposition. These records will

document that appropriate testing is

being conducted to ensure that the

ingredients will not adulterate the infant

formula, and that the containers and

closures will protect the infant formula

against adulteration. Further, these

records will show the basis on which

each ingredient, container, and closure

was released for use in infant formula

production if questions about such

release later arise. Individual lots of

ingredients, containers, and closures are

likely to be used in a number of

different batches of infant formula;

therefore, the agency is proposing that

the records on ingredients, containers,

and closures be a part of the records

pertaining to CGMP. Retaining such

records in the CGMP records, rather

than in each batch record, will eliminate

the duplication of records and simplify

the recordkeeping. The disposition of

the ingredients, containers, and closures

will show which materials were

destroyed because they did not meet the

manufacturers specifications (and not

used in manufacture in compliance with

§ 106.40(d)), and which batches of

infant formula were made using each lot

of ingredients, containers, or closures.

Thus, the manufacturer will know

which lots of ingredients, containers, or

closures were used in making infant

formula and will be able to confirm that

those lots complied with proposed

§ 106.40(d). Moreover, if a batch of

formula is shown to be adulterated,

these records will help the manufacturer

to identify the source of the

adulteration.

Proposed § 106.100(f)(7) requires that

manufacturers make and retain records

that include a full description of the

methodology used to test powdered

infant formulas to verify compliance

with proposed § 106.55(c) and the

methodology used to conduct quality

control testing in accordance with

§ 106.91 (a) and (b). The agency has not

specified in these regulations the

methodologies that must be used to

conduct microbiological and quality

control testing. Thus, FDA has

tentatively concluded that a

manufacturer needs to maintain a record

that fully describes the methodology

that it has decided to use to test

powdered infant formula for

microorganisms and for quality control

testing. Such a record is necessary if

there is to be consistency in the

procedure that the manufacturer follows

in testing each batch of infant formula,

particularly in light of the fact that the

laboratory personnel conducting the

testing are likely to vary. The accuracy

and reproducibility of microbiological

and quality control testing depend on

the procedure used to conduct the test.

FDA is proposing that the full

description of the methodology be

retained as part of the CGMP records,

rather than in the batch record provided

for in proposed § 106.100(e)(5), because

these methods will be used to test

multiple batches of infant formula.

Retaining such records in the CGMP

records, rather than in each batch

record, will mean that the manufacturer

has to maintain only one document,

rather than having to reproduce it each

time that it runs a batch of formula.

Thus, the proposed approach will

eliminate duplication of records and

simplify recordkeeping.

4. Records on Distribution of Infant

Formulas

Proposed § 106.100(g) adds to current

§ 106.100(g) a requirement that records

pertaining to distribution of the infant

formula show that products intended for

export only are in fact exported. It has

recently come to the attention of the

agency that infant formulas produced

for export have been diverted and sold

in the United States. All persons

introducing any new infant formula into

interstate commerce, which includes

persons exporting an infant formula to

a foreign country, are required by

section 412(c) of the act to register and

make a submission to the agency 90

days before marketing the formula. (See

discussion of proposed §§ 106.110 and

106.120.)

As discussed in the section of this

preamble on proposed § 106.120(c), the

agency has tentatively concluded that it

will not require manufacturers who

produce infant formula for export only

to submit the same information that

would be required for products

intended or offered for sale in the

United States. In lieu of the information

required by § 106.120(b), FDA is

proposing to allow manufacturers of

products for export only to give

assurances that the infant formula will

not be sold or offered for sale in

domestic commerce. This provision is

based, in part, on section 801(e) of the

act, which states that a food will not be

deemed to be adulterated or misbranded

under the act if, among other things, it

is not sold or offered for sale in

domestic commerce. Thus, the agency

has tentatively concluded that the

additional recordkeeping requirement

on distribution of infant formulas for

export only in proposed § 106.100(g) is

necessary so that verification that the

infant formula was not in fact sold or

offered for sale in domestic commerce

will be readily available in the

manufacturer’s records.

5. Audit Records

Proposed § 106.100(j) carries forward

the requirement in current § 106.100(j)

that the manufacturer make and retain

records, which include the audit plans

and procedures, that pertain to regularly

scheduled audits. As discussed above,

the written audit plan, which includes

audit procedures, is required under

proposed § 106.94(a) and (b). The

proposed section further requires that

records of audits include the findings of

the audit and a listing of any changes

made in response to these findings. This

requirement is proposed under the

authority of section 412(b)(4)(A)(v) of

the act, which requires that

manufacturers retain all records of the

results of regularly scheduled audits

conducted under the requirements

prescribed by the Secretary (and by

delegation, FDA) under the authority of

section 412(b)(2)(B)(iv).

Proposed § 106.100(j) also requires

that the manufacturer make readily

available for authorized inspection the

audit plans and procedures and a

statement of assurance that the regularly

scheduled audits are being conducted.

This provision implements section

412(b)(4)(B)(ii) of the act, which

requires that the manufacturer provide

written assurance that the regularly

scheduled audits are being conducted

by the manufacturer. However,

proposed § 106.100(j) also provides that

the findings of the audit and any

changes made in response to these

findings need not be made available to

FDA. This provision is brought forward

from current § 106.100(j) and reflects

section 412(b)(4)(B)(ii) of the act, which

states that a ‘‘manufacturer need only

provide written assurances to the

Secretary that the regularly scheduled

audits required by’’ section

412(b)(2)(B)(iv) of the act ‘‘are being

conducted by the manufacturer, and

need not make available to the Secretary

the actual written reports of such

audits.’’

6. Modification of Current

§ 106.100(k)(3)

The agency also is revising current

§ 106.100(k)(3) to reflect the numbering

changes in the regulations on notifying

the agency of a causal relationship

between the consumption of an infant

formula and an infant’s death. The

agency is moving the requirements of

current § 106.120(b) to § 106.150 to

reflect the changes it is proposing in

subpart G. Thus, the reference to

§ 106.120 in § 106.100 (k)(3) will be

changed to read ‘‘§ 106.150,’’ if the
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36195

6While section 412(c)(1) and (c)(1)(B) of the act

state ‘‘No person shall introduce or deliver for

introduction into interstate commerce any new

infant formula unless—such person has at least 90

days before marketing such new infant formula,

made the submission to the Secretary required by’’

section 412(c)(1) of the act, FDA has recognized

since 1986 that this citation is in error (see

‘‘Requirements for Infant Formulas’’ published by

FDA’s Industry Programs Branch, CFSAN), and that

the correct citation is section 412(d)(1). This

correction agrees with the language of section

412(d)(1) of the act, which states what a submission

about any infant formula subject to section 412(c)

of the act should include. It is also consistent with

the rules of statutory construction. See Colonial Life

& Accident Insurance Co. v. American Family Life

Assurance Co., 846 F. Supp. 454, 463 n. 14(D.S.C.

1994) (where the legislature has made a mistake in

reference, and its intent is manifest, the statute may

be read as corrected in order to give effect to the

legislative intent).

agency adopts the relevant proposed

changes.

G. Registration, Submission, and

Notification Requirements

1. Introduction

The act provides for three types of

notices that manufacturers of infant

formula must provide to FDA and sets

forth the general information that must

be included in each type of notice. First,

manufacturers of a new infant formula

must register with FDA, in accordance

with section 412(c)(1)(A) of the act,

providing the name and address of the

firm and all establishments that will

manufacture the new infant formula.

Second, manufacturers must submit to

FDA, in accordance with section 412(d)

of the act, certain information

concerning a new infant formula or an

infant formula in which there is a

change in formulation or processing that

may affect whether the formula is

adulterated under section 412(a) of the

act. Third, manufacturers must notify

FDA, in accordance with section 412(e)

of the act, of any adulterated or

misbranded infant formula that has left

their control.

The agency has not specified the

information that must be included in an

infant formula registration, submission,

or notification. While firms have been

able to function under these

requirements since the 1986

amendments were enacted with respect

to the notice that manufacturers must

provide to the agency under section

412(c) and (d) of the act, inquiries from

industry suggest that manufacturers are

uncertain about the information that

they must provide. Some manufacturers

have needed to make multiple

submissions for a new infant formula

because of deficiencies in the initial

submission. For example, some

submissions have contained information

concerning more than one formula

without clearly identifying which

information applied to which formula.

Some submissions have not contained

the information required by section

412(d)(1) of the act. Therefore, FDA

recognizes that it will be useful both to

manufacturers and to the agency to

issue regulations to ensure that

registrations and submissions required

by the act follow a consistent format and

contain the necessary information for

the agency to determine whether there

is a basis to object to the marketing of

a new infant formula. Such regulations

will facilitate the manufacturer’s

preparation of the notice and also will

facilitate the agency’s review of the

notice once FDA receives it.

These proposed regulations also will

make clear when a registration,

notification, or submission to the agency

is needed. For example, as stated above,

it has recently come to the attention of

the agency that some firms that

manufacture infant formula intended

only for export are not aware of their

registration and submission

responsibilities. Section 412(c)(1) of the

act requires that a person introducing a

new infant formula into interstate

commerce (which includes export to a

foreign country) must register the infant

formula and make the proper

submission 90 days before marketing it.

These proposed regulations make clear

that registration and submission

requirements apply to infant formulas

intended only for export as well as to

infant formula intended for the

domestic market.

Finally, for completeness, FDA has

decided that it would be useful to both

manufacturers and the agency, to carry

forward current § 106.240, concerning

notification of a violative infant

formula, as § 106.150. Doing so will

consolidate in one place in the agency’s

regulations all requirements concerning

notice to the agency to meet the

requirements of section 412(c), (d), and

(e) of the act.

2. New Infant Formula Registration

Proposed § 106.110(a) requires that a

manufacturer of a new infant formula

register with FDA before introducing the

formula, or delivering it for

introduction, into interstate commerce.

Because ‘‘interstate commerce’’ is

defined in section 201(b) of the act as

‘‘(1) commerce between any State or

Territory and any place outside thereof,

and (2) commerce within the District of

Columbia or within any other Territory

not organized with a legislative body,’’

under this provision, a manufacturer is

required to register with FDA before

introducing a new infant formula into

the United States market or before

beginning exporting the formula.

Proposed § 106.110(a) sets out how to

comply with section 412(c)(1)(A) of the

act. Failure to provide the notice

required by section 412(c)(1)(A) of the

act is a prohibited act under section

301(s).

Under section 412(c)(1)(A) of the act,

proposed § 106.110(b) sets out the

information required in a new infant

formula registration. While

manufacturers may register at any time

before introducing a new formula into

interstate commerce, FDA urges that

they do so at the same time that they

submit notice of their intent to market

a new infant formula in accordance with

section 412(c)(1)(B) and (d)(1) of the act.

Receiving registration and the 90 day

submission at the same time will

facilitate the agency’s review.

3. New Infant Formula Submission

Section 412(c)(1)(B) of the act requires

that manufacturers of a new infant

formula submit to FDA a notice of their

intent to market the new formula that

complies with section 412(d)(1) of the

act. The notice must be submitted at

least 90 days before the infant formula

is introduced or delivered for

introduction into interstate commerce 6.

Proposed § 106.120 implements this

requirement.

Proposed § 106.120(a) sets out the

requirement that a manufacturer submit

a notice of its intent to market a new

infant formula and provides the address

to which such notices are to be

submitted.

Proposed § 106.120(b) sets forth the

information that manufacturers must

include in their new infant formula

submission. This proposed regulation

implements and specifies the

information called for in section

412(d)(1) of the act.

a. General information required in a

90-day submission. Because the

registration of a new infant formula

(proposed § 106.110) need not

accompany the new infant formula

submission (proposed § 106.120), and

because a third submission on a

newinfant formula that verifies that the

new infant formula, as produced,

contains all required nutrients (see

proposed § 106.130) will be submitted

separately, FDA has tentatively

concluded that the name of the infant

formula is needed to ensure that all

information on a particular infant

formula is filed together and is available

to determine whether the agency should

object to the marketing of the formula.

Information on the form of the product

is necessary for an accurate evaluation

of the product because different
36196 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

requirements may apply to different

forms of a formula. For example,

powdered infant formula must meet the

microbiological quality requirements in

proposed § 106.55, whereas liquid forms

of a formula do not. Therefore, FDA is

proposing to require this information in

§ 106.120(b)(1), under the authority of

sections 412(d)(1) and 701(a) of the act,

even though it is not explicitly required

in section 412(d)(1).

Proposed § 106.120(b)(2) requires that

the submission include an explanation

of why the formula is a new infant

formula to facilitate a determination by

the agency as to the type of evaluation

the new infant formula requires. For

example, if the formula is a new infant

formula because a new manufacturing

plant will be used to produce it, but the

formulation of the product is not

changed, FDA will evaluate the

processing and arrange to inspect the

new facility but may conclude that

testing to provide assurance that quality

factor requirements have been met is not

necessary. Thus, FDA is proposing to

require the submission of this

information, even though, like the

information required under proposed

§ 106.120(b)(1), submission of this

information is not specifically provided

for in the act. The agency tentatively

concludes that this information is

necessary for the efficient enforcement

of sections 412(c)(1)(B) and (d)(1) of the

act.

b. Formulation and processing

information required in a 90-day

submission. Pursuant to section

412(d)(1)(A) of the act, proposed

§ 106.120(b)(3) requires that the

submission include the quantitative

formulation of the infant formula. The

agency is proposing that, if the notice

concerns more than one form of the

formula, the submission include

quantitative information on each form of

the formula that is the subject of the

notice. FDA is proposing to require that

manufacturers submit the formulation

in units per volume (for liquid formulas)

or units per dry weight (for powdered

formulas) because formulations

expressed in these units will facilitate

agency understanding of the formula.

Manufacturers already will have the

formulation available in these units as a

part of the master manufacturing order,

and submitting the formulations in

these units should not require

additional calculations by the

manufacturer.

Proposed § 106.120(b)(3) also

requires, under section 412(d)(1)(B) of

the act, that the submission 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. For example, if the protein

source in an infant formula is replaced

with a protein source that contains a

different amount of protein (e.g., from

casein to a mixture of casein and whey),

it is important to ensure that the amount

of the new protein source used will

provide the amount of protein required

by § 107.100. As another example, if an

ingredient such as sodium selenite is

added to the formula for the first time,

it is important to ensure that the level

of the ingredient provides selenium (in

the form of selenite) at a level that is

consistent with the infant’s needs and

yet within the safe range of selenium

intake.

Proposed § 106.120(b)(4) requires that

the submission include a description,

when applicable, of any change in

processing of the infant formula, and

that such description 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).

This proposed requirement implements

section 412(d)(1)(B) of the act, which

states that the submission must include

a description of any change in the

processing of an infant formula. FDA is

proposing that the description of the

change in processing include detailed

schematic diagrams comparing the new

processing to the previous processing

because schematic diagrams are efficient

tools for identifying the nature and

significance of changes in processing.

c. Assurance that the infant formula

will not be marketed unless it meets

quality factor and nutrient requirements

of the act. Pursuant to section

412(d)(1)(C) of the act, proposed

§ 106.120(b)(5) requires that the

submission include an assurance that

the infant formula will not be marketed

unless it meets the quality factor

requirements of section 412(b)(1) of the

act and the nutrient content

requirements of section 412(i) of the act.

Proposed § 106.120(b)(5)(i) requires

that the assurance that the formula

meets the quality factor requirements,

which are set forth in subpart E of part

106, be provided by a submission that

complies with § 106.121. Section

412(d)(1)(C) of the act requires that, 90

days before marketing a new infant

formula, a manufacturer submit

assurances that the infant formula will

not be marketed unless it meets the

quality factor requirements established

by regulations under section 412(b)(1).

Section 412(d)(2) of the act requires

that, after the first production of a new

infant formula and before introduction

into interstate commerce of such

formula, the manufacturer submit a

written verification that summarizes test

results and records demonstrating that

such formula complies with the quality

factor requirements. However, FDA has

tentatively concluded that to implement

sections 412 (d)(1) and (d)(2) of the act

in a way that ensures that the statutory

goals are achieved—that is, to ensure

that the agency has all the relevant

information for a sufficient period of

time to conduct a meaningful review of

the nutritional adequacy of the formula

while enabling the infant formula

manufacturer to market its product as

expeditiously as possible—it is

appropriate to require that the

assurances that the quality factors will

be met be provided by means of data

that would otherwise be required as part

of the verification submission. FDA

notes that such a requirement would

only codify current practice. Since

passage of the 1986 amendments, infant

formula manufacturers have been

providing data demonstrating that a new

infant formula meets the quality factor

requirements as a part of the submission

made 90 days before marketing.

Proposed § 106.120(b)(5)(ii) requires

that the assurance that the formula

complies with the nutrient content

requirements, which are set forth in

§ 107.100, be provided by a statement

assuring that the formula will not be

marketed unless it meets the nutrient

requirements of § 107.100, as

demonstrated by testing required under

subpart C of part 106.

The agency acknowledges that there is

an apparent inconsistency in how it

interprets the word ‘‘assurance’’ in

section 412(d)(1)(C) of the act as it

relates to assurance that the infant

formula meets the quality factor

requirements and assurance that the

infant formula meets nutrient content

requirements. FDA has tentatively

concluded, however, that assurance that

the formula will meet the quality factor

requirements is a threshold question

that must be answered affirmatively

before the effort in setting up the line for

first production of the infant formula

would be justified. Therefore, the

agency is proposing to require that the

assurance that the infant formula will

meet the quality factor requirements be

provided by data submitted 90 days

before marketing the formula.

On the other hand, the agency is

proposing that the assurance that the

formula will not be marketed unless it

meets the nutrient requirements of

§ 107.100 can be provided by a

statement to that effect (as opposed to

data) submitted 90 days before

marketing of the formula because the
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36197

data and records demonstrating that the

formula complies with the nutrient

requirements of § 107.100 will not be

available until the production line is set

up, and the first production of the infant

formula has occurred. FDA will receive

verification that the formula meets the

nutrient requirements as a part of the

submission required by section

412(d)(2) of the act (see proposed

§ 106.130(b)(3), below). Therefore, FDA

has tentatively concluded that it is

adequate to receive a commitment from

the manufacturer, 90 days before

marketing, that the infant formula will

not be marketed unless it meets the

nutrient requirements of § 107.100.

d. Assurance that the processing of

the infant formula complies with the

CGMP and quality control procedures of

the act. Under section 412(d)(1)(D) of

the act, proposed § 106.120(b)(6)

requires that the submission include

assurance that the processing of the

infant formula complies with section

412(b)(2) of the act (CGMP, including

quality control procedures).

Proposed § 106.120(b)(6)(i) requires

that the assurance that the processing of

the infant formula complies with

section 412(b)(2) of the act include a

statement that the formula will be

produced in accordance with subparts B

and C of part 106. This proposed

requirement is a necessary element of

the assurance required by section

412(d)(1)(D) of the act because the

requirements for CGMP are set forth in

subpart B and the requirements for

quality control procedures are set forth

in subpart C. In the Congressional

Record (Ref. 1), Senator Metzenbaum

stated that the amendments to the Infant

Formula Act set up requirements

‘‘which will prevent our Nation’s

Children from ever again being

threatened by defective baby formula.

The most important provision of this

amendment is the simple requirement

that each batch of formula must be

tested for each essential nutrient that

must be contained in the formula’’ (Ref.

1).

Proposed § 106.120(b)(6)(ii) requires

that the assurance that the processing of

the infant formula complies with

section 412(b)(2) of the act include the

basis on which the manufacturer has

concluded that each ingredient meets

the requirement of proposed § 106.40(a),

i.e., that the ingredient is an approved

food additive, is authorized by a prior

sanction issued by the agency, or is

GRAS for its intended use. The statute

provides that the manufacturer submit,

90 days before marketing a new infant

formula, assurance that the processing

of the formula complies with the CGMP

regulations, and that the formula is

manufactured in a way that is designed

to prevent its adulteration. FDA has

tentatively concluded that, to

implement the act in a way that will

ensure that the statutory goals are

achieved, that is, to ensure that the

agency has all the relevant information

for a sufficient period of time to conduct

a meaningful review of the formula

while enabling the manufacturer to

market its product as expeditiously as

possible, it is appropriate to require that

the assurance that none of the

ingredients will adulterate the formula

be provided by an explanation of how

each ingredient meets proposed

§ 106.40(a). FDA has tentatively

concluded that this approach is

appropriate because, like the evidence

that the formula meets the quality

factors, evidence that all the ingredients

in the infant formula are safe goes to a

threshold question that must be

answered affirmatively before the effort

in setting up the production line for the

first production of the infant formula

would be justified. Moreover, an infant

formula manufacturer would want to

have information demonstrating that

each of the ingredients in the formula is

safe before marketing the formula,

because without such information, a

responsible manufacturer would not

include the ingredient in its product.

FDA will review the new infant

formula submission to ensure that a safe

product will be produced (sections

201(s), 402(a)(1) and (a)(2), and 409 of

the act). If the agency is not presented

with basis on which it can be satisfied

that the use of an ingredient in an infant

formula will be safe, FDA will not be

able to acquiesce in the marketing of the

formula. The legislative history of the

1986 amendments supports that

Congress anticipated that FDA would

provide this type of review. In the

Congressional Record of September 27,

1986, Senator Metzenbaum stated:

I continue to be concerned, however, that

our food and drug laws do not differentiate

between foods and infant formulas. But they

are fundamentally different. An infant

formula is designed as the sole source of

nutrition for a baby. An infant formula is

used daily. A baby must thrive from its

content for the first and most formative

months of his or her life. I expect the

Secretary to look closely at whether or not

our standards in this area for foods are

adequate standards for infant formula. I have

no reason at this time to suspect that there

is a problem here. But I continue to urge the

Secretary to give thorough consideration to

the important distinctions between infant

formula and other foods, as well as food

additives which may be used with infant

formulas. (Ref. 1)

One way for a manufacturer to satisfy

the agency that proposed § 106.40(a) is

met would be for the manufacturer to

use only ingredients that are: (1) Listed

as GRAS for such use in 21 CFR part

182 or affirmed as GRAS for such use

in 21 CFR part 184 or otherwise GRAS

for such use under the regulations

included in those parts; (2) approved for

such use by a food additive regulation;

or (3) authorized by a prior sanction

issued by FDA.

Alternatively, the requirements of

proposed § 106.40(a) can be met by a

showing that the substance is GRAS

within the meaning of § 170.30 (21 CFR

170.30), which states that ‘‘general

recognition of safety may be based only

on the view of experts qualified by

scientific training and experience to

evaluate the safety of substances

directly or indirectly added to foods’’

(§ 170.30(a)). To clarify this point,

§ 170.30(a) states that ‘‘[g]eneral

recognition of safety requires common

knowledge about the substance

throughout the scientific community

knowledgeable about the safety of

substances directly or indirectly added

to food.’’ The qualified experts can base

their views on either: (1) Scientific

procedures, or (2) in the case of a

substance used in food prior to January

1, 1958, through experience based on

common use in food (section 201(s) of

the act).

Under § 170.30(b), general recognition

of safety based upon scientific

procedures requires the same quantity

and quality of scientific evidence as is

required to obtain approval of the

ingredient as a food additive, and it

must ordinarily be based on published

studies, which may be corroborated by

unpublished studies and other data and

information. If the manufacturer of an

infant formula wishes to use an

ingredient because there is general

recognition of safety based upon

scientific procedures, FDA is proposing

to require in § 106.120(b)(6)(ii) that the

manufacturer include as a part of its

new infant formula 90-day submission

the rationale for why the ingredient is

GRAS and the evidence that

demonstrates that there is common

knowledge about the safety of the

substance throughout the scientific

community knowledgeable about the

safety of such substance. FDA is

proposing that this evidence include a

bibliography of published studies,

copies of those scientific publications

about the substance, and an explanation

as to why, based on the published

studies, the use of the substance in

infant formula is GRAS.

Under § 170.30(c)(1), if a substance is

GRAS based on common use in food

prior to January 1, 1958, this

determination must be based solely on
36198 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

food use of the substance before January

1, 1958, and must ordinarily be based

upon generally available data and

information. Thus, GRAS based on

common use in food prior to January 1,

1958, may be determined without the

quantity or quality of scientific

procedures required for approval of a

food additive regulation. If the

manufacturer of an infant formula

wishes to use an ingredient based solely

on food use of the substance prior to

January 1, 1958, it should provide as a

part of the new infant formula 90-day

submission the evidence supporting that

the ingredient was in common use in

infant formula prior to January 1, 1958,

and an explanation of why that use

provides the basis for general

recognition of the safety of the

substance.

FDA has recognized that it is

impractical to list all substances that are

GRAS for their intended use based on

their common use in food prior to 1958

(see 21 CFR 182.1(a)). The agency

regards such common food ingredients

as salt, pepper, vinegar, and baking

powder as safe for their intended use.

Also, current § 170.30(d) provides that a

‘‘food ingredient of natural biological

origin that has been widely consumed

for its nutrient properties in the United

States prior to January 1, 1958, without

known detrimental effects, which is

subject only to conventional processing

as practiced prior to January 1, 1958,

and for which no known safety hazard

exists, will ordinarily be regarded as

GRAS * * *.’’ Some ingredients are

used in infant formulas even though

they are not listed or affirmed as GRAS

by the agency for their intended use.

Vitamin K, for example, is required to

be a part of an infant formula under

section 412(i) of the act and, in the form

of phylloquinone, is considered to be

safe and suitable for infant formulas

when used in accordance with

prescribed levels in § 107.100, although

no source of vitamin K, such as

phytonadione or phylloquinone, has

been listed or affirmed as GRAS by the

agency. Likewise, sodium selenite has

been added to infant formulas to

provide the amount of selenium that has

been determined to be essential for

infants by NAS (Ref. 19). Published

experimental and clinical data provide

a basis upon which experts qualified by

scientific training and experience could

evaluate the safety of sodium selenite as

a source of selenium for use in infant

formula and could conclude that it is

safe. The agency anticipates that other

ingredients may be shown to be GRAS

because they are generally accepted

sources of substances that are

established as essential for infants by an

authoritative body such as NAS.

However, manufacturers should not take

this acknowledgment to mean that they

are free to declare that the use of any

ingredient they want to use is GRAS.

Any ingredient that cannot meet the

standard of § 170.30 for a GRAS

determination will be viewed by the

agency as a food additive, and any

infant formula that contains a food

additive that the agency has not

approved for use in infant formula is

subject to being acted against by the

agency.

If the safety of an ingredient is not

expressly recognized in an FDA

regulation, the burden will rest on the

manufacturer of the infant formula to

include in its new infant formula

submission an explanation of why the

substance is GRAS under § 170.30,

along with the published and other

information that provides the basis for

that explanation, in accordance with

proposed § 106.120(b)(6)(ii). If the

agency adopts this approach, a failure of

the agency to object to a manufacturer’s

determination that an ingredient is

GRAS in a new infant formula

submission will not constitute a GRAS

affirmation by the agency. However, if

FDA knows of no reason to question the

safety of an ingredient to be used in

infant formula, the agency will not

object to the manufacturer’s relying on

its own determination that use of the

substance is GRAS.

e. Submission 90 days before

marketing a new infant formula

intended only for export. When a new

infant formula is intended only for

export, proposed § 106.120(c) provides

that manufacturers may submit, in lieu

of the information required under

proposed § 106.120(b), 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 to be exported, 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.

This proposed requirement recognizes

that under section 801(e) of the act, in

certain limited circumstances,

manufacturers may lawfully export

products that are adulterated or

misbranded. The information required

under proposed § 106.120(c) will

demonstrate that those limited

circumstances exist. FDA has tentatively

concluded that proposed § 106.120(c)

will provide manufacturers with the

flexibility allowed under section 801(e)

of the act while meeting the

requirements of sections 412(c) and (d)

of the act.

f. Submission 90 days before

marketing—administrative procedures.

Proposed § 106.120(d) states that the

submission will not constitute notice

under section 412 of the act unless it

complies fully with § 106.120(b), and

the information that it contains is set

forth in a manner that is readily

understandable, so that FDA can

complete its review in a timely manner

and advise the manufacturer if it has

any concerns about the marketing of the

formula before the 90 days is up.

Proposed § 106.120(d) makes clear that

the agency will notify the submitter if

the notice is not adequate because it

does not meet the requirements of

sections 412(c) and (d) of the act.

Proposed § 106.120(e) provides that if

a new infant formula submission

contains all the information required by

proposed § 106.120(b), FDA will

acknowledge its receipt and notify the

manufacturer of the date of receipt,

which will be the filing date for the

submission (and the manufacturer will

be able to plan those actions necessary

to begin marketing the new formula in

reliance on that date). Further, pursuant

to section 412(c)(1)(B) of the act,

proposed § 106.120(e) also requires that

the manufacturer not market the new

infant formula until 90 days after the

filing date. Congress provided for 90-

day notice so that the agency would

have sufficient time to examine all of

the material submitted and decide

whether there is any basis for concern

about the marketing of the formula.

Proposed § 106.120(f) makes clear that

if the manufacturer provides additional

information in support of a new infant

formula submission, FDA will

determine whether it represents a

substantive amendment to the

submission, and that, if it does, FDA

will assign the new infant formula

submission a new filing date. FDA is

proposing to adopt § 106.120(f) to clarify

how it will treat amendments to infant

formula notifications. In the 9 years

since the passage of the 1986

amendments, the treatment of

additional submissions has been the

source of some confusion. FDA has

tentatively concluded that it is

necessary to give a new filing date to a

new infant formula submission when a

substantive amendment is made to it so

that the agency has time to examine all

of the material submitted and to

determine whether there is any basis for

concern about the marketing of the

formula.

4. Quality Factor Submission

Proposed § 106.121 sets forth the

requirements for specific information

that a manufacturer must submit to
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36199

FDA, in accordance with proposed

§ 106.120(b)(5), to provide assurance

that the infant formula meets the quality

factor requirements set forth in subpart

E of part 106. FDA has tentatively

concluded that agency access to study

records and data are necessary so that it

can ensure that study results are

meaningfully interpretable, and that the

manufacturer’s conclusion that the

infant formula meets the quality factor

requirements withstands scientific

scrutiny and evaluation. Failure to

adequately document study results and

interpretation raises questions as to the

validity of conclusions and could mean

that infants have been unnecessarily

subjected to testing procedures.

Proposed § 106.121(a) requires that

the manufacturer submit an

explanation, in narrative form, setting

forth its conclusions on how all quality

factor requirements of subpart E of part

106 have been met. This narrative will

facilitate the agency’s review by

summarizing the results, and their

interpretation, that provide the basis on

which the manufacturer has concluded

that the quality factor requirements have

been met, or that the subject infant

formula is eligible for the exemptions

described in proposed § 106.97(a)(2) and

(b)(2).

Proposed § 106.121(b) requires that

the manufacturer submit records that

contain the information collected during

the study for each infant enrolled in the

study. The measurements and

information collected for each infant

enrolled in the study are necessary to an

evaluation of whether the infant formula

supported healthy growth. Proper

identification of the records is necessary

for proper use and analysis of the

records.

Proposed § 106.121(c)(1) requires that

the manufacturer submit a statistical

evaluation of the data from the clinical

study, 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. This evaluation

forms the basis for the manufacturer’s

conclusion as to whether the formula

meets the quality factor requirements.

Without knowledge of the statistical

basis upon which the manufacturer

drew its conclusions, FDA would not

have sufficient information to evaluate

the conclusions reported by the

manufacturer.

Proposed § 106.121(c)(2) requires that

the manufacturer submit a calculation of

the statistical power of the study at its

completion. Proposed

§ 106.97(a)(1)(ii)(E) recommends that

the power calculation used to design the

study be included in the study protocol.

FDA is aware that circumstances (e.g.,

attrition, difficulty in recruiting

sufficient numbers of infants,

unexpectedly high measurement error

in a particular variable) may

unintentionally result in sample sizes

and feeding group assignments that lack

adequate statistical power for detecting

differences between treatment and

control groups, regardless of the

apparent adequacy in planning for the

study protocol. Reviewers must be

aware of changes in the statistical power

of a study so that they do not

inadvertently misinterpret the absence

of differences that occur between

different formulas as meaning there are

no differences. Failure to detect

differences, if they are real, could result

in erroneously concluding that a

formula is safe and suitable for its

intended use when, in fact, it is not. The

agency is proposing to require that the

manufacturer submit this calculation to

FDA so that the agency can

meaningfully review and interpret the

data and study results contained in the

submission.

Proposed § 106.121(d) requires that

the manufacturer submit reports on

attrition and on all occurrences of

adverse events during the study.

FDA has tentatively found that

information on the occurrence of

adverse events is a critical element of

the data that must be evaluated to

determine whether a formula meets

quality factor requirements and is safe

and suitable for infants. Adverse events

associated with the use of an infant

formula, although unexpected, can be a

sign or symptom of a nutritional

inadequacy or of a safety problem with

the infant formula, and failure to use

these results could result in inadvertent

release of an unsafe product.

Conversely, adverse events can be

unrelated to a formula product (e.g.,

flu), but their occurrence can affect the

way in which results are interpreted and

used. For example, illnesses can

influence the interpretation of growth

data and of the laboratory measurements

collected to evaluate the infant formula.

For these reasons, FDA has tentatively

concluded that complete reports,

including the results of followup

investigations, on the occurrence of all

adverse events during the study,

regardless of whether the adverse events

are attributable to the use of the new

infant formula or to some other

illnesses, are necessary to properly

evaluate the conclusions drawn from a

clinical study (proposed

§ 106.121(d)(1)). FDA has tentatively

concluded that a complete report on the

occurrence of an adverse event must

include identification of the infant by

subject number to permit evaluation of

infant growth measurements;

identification of the feeding group to

show whether there is a pattern of

adverse events in one feeding group

versus another; and a complete

description of the adverse event,

including comparisons of the frequency

of occurrence in each feeding group and

information on the health of the infants

during the course of the study,

including the occurrence and duration

of any illness, that occurred during the

trial, so that it is possible to evaluate the

significance of the illness.

As discussed above, it is very

important to be able to evaluate whether

the adverse event is a result of a

nutritional quality factor problem with

the formula product. The results and

evaluation of the infant’s clinical status

are essential to make this evaluation,

and the health of the infant is also

relevant to interpreting study endpoints,

for example, growth data. Therefore,

knowledge of the infant’s health status

is an essential piece of information in

evaluating the circumstances

surrounding an observed adverse event

associated with use of a formula

product. Thus, FDA has tentatively

concluded that evaluations by a health

care professional are necessary to

provide the agency with relevant

information on the circumstances

surrounding the adverse event (see

§ 106.121(d)(2)) to assist the agency in

evaluating the nutritional adequacy and

safety of the formula product for

supporting healthy growth in infants. In

some cases, this clinical assessment may

be carried out by the infant’s health care

provider, rather than the investigators

conducting this clinical study, because

some parents will contact the infant’s

health care provider if the infant

experiences any adverse event during

the course of the study. The agency

expects that the study investigators will

take sufficient measures to obtain all

available information to enhance the

likelihood of being able to meaningfully

interpret the likely relationship of the

adverse event to the formula product

and its impact on study conclusions.

Attrition of infants from a study can

result not only from adverse events and

illnesses but also from a variety of

reasons having no bearing on whether

the new infant formula meets the

quality factor requirements. For

example, an infant enrolled in the study

may be withdrawn from the study

because the parents moved from the

area. The effect of attrition on study

results, however, must be evaluated in

order to be able to meaningfully
36200 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

interpret those results. To properly

evaluate the impact of attrition on study

results, FDA must have information that

permits it to evaluate the likely cause of

the attrition and its relationship to

product use and study measurements.

Therefore, the agency is proposing to

require the submission of this

information on attrition under

§ 106.121(d)(3).

Proposed § 106.121(e) requires that

the manufacturer submit the results of

the Protein Efficiency Ratio. This

proposed submission requirement is

necessary to provide assurance that the

manufacturer has complied with

proposed § 106.97(b) and to provide

assurance that the infant formula meets

the specific quality factor for protein

quality.

Under proposed § 106.121(f), the

manufacturer is required to submit a

statement certifying that it has collected

and considered all information and data

on the ability of the infant formula to

meet the quality factor requirements,

and that it is not aware of anything that

would show that the formula does not

meet the quality factors. This proposed

requirement is necessary to provide

assurance that the manufacturer has

complied with the regulations and

considered all information and data of

which it is aware, and that it has not

made a selective submission of

information that gives a false impression

of the degree or extent to which a

formula meets the quality factor

requirements.

5. Verification Submissions

Proposed § 106.130(a) requires that

manufacturers, after the first

production, but before the introduction

into interstate commerce, of a new

infant formula, verify in a written

submission that the infant formula

complies with the requirements of the

act and is not adulterated. This

proposed requirement implements

section 412(d)(2) of the act, which

requires the submission of a written

verification that summarizes test results

and records demonstrating that a

formula meets the requirements of

section 412(b)(1), (b)(2)(A), (b)(2)(B)(i),

(b)(2)(B)(iii), (b)(3)(A), (b)(3)(C), and (i)

of the act. The failure to provide the

notice required by section 412(d) of the

act is a prohibited act under section

301(s) of the act.

Proposed § 106.130(b)(1) requires that

the verification submission include the

name of the new infant formula, the

filing date for the new infant formula

submission required under proposed

§ 106.120, and the identification number

assigned by FDA to the new infant

formula submission, so that FDA is able

to match the verification submission

with the appropriate new infant formula

submission.

Proposed § 106.130(b)(2) requires that

the verification submission include a

statement that the infant formula to be

introduced into interstate commerce is

the same as that which was the subject

of the new infant formula submission

and for which the manufacturer

provided assurances in accordance with

the requirements of proposed § 106.120.

FDA has tentatively concluded that if

this statement can be made by the

manufacturer, it means that the

assurances that the manufacturer

provided in the new infant formula

submission with respect to the quality

factor requirements and the safety of the

ingredients remain relevant and

applicable to the product. Thus, no

additional information need be included

in the verification to demonstrate

compliance, in accordance with section

412(d)(2) of the act, with section

412(b)(1) or with this aspect of section

412(b)(2)(A).

Proposed § 106.130(b)(3) requires a

summary of test results that show the

levels of each nutrient required by

§ 107.100 in the formula and of any

nutrient added by the manufacturer.

This proposed requirement is necessary

to demonstrate compliance with section

412(i) of the act. Section 412(i) of the act

sets forth those nutrients that an infant

formula must contain in order not to be

adulterated, and the submission of a

summary of test results as required by

section 412(d)(2), and implemented by

§ 106.130(b)(3), is necessary to show

that an infant formula, after the first

production, contains all of the required

nutrients at the required levels.

FDA has tentatively concluded that it

is not necessary to require that the

verification submission summarize test

results or records demonstrating

compliance with sections 412(b)(2)(A)

and (b)(2)(B)(iii) of the act because the

underlying records will be available for

inspection by FDA. FDA has tentatively

concluded that to require the

manufacturer to create a report based on

these records would be to require an

unnecessary expenditure of effort.

However, the agency is proposing to

require (under § 106.130(b)(4)) that the

manufacturer certify as a part of its

verification submission that it has

established procedures that comply

with sections 412(b)(2)(A) and

(b)(2)(B)(iii) of the act.

FDA has tentatively concluded that

requiring additional test results or

records demonstrating compliance with

section 412(b)(2)(B)(i), (b)(3)(A), and

(b)(3)(C) of the act would be

unnecessary because such showings

would be subsumed in the testing to

show whether the formula meets the

requirements of § 107.100 (under

§ 106.130(b)(3)).

Proposed § 106.130(c) makes clear the

consequences of failing to comply with

§ 106.130 and that in such

circumstances, the agency will notify

the submitter that the notice is not

adequate, and that the manufacturer has

not met the requirements of section

412(d)(2) of the act.

6. Submissions Concerning a Change in

Infant Formula That May Adulterate the

Product

Proposed § 106.140(a) provides that,

when a manufacturer makes a change in

the formulation or processing of the

formula that may affect whether the

formula is adulterated under section

412(a) of the act, it shall make a

submission to FDA before the first

processing of such formula. This

proposed requirement implements

section 412(d)(3) of the act, which

requires that manufacturers make the

submission to FDA required by section

412(d)(1) of the act before first

processing when they determine that a

change in formulation or in the

processing of an infant formula may

affect whether the formula is

adulterated under section 412(a) of the

act. Examples of changes that may affect

whether a formula is adulterated under

section 412(a) of the act include, but are

not limited to:

(1) A change in the level of an

ingredient that does not constitute a

major change but that may affect

whether the formula meets the

requirements of section 412(i) of the act

(for example, decreasing the amount of

an ingredient such as sodium chloride

could affect whether the formula

provides two nutrients required by

§ 107.100);

(2) A change in an ingredient in an

infant formula that does not constitute

a major change but that may affect

whether the formula meets the quality

factor requirements of subpart E of part

106 (for example, a change in the level

of an emulsifier could result in a change

in the bioavailability of fat because the

emulsifier may interfere with fat

digestion); or

(3) A change in the processing of the

infant formula that does not constitute

a major change but that may affect

whether the CGMP requirements or the

quality control procedures of subparts B

and C of part 106 are met (for example,

a change in the processing of the infant

formula may affect whether a

specification or a standard for a

particular point in the manufacturing

process where control is deemed
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36201

necessary to prevent adulteration is met;

a change in a processing temperature or

holding time may allow microorganisms

to develop in violation of § 106.55; or a

change in a processing temperature may

affect the level of a labile (temperature

sensitive) nutrient in the formula).

Proposed § 106.140(b)(1) requires that

the submission include information on

the name and physical form of the

product, so that the change in the

formula can be evaluated with other

information that the agency has received

on the formula, and so that an accurate

evaluation of the product can be made

because different requirements may

apply to different forms of a formula.

Proposed § 106.140(b)(2) requires an

explanation of why the change in

formulation or processing may affect

whether the formula is adulterated, so

that the agency can determine what type

of evaluation the submission requires.

For example, if a change in formulation

may affect nutrient levels, the agency

needs to evaluate the nutrient content of

the formula to be assured that this

formulation change will not lead to

production of a formula that will not

provide a required nutrient at the

required amount. Likewise, if a change

in processing may affect whether the

formula is adulterated, the agency will

need to evaluate the formula’s

processing to be assured that the

processing of the formula will still

comply with the CGMP regulations in

subpart B of part 106.

Proposed § 106.140(b)(3) requires that

the submission comply with

§ 106.120(b)(3), (b)(4), (b)(5), and (b)(6).

This proposed requirement implements

section 412(d)(3) of the act, which

provides that manufacturers make the

submission required by section

412(d)(1). FDA has tentatively

concluded that requiring that the

submission comply with these aspects

of § 106.120(b) will promote consistency

in the form and substance of the

information that industry must submit,

and FDA must review. If the

information required on processing by

§ 106.120(b)(4) has already been

provided in compliance with

§ 106.140(b)(2) as a part of the

explanation of why the change in

processing may affect whether the

formula is adulterated, the same

information does not need to be

repeated in the submission. To avoid

redundant submissions, proposed

§ 106.140(b)(3) further provides that if

the information required by

§ 106.120(b)(3), (b)(4), (b)(5), or (b)(6)

has been provided to the agency

previously, and that information is not

affected by the change that is the subject

of the submission, a statement to that

effect, together with the identification

number assigned by the agency to the

relevant infant formula submission, can

be provided in lieu of a new

submission.

Proposed § 106.140(b)(3) requires

inclusion of the identification number

assigned by the agency to the infant

formula submission so that the agency

can have ready access to the relevant

information that was previously

submitted. For example, if the

manufacturer makes a submission as a

result of a change in processing, but the

formulation will remain the same, the

manufacturer need not provide the

information required by § 106.120(b)(3).

Likewise, if the manufacturer makes a

submission as a result of a change in

formulation, but the processing of the

formula remains the same, the

manufacturer need not submit the

information required by § 106.120(b)(4).

A determination of whether the

assurances required by § 106.120(b)(5)

and (b)(6) need to be given is based on

the manufacturer’s reason for providing

the submission. For example, if the

submission is provided because a

change in formulation or processing

may affect whether the formula is

adulterated because it does not meet the

quality factors set forth in subpart E of

part 106, the assurance required by

§ 106.120(b)(5)(i) would have to be

provided. Likewise, if the submission is

provided because a change in

formulation or processing may affect

whether the formula is adulterated

because it does not meet the nutrient

requirements of § 107.100, the assurance

required by § 106.120(b)(5)(ii) would

have to be provided. Further, if the

submission is provided because a

change in processing may affect whether

the formula is adulterated because the

processing of such formula may no

longer be in compliance with CGMP or

with appropriate quality control, as set

forth in subparts B and C of part 106,

or whether the formula is manufactured

in a manner designed to prevent

adulteration, the assurance required by

§ 106.120(b)(6) would have to be

provided.

In proposed § 106.140(c), the agency

sets forth requirements necessary to

ensure that the data and other

information provided in the submission

are in a form that will allow FDA to

complete its review in a timely manner

and to advise the manufacturer if the

agency has any concerns about the

marketing of the formula. Proposed

§ 106.140(c) also makes clear that the

agency will notify the submitter if the

notice is not adequate because it does

not meet the requirements of section

412(d)(3) of the act.

7. Notification of an Adulterated or

Misbranded Infant Formula

If FDA adopts the other regulations

that it has proposed, it will redesignate

current §§ 107.240(a) and (b) as

§ 106.150 so that all notification

requirements on infant formulas can be

found in one place in the agency’s

regulations. In § 106.150(b), FDA has

revised the address to reflect the

reorganization of CFSAN.

H. Conforming and Editorial Changes to

Part 107—Infant Formula

The agency is making conforming and

editorial changes to part 107 to reflect

the changes made by the 1986

amendments and the regulations that

FDA is proposing to adopt in part 106.

The references in part 107 to the

Division of Regulatory Guidance are

being changed to the Division of

Enforcement to reflect the

reorganization of CFSAN in November

1992.

1. Changes in Subpart A

The agency is proposing to add a new

§ 107.1 which will parallel proposed

§ 106.1. Proposed § 107.1 describes the

authority for each of the proposed

subparts and the consequences under

the act of failure to comply with any of

the regulations in the proposed

subparts.

2. Changes in Subpart B of Part 107—

Labeling

The agency is proposing to amend

§ 107.10 to require a statement of the

amount, supplied by 100 kcal, of each

of any nutrient added by the

manufacturer as well as of the listed

nutrients. As discussed previously in

the quality control section of this

document, infant formula manufacturers

are adding ingredients to infant formula

to provide nutrients, such as selenium,

that are not required by § 107.100 to be

in infant formulas. The proposed change

to § 107.10 requires that the amount of

the added nutrients supplied by 100

kcal of the formula be declared on the

label of the infant formula. This

proposed requirement is necessary to

inform the consumer on a consistent

basis of the level of all nutrients

included in an infant formula.

3. Subpart C of Part 107—Exempt Infant

Formulas

At this time the agency is not

proposing to revise the regulations in

§ 107.50 pertaining to infant formulas

that are subject to section 412(h) of the

act. These regulations were finalized in

1985 (50 FR 48183), before passage of

the 1986 amendments. In the near

future, the agency intends to reevaluate
36202 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

the exempt infant formula regulations

and the effect of the 1986 amendments

on exempt infant formulas and to issue

a proposed rule to reflect the results of

this reevaluation. The agency also plans

to evaluate the effect of the Nutrition

Labeling and Education Act of 1990

(Pub. L. 101–535) (the 1990

amendments) on the regulations for

exempt infant formulas. Exempt infant

formulas are specifically exempted from

requirements for health claims and

nutrient content claims by section

403(r)(5)(A) of the act. The basis for

being an exempt infant formula,

according to section 412(h)(1) of the act,

is how the product is represented and

labeled for use. This category of infant

formula recognizes that infants who

suffer from special medical disorders,

such as maldigestion and

malabsorption, inborn errors of

metabolism such as phenylketonuria or

maple syrup urine disease, or severe

kidney disease, require formulas

tailored specifically to their medical

needs. Therefore, it is important that

any claims made for these products be

truthful, not misleading, and adequately

substantiated because these infants

make up a vulnerable population and

must receive the appropriate nutrients

for their medical condition. Because

these formulas are exempt from the

regulations governing claims that were

developed under the 1990 amendments,

the agency plans to evaluate how claims

for these products need to be

substantiated to ensure that infants with

special nutritional needs are receiving

appropriate infant formulas.

4. Subpart E—Infant Formula Recalls

Current § 107.240(a) sets out the

requirements for notification of a

violative infant formula, and current

§ 107.240(b) sets out the method of

notification. As stated above, the agency

is moving the provisions of current

§ 107.240(a) and (b) to § 106.150, so that

all of the agency’s notification

requirements are in one place. The

agency is renumbering current

§ 107.240(c)(1), (c)(2), and (c)(3) as

§ 107.240(a), (b), and (c).

Section 107.250 gives directions on

the termination of an infant formula

recall. The agency is changing the

reference to the Division of Regulatory

Guidance to the Division of

Enforcement in § 107.250 to reflect the

1992 reorganization of CFSAN.

V. Environmental Impact

The agency has carefully considered

the potential environmental effects of

this action. FDA has concluded that the

action will not have a significant impact

on the human environment, and that an

environmental impact statement is not

required. The agency’s finding of no

significant impact and the evidence

supporting that finding, contained in an

environmental assessment, may be seen

in the Dockets Management Branch

(address above) between 9 a.m. and 4

p.m., Monday through Friday.

VI. Analysis of Impacts

FDA has examined the impacts of the

proposed rule under Executive Order

12866 and the Regulatory Flexibility Act

(Pub. L. 96–354). Executive Order 12866

directs agencies to assess all costs and

benefits of available regulatory

alternatives and, when regulation is

necessary, to select regulatory

approaches that maximize net benefits

(including potential economic,

environmental, public health and safety,

and other advantages; distributive

impacts; and equity). According to

Executive Order 12866, a regulatory

action is ‘‘economically significant’’ if it

meets any one of a number of specified

conditions, including having an annual

effect on the economy of $100 million

or adversely affecting in a material way

a sector of the economy, competition, or

jobs. A regulation is considered

‘‘significant’’ under Executive Order

12866 if it raises novel legal or policy

issues.

The Regulatory Flexibility Act

requires Federal agencies to minimize

the economic impact of their regulations

on small businesses. FDA finds that this

proposed rule is neither an

economically significant nor a

significant regulatory action as defined

by Executive Order 12866. In

compliance with the Regulatory

Flexibility Act, the agency certifies that

this proposed rule, if issued, will not

have a significant impact on a

substantial number of small businesses.

Therefore, under the Regulatory

Flexibility Act, no further analysis is

required. The agency examined three

options in determining the economic

impact of this proposed regulations. A

summary of the options follow:

A. Options

FDA has three primary options: (1)

Adopt regulations with more stringent

requirements than the proposed

regulations; (2) adopt the proposed

regulations; or (3) adopt regulations

with less stringent requirements than

the proposed regulations.

1. Option 1—Adopt Regulations More

Stringent Than the Proposed

Regulations

FDA believes infant formula

manufacturers already comply with

most of the requirements of this

proposed rule. One option would be to

add provisions to this proposed rule

that would require activity beyond that

which is currently engaged in by infant

formula manufacturers or that is likely

to be engaged in by manufacturers

entering the infant formula industry.

Potential requirements of this type

include specific production and inprocess control systems, specific

equipment or types of personnel, and

additional testing and recordkeeping.

Under this option, incumbent

manufacturers would face higher

production costs and would pass most

of the costs on to consumers of infant

formula. In addition, the startup and

operating costs would increase, and

thus discourage entry into the infant

formula industry. The ability of new

firms to enter an industry is an

important element in promoting price

competition and innovation. These

additional requirements would reduce

price competition in the infant formula

industry.

The price of infant formula is

probably linked to certain risky infant

feeding practices. With very high infant

formula prices, some consumers may

increase risks to infants by improperly

diluting formula with water or other

substances; using inappropriate

substitutes for formula or breast milk; or

prematurely switching from formula to

cow’s milk. For example, preliminary

results of an FDA study on infant

formula feeding practices showed that

approximately 20 percent of infants

(younger than 2 months) had their

formula diluted by cereal, which is

cheaper than infant formula.

2. Option 2—Adopt the Proposed

Regulations

There are two types of costs

associated with this option: precluded

future cost cutting behavior and direct

compliance costs.

a. Future cost cutting behavior. This

type of cost may arise because the

proposed rule precludes cost cutting

behavior by either incumbent firms or

firms entering the infant formula

industry. Infant formula manufacturers

currently undertake a considerable

amount of activity, such as infant

growth studies, that is designed to

ensure the safety of infant formula but

is not explicitly required by either

current law or regulation. In the absence

of this regulation, which mandates this

activity, either incumbent or future

manufacturers may choose not to

undertake this activity in the future.

However, because of reputation effects

and liability laws, these costs are likely

to be low.
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36203

b. Direct compliance costs. (i). CGMP.

FDA believes that infant formula

manufacturers already comply with

most of the proposed CGMP’s. These

CGMP’s include those dealing with: (1)

Production and in-process control

systems, including the evaluation of any

deviation from these procedures or from

established standards or specifications;

(2) controls designed to prevent

adulteration of infant formula by

workers, by facilities, and during

packaging and labeling; (3) controls to

prevent adulteration during

manufacturing, including recording and

justifying deviations from the master

manufacturing order and evaluating

deviations from processing times; (4)

controls on the release and storage of

finished infant formula; (5) all

requirements relating to batch

production and control records, and to

coding; and (6) all requirements dealing

with general quality control procedures,

including the testing of one batch of

each physical form of infant formula at

least once every 3 months.

If all manufacturers already comply

with these proposed CGMP’s, then no

compliance costs will result from them.

FDA requests comments on whether all

infant formula manufacturers are

already in compliance with the

proposed CGMP’s listed above.

FDA believes that all infant formula

manufacturers already comply with the

proposed CGMP’s dealing with controls

to prevent adulteration caused by

ingredients, containers, and closures.

The provision that FDA may object to

the use of a particular substance in an

infant formula during its prenotification

review of ingredients used in a formula

because it believes that the substance is

not safe and suitable for that use does

not represent a change in the way FDA

reviews infant formula ingredients. This

provision recognizes the fact that

manufacturers may make independent

GRAS determinations about ingredients.

When a manufacturer makes such a

determination, that manufacturer is not

necessarily required to have the relevant

ingredient affirmed as GRAS by FDA.

However, FDA is reserving the right to

review infant formula ingredient lists

and documentation concerning whether

particular ingredients are safe and

suitable for use in infant formula.

Theoretically, this provision could lead

to a reduction in the number of

ingredients that are independently

determined to be GRAS and a

corresponding increase in the number of

ingredients for which food additive

petitions are required. Petitions for

direct food additives can take between

1 to 6 years to complete and cost

approximately $1 million per year.

However, because manufacturers of

infant formula generally obtain FDA

concurrence on the safety and

suitability of ingredients used in infant

formula before making these

determinations, FDA believes no

additional compliance costs will be

generated by this provision.

FDA also believes that infant formula

manufacturers already comply with

many of the other proposed CGMP’s.

Provisions of CGMP’s that some infant

formula manufacturers may not

currently be in compliance include the

following:

(1) Controls to prevent adulteration

caused by equipment or utensils. Some

manufacturers may not repair or replace

instruments and controls when those

instruments and controls cannot be

adjusted to within essential agreement

with the reference standard. In addition,

most manufacturers probably do not

perform a written evaluation of all

affected product, or of actions taken

when calibration results indicate that a

specification or standard for a point

where control is deemed necessary to

prevent adulteration has not been met.

FDA cannot estimate the repair or

replacement costs of instruments and

controls at this time. Written

evaluations will take a supervising

technician an estimated 2 hours to

complete, which will generate some

small compliance costs.

(2) Controls to prevent adulteration

because of automatic, mechanical, and

electronic equipment. Most

manufacturers will probably have to

perform additional analysis of software

modifications. FDA preliminarily

estimates this analysis will add

approximately 1 month to the time

required to analyze programming and

software modifications. One or two

software modifications are probably

made each year at each of the fifteen

plants that produce infant formula.

Assuming that a single computer

scientist works on the additional

activity required, compliance costs are

estimated to be about $100,000 per year.

ii. Audits, Quality factors, registration

and notification requirements, and

infant formula recalls. FDA believes

that infant formula manufacturers

already comply with the following

provisions: (1) Regularly scheduled

audits to determine compliance with

CGMP’s and Quality Control Procedures

(QCP’s), (2) growth and development

studies to be submitted under certain

conditions and new notification

requirements (FDA already requests and

receives these quality factor growth and

development studies and notification

material based on FDA’s interpretation

of the language of the 1986

amendments), and (3) all provisions

involving registration and notification

requirements.

If infant formula manufacturers are

already complying with these

provisions, then no compliance costs

will be generated by these provisions.

FDA requests information on whether

all infant formula manufacturers already

comply with all provisions listed above,

particularly those provisions dealing

with quality factors.

iii. Records. Under the current

proposal, the records produced and

maintained by infant formula

manufacturers to establish compliance

with FDA regulations will have to be

expanded to include all new CGMP’s

and QCP’s. FDA believes most of the

specified records are already being kept

by all firms; however, some records may

not be. A plausible assumption is that

current annual industry expenditures on

recordkeeping may increase by about 10

percent, or $450,000 per year based on

information received from industry on

current recordkeeping costs. FDA

requests information on the cost of

increased recordkeeping.

iv. Administrative costs. Interpreting

and implementing changes in CGMP

and QCP regulations generate

administrative costs even when all

activity required in those CGMP’s and

QCP’s is already being done. FDA does

not have information on the

administrative costs involved in

interpreting and implementing changes

in CGMP and QCP regulations; however,

it is plausible to suppose that 20 percent

of the total compliance costs other than

administrative costs may be used to

reflect administrative costs.

Administrative costs under this

assumption would be approximately

$100,000 and would accrue in the first

year only. FDA requests information on

administrative costs.

3. Option 3—Adopt Regulations Less

Stringent Than the Proposed

Regulations

Another option is to limit the activity

required by this proposed rule to

activity already engaged in by all

incumbent infant formula

manufacturers. In this case, there would

be no compliance costs based on current

behavior. However, in the absence of

this proposed rule, incumbent or new

manufacturers might choose not to

undertake all activity specified in this

proposed rule. Therefore, the only costs

associated with this option are the costs

associated with precluded potential

future behavior on the part of

incumbent or new manufacturers.
36204 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

B. Benefits

1. Option 1—Adopt Regulations More

Stringent Than the Proposed

Regulations

More stringent regulations for infant

formula would cause infant formula

manufacturers to undertake further

activity to ensure the safety of infant

formula. If there were identifiable risks

from infant formula that were not

addressed by this proposal, then this

additional activity might decrease those

health risks. However, FDA is not aware

of identifiable health risks from infant

formula that are not addressed by this

proposal.

2. Option 2—Adopt the Proposed

Regulations

The proposed regulation has two

primary benefits: A potential direct

reduction in the health risks posed by

infant formula, and a potential

reduction in the cost of entering the

infant formula industry. The latter effect

could lead to an increase in the

competitiveness of the infant formula

industry, resulting in lower infant

formula prices and a reduction in the

incidence of risky infant feeding

practices linked to high infant formula

prices.

One example of a current activity that

can be linked to a direct reduction in

health risks but that is not explicitly

required by current law or regulation is

the performance of growth studies for

new infant formulas. FDA currently

requests and receives these studies to

demonstrate that the infant formula

meets the quality factor requirements of

section 412(b)(1) of the act. However,

because section 412(b)(1) of the act does

not list specific quality factors that

infant formulas must meet, a quality

factor for healthy growth currently is

not expressly stipulated. In the absence

of this proposed rule, manufacturers

could decline to perform these growth

studies in the future with a potential

consequence that products that do not

support normal growth would be

marketed. Low growth rates would not

be detected by existing regulatory and

legal requirements that measure only

the levels of required nutrients because

the required nutrients may be present

but not be bioavailable, and there is no

mechanism for testing bioavailability

other than the proposed studies.

An example of a formula associated

with low growth rates that would not

have been detected in the absence of

growth studies was an experimental

formula that contained a source of fatty

acids not previously used in infant

formula. Because only a small amount

of the new fat source was added to a

commercial formula, it is reasonable to

assume that all required nutrients were

present within legal specifications.

Consequently, it would likely have met

all current regulations. Nonetheless, this

formula was found to result in low

infant growth rates (Ref. 87). In this

case, the manufacturer undertook the

necessary growth studies and detected

the problem on its own. However,

manufacturers might not undertake

these studies on their own in the future.

In addition, even if manufacturers

continue to undertake these studies in

the absence of this regulation, they may

not do these studies correctly.

In general, low rates of infant growth

are associated with higher than normal

levels of infant morbidity. If a problem

of this type were to occur, a large

number of infants could potentially be

affected.

Other types of current activity can

also be linked to a direct reduction in

health risks and also are not explicitly

required by current law or regulation. In

the absence of this regulation,

incumbent or new manufacturers may

not undertake this activity in the future.

However, as explained earlier, because

of reputation effects and legal liability,

such a refusal seems unlikely.

An example of a health risk from

infant formula is the 1978 incident,

discussed elsewhere in this document,

in which a required nutrient was

missing from an infant formula.

Recurrence of this particular problem is

unlikely because section 412(d)(1)(A) of

the act already explicitly requires the

submission of the quantitative

formulation of an infant formula as part

of the mandatory FDA notification of a

new infant formula. Recurrence of this

problem is also made unlikely because

section 412(b)(2) of the act already

explicitly requires the testing of infant

formula for all required nutrients.

However, the risk of a formula being

sold without a required nutrient is

minimized to the extent possible by

specifically clarifying this part of the

infant formula law in the regulation.

Another example of a health risk

associated with infant formula is an

incident in which infant formula was

found to contain Salmonella. It appears

that the manufacturer was testing for

Salmonella in a manner consistent with

the testing requirements of this

proposed rule, and therefore it is not

clear that this particular incident would

have been avoided if the proposed rule

had been in effect. This proposed rule

will reduce the risk of microbiological

contamination, however, because it

requires manufactures to institute a

production and in-process control

system. The production and in-process

control system establishes standards or

specifications to be met throughout the

production of their product. Other

provisions of the proposed regulation

that will also help to prevent

microbiological contamination of infant

formulas are controls to prevent

adulteration by workers (proposed

§ 106.10), controls on the required

temperature of cold storage

compartments used for storing

ingredients and uncanned infant

formula (proposed § 106.30(e)(2)),

controls on the monitoring of the

temperature of both cold storage and

thermal processing equipment

(proposed § 106.30(e)), controls on the

spray-drying process for powdered

infant formula including the filtering of

the intake air before heating to prevent

microbial growth (proposed

§ 106.50(d)(2)), and controls to ensure

that each container of finished product

is properly sealed (proposed

§ 106.50(d)(4)).

The incident in which infant formula

was found to contain Salmonella

resulted in two reported cases of

salmonellosis in infants. The average

value of preventing a single case of

salmonellosis is estimated to be about

$2,000 (Ref. 88). If an incident like this

is avoided in the future because of this

proposed rule, the value of the adverse

health effects avoided would be a

benefit of this proposed rule.

This incident also resulted in two

recalls. FDA estimates a combined cost,

including costs that accrued to both the

manufacturer and FDA of approximately

$0.7 million per recall. If an incident

like this is avoided in the future because

of this proposed rule, the recall costs

that would otherwise have been

associated with this incident would also

be a benefit of this proposed rule.

Another benefit of the proposed

regulations is a potential reduction in

the administrative and time costs of

entering the infant formula industry.

Currently, infant formula manufacturers

must analyze and interpret the relevant

laws to determine the legal

requirements involved in the

manufacture of infant formula.

Incumbent firms have tended to accept

FDA’s interpretations of these laws and

have received information on this

interpretation incrementally over time,

chiefly through direct contact with FDA

on various issues.

It is reasonable to expect that

potential entrants into the infant

formula industry would also prefer to

rely on FDA’s interpretations of the

relevant laws. However, considerable

time and administrative costs are

involved in obtaining this information

because there is no established
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36205

mechanism by which manufacturers can

obtain this information other than direct

communication with FDA on various

particular issues. By providing an

explicit specification of the activities

that are required by the relevant laws,

the proposed regulations, if adopted,

will reduce the time and administrative

costs involved in entering this industry.

In order to determine the net effect of

the proposed rule on the cost of entering

the infant formula industry, the

reduction in time and administrative

costs must be weighed against the

additional compliance costs imposed by

this proposed rule on new firms. These

countervailing compliance costs are

probably low because new firms will

probably undertake voluntarily the same

activity that is currently undertaken

voluntarily by incumbent

manufacturers. Therefore, the net effect

of this proposed rule is likely to be the

reduction in the cost of entering the

infant formula industry. Publication of

the proposed and final regulations will

provide a means of expedited entry for

new firms into the infant formula

market.

A reduction in the cost of entering the

infant formula industry will promote

both price competition and innovation

in this industry. Increased price

competition may lead to health benefits

because, as stated above, high infant

formula prices may encourage some

consumers to: (1) Improperly dilute

infant formula to reduce the cost per

serving; (2) prematurely switch from

infant formula to cow’s milk; or (3) use

inappropriate substitutes for breast milk

and infant formula.

A final benefit of this proposed rule

is the cost savings generated by the

elimination of the current FDA

requirement that a vitamin D rat

bioassay be performed for all major

changes in infant formula. In 1992, there

were approximately 50 major changes.

The cost of a rat bioassay for vitamin D

for infant formula at a private lab is

about $1,070 (Ref. 89). Infant formula

manufacturers should therefore save

approximately $54,000 in testing costs

per year.

3. Option 3—Adopt Regulations Less

Stringent than the Proposed Regulations

Except for the value of the risk

reductions resulting from requirements

that go beyond activity currently

undertaken by infant formula

manufacturers the benefits of this option

are identical to those of Option 2.

C. Conclusions

In accordance with Executive Order

12286, FDA has analyzed the economic

effects of this proposed rule and has

determined that this rule, if issued, will

not be a significant rule as defined by

that order. In accordance with the

Regulatory Flexibility Act, FDA certifies

that the proposed rule will not have a

significant impact on a substantial

number of small businesses.

The primary compliance costs of

Option 2 include both direct costs of

new requirements and precluded

production cost reductions which may

occur without this regulation. FDA has

estimated direct costs to incumbent

manufacturers to be approximately $0.7

million in the first year and $0.6 million

each additional year. An additional cost

to incumbent manufacturers is the cost

of repairing or replacing instruments

and controls when those instruments

and controls cannot be adjusted to

agreement with the reference standard.

FDA has insufficient information to

estimate this cost. FDA does not expect

compliance with the proposed

regulations to cause any significant

increase in the price of infant formula

products. However, the agency requests

comments about any potential effects of

the proposed regulations on the price of

infant formula products.

The primary benefit of Option 2 is the

reduction in the risk that defective

infant formula will be produced, go

undetected, and reach the market. FDA

has insufficient information to estimate

this potential benefit. In addition, this

proposed rule is also expected to reduce

the time and administrative costs of

entering the infant formula industry.

This benefit may increase price

competition in the infant formula

industry and reduce the health risks

associated with high infant formula

prices. FDA also has insufficient

information to estimate these benefits.

Except for the costs and benefits

associated with activity required by this

proposed rule that some incumbent

manufacturers do not currently

undertake, the costs and benefits of

Option 3 are identical to those of Option

2. FDA has insufficient information to

estimate either the costs or benefits of

this option.

Option 1 is expected to have higher

costs and lower benefits than either

Option 2 or Option 3.

VII. Paperwork Reduction Act of 1995

This proposed rule contains

information collection provisions that

are subject to review by the Office of

Management and Budget (OMB) under

the Paperwork Reduction Act of 1995

(44 U.S.C. 3501–3520). The title,

description, and respondent description

for the proposed collection of

information are shown below, along

with an estimate of the annual

recordkeeping and periodic reporting

burden. Included in the estimate is the

time for reviewing instructions,

searching existing data sources,

gathering and maintaining the necessary

information, and completing and

submitting the registrations,

notifications, and other submissions

that would be required under the

proposed regulations.

FDA solicits public comment in order

to: (1) Evaluate whether the proposed

collection of information is necessary

for the proper performance of the

functions of the agency, including

whether the information will have

practical utility; (2) evaluate the

accuracy of the agency’s estimate of the

burden of the proposed collection of

information, including the validity of

the methodology and assumptions used;

(3) enhance the quality, utility, and

clarity of the information to be

collected; and (4) minimize the burden

of the collection of information on those

who are to respond, including through

the use of automated collection

techniques, where appropriate or other

forms of information technology.

Title: Current Good Manufacturing

Practice, Quality Control Procedures,

Quality Factors, Notification

Requirements, and Records and Reports,

for the Production of Infant Formula.

Description: FDA is proposing

regulations on recordkeeping

requirements that include: (1) Records

pertaining to batch production and

control; (2) records pertaining to current

good manufacturing practice and quality

control; (3) records pertaining to

distribution of the infant formula; and

(4) records pertaining to regularly

scheduled audits. FDA is also proposing

regulations on reporting requirements

pertaining to: (1) Registration of a new

infant formula; (2) submission

requirements for a new infant formula;

(3) submission requirements to provide

assurance that an infant formula meets

the quality factor requirements; (4)

submission requirements when there is

a change in the formulation or

processing of the formula that may

affect whether the formula is

adulterated; and (5) submission

requirements to provide assurance that

the infant formula complies with the

requirements of the Federal Food, Drug,

and Cosmetic Act and is not

adulterated.

Description of Respondents: Infant

Formula Manufacturers.
36206 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

ESTIMATED ANNUAL RECORDKEEPING BURDEN

21 CFR

No. of recordkeepers

Annual

frequency

of recordkeeping

Total annual

records

Hours per

recordkeeping

Total

hours

106.6 .......................................................................................................................................... 5 1 5 200 1,000

106.20(f)(4) and 106.100(f)(1) ................................................................................................... 5 52 260 3 780

106.30(d) and 106.100(f)(2) ....................................................................................................... 5 25 125 4 500

106.30(e)(3)(ii) and 106.100(f)(3) .............................................................................................. 5 365 1,825 2 3,650

106.30(f) and 106.100(f)(4) ........................................................................................................ 5 365 1,825 3 5,475

106.35(c) and 106.100(f)(5) ....................................................................................................... 5 2 10 500 5,000

106.40(d) .................................................................................................................................... 5 20 100 30 3,000

106.40(g) and 106.100(f)(6) ....................................................................................................... 5 122 610 4 2,440

106.50 ........................................................................................................................................ 5 1 5 200 1,000

106.55(d) 106.100(e)(5)(ii), and 106.100(f)(7) ........................................................................... 5 182 910 3 2,730

106.60(c) .................................................................................................................................... 5 1 5 40 200

106.91(c), 106.100(e)(5)(i), and 106.100(f)(7) ........................................................................... 5 365 1,825 4 7,300

106.94 ........................................................................................................................................ 5 1 5 88 440

106.97 ........................................................................................................................................ 5 0.6 3 225 675

106.100(e) .................................................................................................................................. 5 365 1,825 9 16,425

Total .................................................................................................................................... .................... .................... .................... .................... 50,615

ESTIMATED ANNUAL REPORTING BURDEN

21 CFR No of respondents

Annual

frequency

per response

Total annual responses

Hours per

response

Total

hours

106.110 ...................................................................................................................................... 3 NA 20 1 20

106.120 ...................................................................................................................................... 3 NA 20 49 980

106.121 ...................................................................................................................................... 3 NA 10 50 500

106.130 ...................................................................................................................................... 3 NA 20 2 40

106.140 ...................................................................................................................................... 3 NA 25 5–10 125–250

Total .................................................................................................................................... .................... .................... .................... .................... 1,790

Total Recordkeeping and Reporting Burden ...................................................................... 52,405

FDA tentatively concludes that there

are no capital costs or operating and

maintenance costs associated with the

reporting and recordkeeping provisions

of this proposed rule. However, the

agency welcomes comments on any

such anticipated costs. As required by section 3507(d) of the

Paperwork Reduction Act of 1995, FDA

has submitted a copy of this proposed

rule to OMB for its review of the

information collection requirements.

Other organizations and individuals

interested in submitting comments

regarding this burden estimate or any

aspect of these information collection

requirements, including suggestions for

reducing the burden, should direct them

to the Office of Information and

Regulatory Affairs, OMB, New

Executive Office Bldg., 725 17th St.

NW., rm. 10235, Washington, DC 20503,

ATTN: Desk Officer for FDA. Written

comments on the information collection

should be submitted by August 8, 1996.

VIII. Requests for Comments

Interested persons may, on or before

October 7, 1996, submit to the Dockets

Management Branch (address above)

written comments regarding this

proposal. Two copies of any comments

are to be submitted, except that

individuals may submit one copy.

Comments are to be identified with the

docket number found in brackets in the

heading of this document. Received

comments may be seen in the office

above between 9 a.m. and 4 p.m.,

Monday through Friday.

IX. References

The following references have been

placed on display in the Dockets

Management Branch (address above)

and may be seen by interested persons

between 9 a.m. and 4 p.m., Monday

through Friday.

1. Congressional Record—Senate S 14042–

14047, September 27, 1986.

2. Hamill, P. V. V., T. A. Drizd, C. L. Johnson,

R. B. Reed, A. F. Roche, W. M. Moore,

‘‘Physical Growth: National Center for

Health Statistics Percentiles,’’ American

Journal of Clinical Nutrition, 32:607–

629, 1979.

3. Chumlea, W. C. ‘‘Growth and

Development’’ Chapter 1 in Handbook of

Pediatric Nutrition, edited by Queen, P.

M., and C. E. Lang, ASPEN Publication

Gaithersburg, MD, 1993. 4. Fomon, S. J., and S. E. Nelson, Chapter 4,

Size and growth in Nutrition of Normal

Infants, edited by Fomon, S. J., MosbyYear Book, Inc., St. Louis, MO, 1993.

5. House of Representatives, House Report

96–936 ‘‘Infant Formula Act of 1980

(H.R. 6940),’’ May 12, 1980.

6. Committee on Nutrition, American

Academy of Pediatrics, ‘‘Clinical Testing

of Infant Formulas With Respect to

Nutritional Suitability for Term Infants,’’

Elk Grove Village, IL, June 1988 (under

contract to FDA, Contract No. 223–86–

2117, June 1988).

7. Congressional Record, vol. 126, House

H11787–11793, May 20, 1980.

8. FDA, Guidelines Concerning Notification

and Testing of Infant Formulas, 1987.

9. Infant Formula Council, ‘‘Recommended

Current Good Manufacturing Practice for

Infant Formula,’’ July 1992.

10. FDA, DHHS, ‘‘FDA Fact Sheet: Shigella

in Food,’’ December 1969.

11. Bryan, F. L., ‘‘Emerging Foodborne

Diseases: II. Factors that Contribute to

Outbreaks and Their Control,’’ Journal of

Milk and Food Technology, 35(11):632–

638, November 1972.

12. Bryan, F. L., ‘‘Emerging Foodborne

Diseases: I. Their Surveillance and

Epidemiology,’’ Journal of Milk and

Food Technology, 35(10):618–625,

October 1972.

13. Bryan, F. L., ‘‘What the Sanitarian Should

Know About Staphylococci and

Salmonellae in Non-Dairy Products: I.

Staphylococci,’’ Journal of Milk and

Food Technology, 31(4); 110–116, April

1968.

14. William F. Hooten, Warning Letter,

November 9, 1993.
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36207

15. Placencia, A. M., and G. S. Oxborrow,

‘‘Use of the Reuter Centrifugal Air

Sampler in Good Manufacturing

Practices Inspections,’’ U.S. Food and

Drug Administration, Sterility Research

Center, Minneapolis Center of

Microbiological Investigations,

Minneapolis, MN, December 1984.

16. Committee on Biologic Effects of

Atmospheric Pollutants, Division of

Medical Sciences, National Research

Council, Chapter 9 ‘‘Effects of Fluoride

on Human Health’’ in Fluorides.

National Academy of Sciences,

Washington, DC, pp. 163–221, 1971.

17. Committee on Nutrition of American

Academy of Pediatrics, Fluoride

Supplementation: Revised Dosage

Schedule, Pediatrics, 63:150–152, 1979.

18. Barness, L. A., ‘‘Fluoride in Infant

Formulas and Fluoride

Supplementation,’’ Letter to the Editor,

Pediatrics, 67:582–583, 1981.

19. Subcommittee on the 10th Edition of the

Recommended Dietary Allowances, Food

and Nutrition Board, Commission on

Life Sciences, National Research

Council. ‘‘Recommended Dietary

Allowances, 10th ed.,’’ Washington, DC,

National Academy Press, 1989.

20. Cross Connection Control Committee,

Pacific Northwest Section, American

Water Works Associations, With the

Assistance of EPA, ‘‘Cross Connection

Control Manual Accepted Procedures

and Practice,’’ 5th ed., May 1990.

21. Food Service Sanitation Manual

including A Model Food Service

Sanitation Ordinance, U.S. Department

of Health, Education, and Welfare,

Washington, DC 20204.

22. Lentsch, S., ‘‘Sanitizers for an Effective

Cleaning Program,’’ Klenzade Division,

Economics Laboratories, St. Paul, MN.

23. Moody, M. W., ‘‘How Cleaning

Compounds Do the Job,’’ Seafood

Technology Cooperative Extension

Service, Louisiana State University,

undated.

24. Refrigerated Foods and Microbiological

Criteria Committee, National Food

Processors Association, ‘‘Factors to be

Considered in Establishing Good

Manufacturing Practices for the

Production of Refrigerated Foods,’’ Dairy

and Food Sanitation, 8(6):288–291, June

1988.

25. Center for Drugs and Biologics and Office

of Regulatory Affairs, Food and Drug

Administration ‘‘Guideline on Sterile

Drug Products Produced by Aseptic

Processing’’ Division of Manufacturing

and Product Quality, Office of

Compliance, Center for Drugs and

Biologics, Food and Drug

Administration, Rockville, MD 20857,

June 1987.

26. The American National Standards

Institute, International Standard, Quality

Management and Quality Assurance

Standards—Part 3 Guidelines for the

Application of ISO 9001 to the

Development, Supply and Maintenance

of Software, pp. 1–2.

27. Institute for Electrical and Electronics

Engineers, Inc. (IEEE), IEEE Standard

Glossary of Software Engineering

Terminology IEEE Std 610.12—1990.

28. Glossary of Computerized Systems and

Software Development Terminology.

Division of Field Investigations, Office of

Regional Operations, Office of

Regulatory Affairs, U.S. Food and Drug

Administration, August 1995.

29. Tetzlaff, R. F., ‘‘GMP Documentation

Requirements for Automated Systems:

Part I,’’ Pharmaceutical Technology,

March 1992.

30. Tetzlaff, R. F., ‘‘GMP Documentation

Requirements for Automated Systems:

Part II,’’ Pharmaceutical Technology,

April 1992. 31. Tetzlaff, R. F., ‘‘GMP

Documentation Requirements for

Automated Systems: Part III,’’

Pharmaceutical Technology, May 1992.

32. Letters from the Infant Formula Council

on the Lead Level in Infant Formulas.

33. Rowe, B., D. H. Hutchinson, R. J. Gilbert,

B. H. Hales, N. T. Begg, H. C. Dawkins,

M. Jacob, F. A. Rae, and M. Jepson,

‘‘Salmonella ealing Infections Associated

with the Consumption of Infant Dried

Milk,’’ The Lancet, 2(8564):900–903,

1987.

34. Poelma, P. L., W. H. Andrews, J. H.

Silliker, ‘‘Salmonella’’ in Compendium

of Methods for the Microbiological

Examination of Foods, 2d ed., edited by

Marvim L. Speck, American Public

Health Association, Washington, DC,

1984.

35. D’Aoust, J. Y., Salmonella, Chapter 9 in

Foodborne Bacterial Pathogens, edited

by Doyle, M. P., Marcel Dekker, Inc.,

New York, NY, 1989.

36. Quie, P. G. ‘‘Antimicrobial Defenses in

the Neonate,’’ Seminars in Perinatology,

14:2–9, 1990.

37. Farber, J. M., P. I. Peterkin, ‘‘Listeria

Monocytogenes, a Food-borne Patogen,’’

Microbiological Reviews, 55:476–511,

1991.

38. National Advisory Committee on

Microbiological Criteria for Foods,

‘‘Listeria monocytogenes,’’ International

Journal of Food Microbiology, 14:185–

246, 1991.

39. Benenson, A. S., ed., ‘‘Control of

Communicable Diseases in Man,’’ 15th

ed., American Public Health Association,

pp. 170–177, 1991.

40. Bennett, R. W., and S. M. Harmon,

‘‘Bacillus cereus Food Poisoning’’ in

Laboratory Diagnosis of Infectious

Diseases: Principles and Practice; vol. 1,

Bacterial, Mycotic, and Parasitic

Diseases; edited by Balows, A., W. J.

Hausler, Jr., M. Ohashi, and A. Turano,

vol. 1, pp. 83–93, Springer-Verlag, New

York, 1988.

41. The International Commission on

Microbiological Specifications for Foods

(ICMSF) of the International Association

of Microbiological Societies, Chapter 12:

Sampling Plans for Milk and Milk

Products in Microorganisms in Foods 2.

Sampling for Microbiological Analysis:

Principles and Specific Applications,

University of Toronto Press, Toronto,

Canada; 1974.

42. Schwab, A. H., A. Swartzentruber, B. A.

Wentz, R. B. Read, Jr., ‘‘Microbiological

Quality of Dry-milk Mixes and Milk

Substitute Infant Formulas,’’ Applied

and Environmental Microbiology,

43:389–391, 1982.

43. Collins-Thompson, D. L., K. F. Weiss, G.

W. Riedel, and S. Charbonneau,

‘‘Microbiological Guidelines and

Sampling Plans for Dried Infant Cereals

and Powdered Infant Formula from a

Canadian National Microbiological

Survey,’’ Journal of Food Protection,

43(8):613–616, 1980.

44. FDA Enforcement Report, July 14, 1993.

45. Jackson, G. J., C. F. Langford, and D. L.

Archer, ‘‘Control of Salmonellosis and

Similar Foodborne Infections,’’ Food

Control, 2(1), pp. 26–34, 1991.

46. Food and Drug Administration

Bacteriological Analytical Manual, 7th

ed., AOAC International, Gaithersburg,

MD, 1992.

47. Flowers, R. S., W. Andrews, C. W.

Donnelly, and E. Koenig, ‘‘Pathogens in

Milk and Milk Products’’ in Standard

Methods for the Examination of Dairy

Products, 16th ed., edited by Marshall, R.

T., American Public Health Association,

Washington, DC 20005, 1992.

48. Harmon, S. M., D. A. Kautter, ‘‘Incidence

and Growth Potential of Bacillus cereus

in Ready-to-Serve Foods,’’ Journal of

Food Protection, 54(5):372–374, 1991.

49. Golden, D. A., ‘‘Microbiological

Evaluation of Powdered Infant Formula,’’

Report submitted to the U.S. Food and

Drug Administration, Center for Food

Safety and Applied Nutrition.

50. FDA Consumer, Defendants: Watson

Foods Co., Inc., Civil No. CV–85–4659,

p. 40, October 1988.

51. Memorandum of Records from Nicholas

Dvy, FDA, dated June 25, 1996.

52. Establishment Inspection Report, 1992.

53. Memo from Alan J. Sheppard to Carolyn

W. Miles, on Status of Vitamin D Rat

Bioassay, May 12, 1994.

54. Tanner, J. T., S. A. Barnett, and M. K.

Mountford, ‘‘Analysis of Milk-based

Infant Formula,’’ Phase IV. Iodine,

Linoleic Acid, and Vitamins D and K:

U.S. Food and Drug AdministrationInfant Formula Council: Collaborative

Study, Journal of the Association of

Official Analytical Chemists

International, 76:1042–1056, 1993.

55. Southgate, D. A. T., ‘‘Conceptual Issues

Concerning the Assessment of Nutrient

Bioavailability,’’ in Nutrient Availability:

Chemical and Biological Aspects, edited

by Southgate, D., I. Johnson, and G. R.

Fenwick, Royal Society of Chemistry,

1989.

56. Jensen, R. G., M. M. Hagerty, and K.E.

McMahon, ‘‘Lipids of Human Milk and

Infant Formulas: A Review,’’ American

Journal of Clinical Nutrition, 31:990–

1016, 1978.

57. Jenson, R. G., and G. L. Jensen, ‘‘Specialty

Lipids for Infant Nutrition, I. Milks and

Formulas,’’ Journal of Pediatric

Gastroenterology and Nutrition, 15:232–

245, 1992.
36208 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

58. Ziegler, E. E., S. J. Fomon, S. E. Nelson

et al., ‘‘Cow Milk Feeding in Infancy:

Further Observations on Blood Loss

From the Gastrointestinal Tract,’’ Journal

of Pediatrics, 116:11–18, 1990.

59. American Academy of Pediatrics,

‘‘Commentary on Breast-Feeding and

Infant Formulas, with Proposed

Standards for Formulas,’’ Pediatrics,

57:278–285, 1976.

60. Committee on Labor and Human

Resources Report (Senate) August 26,

1980.

61. Saarinen, U. M., M. A. Siimes, P. R.

Dallman, ‘‘Iron Absorption in Infants:

High Bioavailability of Breast Milk Iron

as Indicated by the Extrinsic Tag Method

of Iron Absorption and by the

Concentration of Serum Ferritin,’’

Journal of Pediatrics, 91:36–39, 1977.

62. Hallberg, L., L. Rossander-Hulten, M.

Brune, A. Gleerup, ‘‘Bioavailability in

Man of Iron in Human Milk and Cow’s

Milk in Relation to Their Calcium

Contents,’’ Pediatric Research, 31:524–

527, 1992.

63. Derman, D. P., D. Ballot, T. H. Bothwell,

B. J. MacFarlane, R. D. Baynes, A. P.

MacPhail, M. Gillooly, J. E. Bothwell,

and W. R. Bezwoda, ‘‘Factors Influencing

the Absorption of Iron From Soya-Bean

Protein Products,’’ British Journal of

Nutrition, 57:345–353. 1987.

64. Koo, W. W. K., and R. G. Tsang,

‘‘Calcium, Magnesium, Phosphorus, and

Vitamin D,’’ In Nutrition Needs of the

Preterm Infant, edited by Tsang, R. C., et

al., Academic Press, 1993

65. Steichen, J. J., T. L. Gratton, and R. C.

Tsang, ‘‘Osteopenia of Prematurity: The

Cause and Possible Treatment,’’ Journal

of Pediatrics, 96:528–34, 1980.

66. Koletzko, B., R. Tangerman, R. Von Kries,

et al. ‘‘Intestinal Milk-Bolus Obstruction

in Formula-Fed Premature Infants Given

High Doses of Calcium,’’ Journal of

Pediatric Gastroenterology and Nutrition

7:548–553, 1988.

67. Ziegler, E. E., and S. J. Fomon, ‘‘Lactose

Enhances Mineral Absorption in

Infancy,’’ Journal of Pediatric

Gastroenterology and Nutrition, 2:288–

294, 1983.

68. Moya, M., E. Cortes, M. I. Ballester et al.,

‘‘Short-term Polycose Substitution for

Lactose Reduces Calcium Absorption in

Healthy Term Babies,’’ Journal of

Pediatric Gastroenterology and

Nutrition, 14:57–61, 1992.

69. Shenai, J. P., B. M. Jhaveri, J. W. Reynolds

et al., ‘‘Nutritional Balance Studies in

Very Low Birth Weight Infants: Role of

Soy Formula,’’ Pediatrics, 67:631–637,

1981.

70. Lindroth, M., U. Westgren, and S. Laurin,

‘‘Rickets in Very Low Birth Weight

Infants; Influence of Supplementation

with Vitamin D, Phosphorus, and

Calcium,’’ Acta Pediatrica Scandinavica,

75:927–931, 1986.

71. Chan, G. M., and L. J. Mileur,

‘‘Posthospitalization Growth and Bone

Mineral Status of Normal Preterm

Infants,’’ American Journal of Diseases in

Childhood, 139:896–8, 1985.

72. Food and Drug Administration, Public

Health Service, U.S. Department of

Health and Human Services, Guidelines

for the Format and Content of the

Clinical and Statistical Sections of New

Drug Applications July, 1988.

73. American Academy of Pediatrics.

Pediatric Nutrition Handbook, 3d ed.,

1993.

74. Roche, A. F., S. Guo, and W. M. Moore,

‘‘Weight and Recumbent Length From 1

to 12 Mo of Age: Reference Data for 1–

Mo Increments,’’ American Journal of

Clinical Nutrition, 49:599–607, 1989.

75. Moore, W. M., and A. F. Roche,

‘‘Pediatric Anthropometry,’’ Ross

Laboratories.

76. Behrman, R. E., Nelson Textbook of

Pediatrics, 14th ed., W. B. Saunders Co.,

Philadelphia, 1992.

77. Sarwar, G., R. W. Peace, and H. G.

Botting, ‘‘Differences in Protein

Digestibility and Quality of Liquid

Concentrate and Powder Forms of MilkBased Infant Formulas Fed to Rats,’’

American Journal of Clinical Nutrition,

49:806–13, 1989.

78. Rudloff, S., and B. Lonnerdal, ‘‘Solubility

and Digestibility of Milk Proteins in

Infant Formulas Exposed to Different

Heat Treatments,’’ Journal of Pediatric

and Gastroenterology and Nutrition,

15:25–32, 1992.

79. Fomom, S. J., and S. E. Nelson, Chapter

11, Calcium, Phosphorus, Magnesium,

and Sulfur in Nutrition of Normal

Infants, edited by Fomon, S. J., MosbyYear Book, Inc., St. Louis, MO, 1993.

80. Ryan, S. A., J. Truscott, M. Simpson, and

J. James, ‘‘Phosphate, Alkaline

Phosphatase and Bone Mineralization in

Preterm Neonates,’’ Acta Pediatrica,

82:518–521, 1993.

81. Minton, S. D., J. J. Steichen, and R. C.

Tsang, ‘‘Bone Mineral Content in Term

and Preterm Appropriate-for-GestationalAge Infants,’’ Journal of Pediatrics,

95:1037–1042, 1979.

82. Steichen, J. J., P. A. Steichen Asch, and

R. C. Tsang, ‘‘Bone Mineral Content

Measurement in Small Infants by Singlephoton Absorptiometry: Current

Methodologic Issues,’’ Journal of

Pediatrics, 113 (suppl): 181–187, 1988.

83. Chan, G. M., ‘‘Performance of DualEnergy X-ray Absorptiometry in

Evaluating Bone, Lean Body Mass, and

Fat in Pediatric Subjects,’’ Journal of

Bone and Mineral Research, 7:369–374,

1992.

84. Braillon, P. M., B. L. Salle, J. Brunet, F.

H. Glorieux, P. D. Delmas, and P. J.

Meunier, ‘‘Dual Energy X-ray

Absorptiometry Measurement of Bone

Mineral Content in Newborns:

Validation of the Technique,’’ Pediatric

Research, 32:77–80, 1992.

85. Salle, B. L., and F. H. Glorieux,

‘‘Assessment of Bone Mineral Content in

Infants: The New Age,’’ Acta Pediatrica,

82:709–10, 1993.

86. Fomon, S. J., Chapter 14, Iron in Nutrition

of Normal Infants, edited by Fomon, S.

J., Mosby-Year Book, Inc., St. Louis, MO,

1993.

87. Carlson, S. E., R. J. Cooke, S. H.

Werkman, and E. A. Tolley, ‘‘First Year

Growth of Preterm Infants Fed Standard

Compared to Marine Oil n-3

Supplemented Formulas,’’ Lipids,

27:901–907, 1992.

88. Memorandum of telephone conversation

between Marty Hudtloff, FDA, and Ed

Puro, FDA, March 15, 1994; cost of

Maple Island recalls note, memorandum

from Robert Fish, March 7, 1994;

memorandum from Martin Hudtloff,

February 28, 1994; Establishment History

Report on B2110076.

89. Memorandum of telephone conversation

between Hazleton Labs and Ed Puro,

FDA, March 17, 1993.

List of Subjects

21 CFR Part 106

Food grades and standards, Infants

and children, Nutrition, Reporting and

recordkeeping requirements,

Incorporation by reference.

21 CFR Part 107

Food labeling, Infants and children,

Nutrition, Reporting and recordkeeping

requirements, Signs and symbols.

Therefore, under the Federal Food,

Drug, and Cosmetic Act and under

authority delegated to Commissioner of

Food and Drugs, it is proposed that 21

CFR parts 106 and 107 be amended as

follows:

PART 106—INFANT FORMULA—

REQUIREMENTS PERTAINING TO

CURRENT GOOD MANUFACTURING

PRACTICE, QUALITY CONTROL

PROCEDURES, QUALITY FACTORS,

RECORDS AND REPORTS, AND

NOTIFICATIONS

1. The authority citation for 21 CFR

part 106 continues to read as follows:

Authority: Secs. 201, 412, 701 of the

Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 350a, 371).

2. The heading for part 106 is revised

to read as set forth above.

3. Section 106.1 is revised to read as

follows:

§ 106.1 Status and applicability of the

regulations in part 106.

(a) The criteria set forth in 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.

(b) The criteria set forth in subpart E

of this part prescribe the quality factor

requirements that infant formula must
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36209

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.

(c) The criteria set forth in 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.

(d) The criteria set forth in 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.

4. Section 106.3 is revised to read as

follows:

§ 106.3 Definitions.

The definitions in this section and the

definitions contained in section 201 of

the Federal, Food, Drug, and Cosmetic

Act (the act) shall apply to infant

formula requirements in 21 CFR part

106 and part 107 of this chapter.

(a) Batch means a specific quantity of

an infant formula or other material that

is intended to have uniform character

and quality, within specified limits, and

is produced according to a single

manufacturing order during the same

cycle of manufacture.

(b) Final-product-stage means the

point in the manufacturing process,

before distribution of an infant formula,

at which the infant formula is

homogeneous and is not subject to

further degradation due to processing.

(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.

(d) Infant means a person not more

than 12 months of age.

(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.

(f) In-process batch means a

combination of ingredients at any point

in the manufacturing process before

packaging.

(g) Lot means a batch, or a specifically

identified portion of a batch, having

uniform 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 character and quality

within specified limits.

(h) Lot number, control number, or

batch number means any distinctive

combination of 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.

(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:

(1) Any infant formula produced by a

manufacturer who is entering the U.S.

market;

(2) Any infant formula powder

processed and introduced for

commercial or charitable distribution by

a manufacturer who previously only

produced liquids (or vice versa);

(3) Any infant formula 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;

(4) Any infant formula manufactured

on a new processing line or in a new

plant;

(5) Any infant formula manufactured

containing a new constituent not listed

in section 412(i) of the act, such as

taurine or L-carnitine;

(6) Any infant formula processed by a

manufacturer on new equipment that

utilizes a new technology or principle

(e.g., a change from terminal

sterilization to aseptic processing); and

(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).

(j) 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.

(k) Microorganisms means yeasts,

molds, bacteria, and viruses and

includes, but is not limited to, species

having public health significance.

(l) New infant formula means:

(1) An infant formula manufactured

by a person that has 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.

(m) Nutrient means any vitamin,

mineral, or other substance or

ingredient that is required in accordance

with the table set out in section 412(i)(1)

of 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.

(n) Nutrient premix means a

combination of ingredients containing

two or more nutrients received from a

supplier or prepared by an infant

formula manufacturer.

(o) Quality factors mean those factors

necessary to demonstrate 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.

(p) Representative sample 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.

(q) Shall is used to state mandatory

requirements.

(r) Should is used to state

recommended or advisory procedures or

to identify recommended equipment.

5. Part 106 is amended by

redesignating subparts B, C, and D as

subparts C, F, and G, respectively, and

adding new subparts B, D, and E; and

by revising newly redesignated subparts

C and G to read as follows:

* * * * *
36210 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

Subpart B—Current Good Manufacturing

Practice

Sec.

106.5 Current good manufacturing practice.

106.6 Production and in-process control

system.

106.10 Controls to prevent adulteration by

workers.

106.20 Controls to prevent adulteration

caused by facilities.

106.30 Controls to prevent adulteration

caused by equipment or utensils.

106.35 Controls to prevent adulteration due

to automatic (mechanical or electronic)

equipment.

106.40 Controls to prevent adulteration

caused by ingredients containers, and

closures.

106.50 Controls to prevent adulteration

during manufacturing.

106.55 Controls to prevent adulteration

from microorganisms.

106.60 Controls to prevent adulteration

during packaging and labeling of infant

formula.

106.70 Controls on the release of finished

infant formula.

106.80 Traceability.

106.90 Audits of current good

manufacturing practice.

Subpart C—Quality Control Procedures

106.91 General quality control.

106.92 Audits of quality control

procedures.

Subpart D—Conduct of Audits

106.94 Audit plans and procedures.

Subpart E—Quality Factors for Infant

Formulas

106.96 Quality factors in infant formulas.

106.97 Assurances for quality factors.

* * * * *

Subpart G—Registration, Submission, and

Notification Requirements

106.110 New infant formula registration.

106.120 New infant formula submission.

106.121 Quality factor submission.

106.130 Verification submission.

106.140 Submission concerning a change in

infant formula that may adulterated the

product.

106.150 Notification of an adulterated or

misbranded infant formula.

* * * * *

Subpart B—Current Good Manufacturing

Practice

§ 106.5 Current good manufacturing

practice.

(a) The regulations set forth in this

subpart and, for liquid infant formulas,

in part 113 of this chapter define the

minimum current good 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 § 107.100 of this chapter and is

manufactured in a manner designed to

prevent its adulteration.

(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 control

system.

(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 stages of

processing, from the receipt and

acceptance of the raw materials,

ingredients, and components through

the storage and distribution of the

finished product and shall be designed

to ensure that all the requirements of

this subpart are met.

(b) The production and 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.

(c) At any point, step, or stage in the

production process where control is

necessary to prevent adulteration, the

manufacturer shall:

(1) Establish standards or

specifications to be met;

(2) Monitor the production and inprocess control point, step, or stage;

(3) Establish corrective action plans

for use when a standard or specification

established in accordance with

paragraph (b)(1) of this section is not

met;

(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

deviations from standards or

specifications that have been

established in accordance with

paragraph (c)(1) of this section. This

review shall be conducted by an

individual qualified by training and

experience to conduct such reviews;

and

(5) Establish recordkeeping

procedures, in accordance with

§ 106.100(e)(3), that ensure that

compliance with the requirements of

this section is documented.

§ 106.10 Controls to prevent adulteration

by workers.

(a) There shall be 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.

(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:

(1) Wearing clean outer garments and,

as necessary, protective apparel such as

head, face, hands, and arm coverings;

and

(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.

(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.

§ 106.20 Controls to prevent adulteration

caused by facilities.

(a) Buildings used in the 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.

(b) Separate areas shall be designated

for holding raw materials, in-processing

materials, and final product infant

formula:

(1) Pending release for use in infant

formula production or pending release

of the final product,

(2) After rejection for use in infant

formula and before disposition, and

(3) After release for use in infant

formula production or after release of

the final product.

(c) Lighting shall allow easy

identification of raw materials,
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36211

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.

(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.

(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.

(f)(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. The water shall be supplied

under continuous positive pressure in a

plumbing system that is free of defects

that could contaminate an infant

formula.

(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.

(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.

(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.

(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.

(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.

(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.

§ 106.30 Controls to prevent adulteration

caused by equipment or utensils.

(a) Equipment used in the

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.

(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, inprocess 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.

(c) 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, closures, or in-process

materials or with infant formula itself.

(d)(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 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 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 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 to

ensure the accuracy of the instrument.

Manufacturers shall make and retain

records of the accuracy checks in

accordance with § 106.100(f)(2).

(2) Instruments and controls that

cannot be adjusted to agree with the

reference standard shall be repaired or

replaced.

(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).

(e)(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.

(2) Cold storage compartments shall

be maintained at a temperature of 40 °F

(4.4 °C) or below.

(3)(i) Cold storage compartments and

thermal processing equipment shall be

equipped with easily readable, accurate

temperature-indicating devices.

(ii) Thermal processing equipment

shall be equipped with temperaturerecording devices that will reflect the

true temperature on a continuing basis.

Cold storage compartments shall be

equipped with either temperaturerecording 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 maximumindicating 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 § 106.100(f)(3), of the temperatures

indicated or recorded by these devices.
36212 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

(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 temperatureindicating device for cold storage

compartments.

(f) Equipment and utensils used in the

manufacture of infant formula shall be

cleaned, sanitized, and maintained at

regular intervals to prevent adulteration

of the infant formula. An individual

qualified by training or experience to

conduct such a review shall check all

cleaning, 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 § 106.100(f)(4).

(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.

§ 106.35 Controls to prevent adulteration

due to automatic (mechanical or electronic)

equipment.

(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.

(2) For the purposes of this section,

‘‘software’’ means any programs,

procedures, rules, and associated

documentation used in the operation of

a system.

(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.

(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.

(b)(1) All 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.

(2) The infant formula manufacturer

shall ensure that hardware is routinely

calibrated, inspected, and checked

according to written procedures.

(3) The infant formula manufacturer

shall check and document the accuracy

of input into, and output generated by,

any 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

complexity and reliability of the system

and the level of risk associated with the

safe operation of the system.

(4) The infant formula manufacturer

shall ensure that all systems are

validated before their first use to

manufacture commercial product.

(5) The infant formula manufacturer

shall ensure that any system that is

modified is revalidated after the

modification and before use of the

modified system to manufacture

commercial product. All modifications

to 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.

(c) The infant formula manufacturer

shall make and retain records, in

accordance with § 106.100(f)(5),

concerning automatic (mechanical or

electronic) equipment.

§ 106.40 Controls to prevent adulteration

caused by ingredients, containers, and

closures.

(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.

(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.

(c) 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.

(d) Infant formula manufacturers shall

develop written specifications for their

acceptance or rejection of ingredients,

containers, and closures used 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.

(e) Ingredients, containers and

closures shall be stored in areas clearly

designated for:

(1) Materials pending release for use,

(2) Materials released for use, or

(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

controlled under a quarantine system

designed to prevent its use in the

manufacture of infant formula.

(f) If an ingredient, a container, or a

closure that has been tested and

examined is exposed to air, heat, or

other conditions that may adversely

affect it, the ingredient, container, or

closure shall be retested or reexamined

to ensure that it still meets the

manufacturer’s specifications.

(g) 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.

§ 106.50 Controls to prevent adulteration

during manufacturing.

(a)(1) Manufacturers shall prepare and

follow a written master manufacturing

order that establishes controls and

procedures for the production of an

infant formula.

(2) The manufacturer shall 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
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36213

deviations from the master

manufacturing order and any corrective

actions taken.

(3) Changes made to the 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.

(b) The manufacturer shall establish

controls to ensure that each raw or inprocess 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.

(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

used during the production of a batch of

an infant formula.

(d) The manufacturer shall establish

controls to ensure that the nutrient

levels required by § 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:

(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;

(2) The spray-drying process for

powdered infant formula, including the

filtering of the intake air before heating,

to prevent microbial and other

contamination;

(3) The removal of air from the

finished product to ensure that nutrient

deterioration does not occur;

(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:

(i) Detect visible closure or seal

defects, and

(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.

(e) The manufacturer shall 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.

(f) The manufacturer shall establish

controls that ensure that rejected inprocess materials:

(1) Are clearly identified as having

been rejected for use in an infant

formula;

(2) Are controlled under a quarantine

system designed to prevent their use in

manufacturing or processing operations

for which they are unsuitable;

(3) Meet the appropriate

specifications, if reprocessed, before

being released for use in infant formula.

§ 106.55 Controls to prevent adulteration

from microorganisms.

(a) Manufacturers of liquid infant

formula shall comply with the

procedures specified in part 113 of this

chapter for liquid infant formula.

(b) Manufacturers 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.

(c) Any powdered infant formula that

contains any microorganism 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.

Microorganism M value 1

Aerobic Plate Count

(APC).

10,000 CFU/gram

(g). 2

Coliforms 3 ................. 3.05 MPN/g. 4,5

Fecal coliforms 6 ........ 3.05 MPN/g.

Salmonella ................. 0. 7

Listeria

monocytogenes.

0. 7

Microorganism M value 1

Staphylococcus

aureus.

3.05 MPN/g.

Bacillus cereus 8 ........ 100 MPN/g or CFU/g.

1The 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.

3 M values for coliforms greater than 3.05

are not violative if testing for fecal coliforms

results in an M value equal to or less than

3.05. 4 MPN/g, most probable number per g.

5The MPN value of 3.05 in this table is derived from the tables of calculated MPN values

that appear in 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 testing for fecal coliforms is required

when the M value for coliforms is less than or

equal to 3.05. 7 None detected.

8B. cereus testing must be performed only if

the APC exceeds 100 CFU/g.

(d) Manufacturers shall make 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 adulteration

during packaging and labeling of infant

formula.

(a) Manufacturers shall examine

packaged and labeled infant formula

during finishing operations to ensure

that containers and packages in the lot

have the correct label, the correct useby date, and the correct code established

under § 106.80.

(b) Labels shall be designed, printed,

and applied so that the labels remain

legible and attached during the

conditions of processing, storage,

handling, distribution, and use.

(c) All infant formula held in a single

package shall be the same product

bearing the same code, established

under § 106.80. Packaging used to hold

multiple containers of infant formula

shall be labeled with the product name,

the name of the manufacturer or

shipper, and the code.

§ 106.70 Controls on the release of

finished infant formula.

(a) The manufacturer 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.

(b) Each batch of infant formula that

fails to meet the manufacturer’s

specifications shall be rejected.

Although the batch may be reprocessed,

any batch of infant formula that is

reprocessed shall be shown to meet the
36214 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

requirements of § 106.70(a) before it is

released.

(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.

§ 106.80 Traceability.

(a) Manufacturers shall 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.

(b) Batches of powdered 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

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 current good manufacturing

practice but who has no direct

responsibility for the matters being

audited.

Subpart C—Quality Control

Procedures

§ 106.91 General quality control.

(a) Nutrient testing to ensure that each

batch of infant formula provides

nutrients in accordance with § 107.100.

Manufacturers shall test each batch as

follows:

(1) Each nutrient premix 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;

(2) During the 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.

(3) At the final-product-stage, before

distribution of an infant formula, each

batch shall be tested for vitamins A, C,

E, and thiamin.

(4) During the manufacturing process

or at the final-product-stage, before

distribution, each batch shall be tested

for all nutrients 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 conducted for compliance with

paragraphs (a)(1) or (a)(3) of this section.

(b) Stability testing. Every 3 months,

manufacturers shall collect

representative samples from the finalproduct-stage 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

§ 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

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; except that:

(1) If the infant formula is a new

infant formula, manufacturers 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

(2) 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 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

affected by the change.

(c) Quality control records.

Manufacturers shall make and retain

quality control records in accordance

with § 106.100(e)(5)(i) and (f)(7).

§ 106.92 Audits of quality control

procedures.

A manufacturer of an infant formula,

or an agent of such a manufacturer, shall

conduct regularly scheduled audits 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.

Subpart D—Conduct of Audits

§ 106.94 Audit plans and procedures.

(a) Manufacturers shall develop and

follow a written audit plan that is

available at the manufacturing facility

for FDA inspection.

(b) The audit plan shall include audit

procedures that set out the methods the

manufacturer 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.

(c) The audit procedures shall

include, but not be limited to:

(1) An evaluation of the production

and in-process control system

established under § 106.6(b) by:

(i) Observing the production of infant

formula and comparing the observed

process to the written production and

in-process control plan required under

§ 106.6(b);

(ii) Reviewing records of the

monitoring of points, steps, or stages

where control is deemed necessary to

prevent adulteration; and

(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; and
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36215

(2) A review of a representative

sample of all records maintained in

accordance with § 106.100(e) and (f).

Subpart E—Quality Factors for Infant

Formulas

§ 106.96 Quality factors in infant formulas.

(a) All infant formulas shall, 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.

(b) All infant formulas shall be

capable of supporting normal physical

growth of infants.

(c) 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 Assurances for quality factors.

(a) General quality factor of normal

physical growth. (1) The manufacturer

shall conduct an adequate and wellcontrolled 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.

(i) The manufacturer shall:

(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.

(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.

(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.

(ii) The clinical study protocol

should:

(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;

(B) Describe the necessary

qualifications and experience of

investigators;

(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;

(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.

(E) Describe the sample size

calculations and the power calculations

and the basis for selecting the sample

size and study design;

(F) Describe the plan to identify and

evaluate any adverse effects;

(G) Describe the quality control

procedures used to ensure the validity

and reliability of the measurements

collected.

(H) Describe and compare the

composition of the test and control

formulas.

(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.

(2) The manufacturer may request an

exemption from the requirements of

paragraph (a)(1) of this section if:

(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

§ 106.96;

(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;

(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.

(b) Specific quality factor for protein

quality of infant formula. (1) The

manufacturer 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 shall establish the

biological quality of the protein in its

infant formula 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.

(2) The manufacturer may request an

exemption from the requirements of

paragraph (b)(1) of this section if:

(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 § 106.96;

(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
36216 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

quality factor requirements prescribed

in § 106.96.

6. In newly redesignated subpart F,

§ 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.

* * * * *

(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:

(1) The master manufacturing order.

The master manufacturing order shall

include but is not limited to:

(i) The significant steps in the

production of the batch and the date on

which each significant step occurred;

(ii) The identity of equipment and

processing lines 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;

(iii) The identity of each batch or lot

of ingredients, containers, and closures

used in producing the batch of formula;

(iv) The amount of each ingredient to

be added to the batch of infant formula

and a check (verification) that the

correct amount was added; and

(v) Copies of all labeling 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.

(2) Any deviations from the master

manufacturing order and any corrective

actions taken because of the deviations.

(3) Documentation, in accordance

with § 106.6(c), of the monitoring at any

point, step, or stage in their production

process where control is deemed

necessary to prevent adulteration. These

records shall include, but not be limited

to:

(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;

(ii) The actual values obtained during

the monitoring operation, any

deviations from established standards or

specifications, and any corrective

actions taken;

(iii) Identification of the person

monitoring each point, step, or stage in

their production process where control

is deemed necessary to prevent

adulteration.

(4) The conclusions and followup,

along with the identity, of the

individual qualified by training or

experience who investigated:

(i) Any deviation from the master

manufacturing order and any corrective

actions taken;

(ii) A finding that a batch or any of its

ingredients failed to meet the infant

formula manufacturer’s specifications;

and

(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.

(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:

(i) The results of all quality control

testing conducted, in accordance with

§ 106.91(a) and (b), to verify that each

nutrient required by § 107.100 of this

chapter is present in each batch of

infant formula at the level required by

§ 107.100, and that any nutrient added

by the manufacturer is present at the

appropriate level with:

(A) A summary table identifying the

stages of the manufacturing process at

which the nutrient analysis for each

required nutrient under § 106.91(a) is

conducted, and

(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

(ii) For powdered 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).

(f) Manufacturers shall make and

retain all records pertaining to current

good manufacturing practice as

described in subpart B of this part,

including but not limited to:

(1) Records, in accordance with

§ 106.20(f)(3), of the frequency and

results of testing of the water used in the

production of infant formula;

(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.

(3) Records, in accordance with

§ 106.30(e)(3)(ii), of the temperatures

monitored for cold storage

compartments and thermal processing

equipment.

(4) Records, in accordance with

§ 106.30(f), on equipment cleaning,

sanitizing, and maintenance that show

the date and time of such cleaning,

sanitizing, and 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 maintenance shall date

and sign or initial the record indicating

that the work was performed.

(5) Records, in accordance with

§ 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:

(i) A list of all systems used with a

description of computer files and the

inherent limitations of each system;

(ii) A copy of all software used;

(iii) Records that document

installation, calibration, testing or

validation, and maintenance of the

systems used;

(iv) A list of all persons authorized to

create or modify software;

(v) Records that document

modifications to software, including the

identity of the person who modified the

software;

(vi) Records that document retesting

or revalidation of modified systems; and

(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.

(6) Records, in accordance with

§ 106.40(g), on ingredients, containers,

and closures used in the manufacture of

infant formula. These records shall

include, but are not limited to:
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36217

(i) The identity and quantity of each

lot of ingredients, containers, and

closures;

(ii) The name of the supplier;

(iii) The supplier’s lot numbers;

(iv) The name and location of the

manufacturer of the ingredient,

container, and closure, if different from

the supplier;

(v) The date of receipt;

(vi) The receiving code as specified;

and

(vii) The results of any test or

examination (including retesting and

reexamination) performed on the

ingredients, containers, and closures

and the conclusions derived therefrom

and the disposition of all ingredients,

containers, or closures.

(7) A full description 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).

(g) The manufacturer shall maintain

all records pertaining to distribution of

the infant formula, including records

that show that products produced for

export only are exported. Such records

shall include, but not be limited to, all

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.

(h) [Reserved]

* * * * *

(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.

(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 shall, within 15 days of

receiving such information, conduct an

investigation and notify the agency as

required in § 106.150.

* * * * *

Subpart G—Registration, Submission,

and Notification Requirements

§ 106.110 New infant formula registration.

(a) Before a new infant formula may

be introduced or 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.

(b) The new infant formula

registration shall include:

(1) The name of the new infant

formula,

(2) The name of the manufacturer,

(3) The place of business of the

manufacturer, and

(4) All establishments at which the

manufacturer intends to manufacture

such new infant formula.

§ 106.120 New infant formula submission.

(a) At least 90 days before a new

infant formula is introduced or

delivered for introduction into interstate

commerce, a manufacturer shall submit

notice of its intent to do so to the Food

and Drug Administration at the address

given in § 106.110(a). An original and

two copies of the notice of its intent to

do so shall be submitted.

(b) The new infant formula

submission shall include:

(1) The name and physical form (e.g.,

powder, ready-to feed, or concentrate) of

the infant formula;

(2) An explanation of why the formula

is a new infant formula;

(3) The quantitative formulation of

each form of the 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;

(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);

(5) Assurance that the 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.

(i) Assurance that the 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 § 106.121.

(ii) Assurance that 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;

(6) 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:

(i) A statement that the formula will

be produced in accordance with

subparts B and C of this part;

(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.

(c) For products for export only, 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.

(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 if the

notice is not adequate because it does

not meet the requirements of section

412(c) and (d) of the act.

(e) If a new infant formula submission

is adequate, FDA will acknowledge its

receipt and notify the manufacturer of

the date of receipt. The date that the

agency receives the new infant formula
36218 Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules

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.

(f) If the manufacturer 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 and, when

applicable, notify the manufacturer 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.

§ 106.121 Quality factor submission.

To provide assurance that an infant

formula meets the quality factor

requirements set forth in subpart E of

this part, the manufacturer shall submit

the following data and information:

(a) An explanation, in narrative form,

setting forth how all quality factor

requirements of subpart E of this part

have been met.

(b) Records that contain the

information required by proposed

§ 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.

(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.

(2) Calculation of the statistical power

of the study at its completion.

(d) A report on attrition and on all

occurrences of adverse events during

the study, which shall include:

(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;

(2) A clinical assessment, by a health

care provider, of the infant’s health

during each suspected adverse event;

(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.

(e) The results of the Protein

Efficiency Ratio, in accordance with

§ 106.97(b).

(f) A statement certifying that the

manufacturer 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

is not aware of any information or data

that would show that the formula does

not meet the quality factors

requirements.

§ 106.130 Verification submission.

(a) Manufacturers 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 § 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.

(b) The verification submission shall

include the following information:

(1) The name of the new infant

formula; the filing date for the new

infant formula submission, in

accordance with § 106.120, for the

subject formula; and the identification

number assigned by the agency to the

new infant formula submission;

(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 provided

assurances in accordance with the

requirements of § 106.120;

(3) A summary of test 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.

(4) A certification that the

manufacturer has established current

good manufacturing practices including

quality control procedures and inprocess 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.

(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 that the notice is not

adequate.

§ 106.140 Submission concerning a

change in infant formula that may

adulterate the product.

(a) When a manufacturer makes a

change in the formulation or processing

of the formula that may affect whether

the formula is adulterated under section

412(a) of the Federal Food, Drug, and

Cosmetic Act (the act), it shall, before

the first processing of such formula,

make a submission to the Food and

Drug Administration at the address

given in § 106.110(a). An original and

two copies shall be submitted.

(b) The submission shall include:

(1) The name and physical form of the

infant formula (i.e., powder, ready-tofeed, or concentrate);

(2) An explanation of why the change

in formulation or processing may affect

whether the formula is adulterated; and

(3) A submission that 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.

(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 notify the submitter if the

notice is not adequate because it does

not meet the requirements of section

412(d)(3) of the act.

§ 106.150 Notification of an adulterated or

misbranded infant formula.

(a) A manufacturer shall promptly

notify FDA in accordance with

paragraph (b) of this section, when the

manufacturer has knowledge (that is,

the actual knowledge that the

manufacturer 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 and that has left an

establishment subject to the control of

the manufacturer:

(1) May not provide the nutrients

required by section 412(i) of the act or

by regulations issued under section

412(i)(2); or
Federal Register / Vol. 61, No. 132 / Tuesday, July 9, 1996 / Proposed Rules 36219

(2) May be otherwise adulterated or

misbranded.

(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 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 § 5.115 of this chapter.

PART 107—INFANT FORMULA

7. The authority citation for 21 CFR

part 107 continues to read as follows:

Authority: Secs. 201, 403, 412, 701 of the

Federal Food, Drug, and Cosmetic Act (21

U.S.C. 321, 343, 350a, 371).

8. Section 107.1 is added to subpart

A to read as follows:

§ 107.1 Status and applicability of the

regulations in part 107.

(a) The criteria set forth 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.

(b) The criteria set forth 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.

(c) Subpart D of this part 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.

9. Section 107.10 is amended by

revising the introductory text of

paragraph (a)(2) to read as follows:

§ 107.10 Nutrient information.

(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:

* * * * *

10. Section 107.240 is revised to read

as follows:

§ 107.240 Notification requirements.

(a) Telephone report. When 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.

(b) Initial written report. 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:

(1) Number of consignees 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.

(2) Number of consignees responding

to the recall communication and

quantity of recalled infant formula on

hand at the time it was received.

(3) Quantity of recalled infant formula

returned or corrected by each consignee

contacted and the quantity of recalled

infant formula accounted for.

(4) Number and results of

effectiveness checks that were made.

(5) Estimated timeframes for

completion of the recall.

(c) Status reports. The 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.

11. Section 107.250 is amended by

revising the introductory text to read as

follows:

§ 107.250 Termination of an infant formula

recall.

The recalling firm may submit a

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:

* * * * *

Dated: April 19, 1996.

David A. Kessler,

Commissioner of Food and Drugs.

Donna E. Shalala,

Secretary of Health and Human Services.

[FR Doc. 96–17058 Filed 7–8–96; 8:45 am]

BILLING CODE 4160–01–P