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

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

Sec. 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

[[Page 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 Sec. 107.100 (50 FR 45106). For the purpose of

this document, the nutrients that are required to be in infant formula

under Sec. 107.100 will be referred to as ``required nutrients,'' and

the levels of these required nutrients established in Sec. 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,

[[Page 36156]]

if an infant formula has been relabeled with an incorrect label (e.g.,

a milk-based 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 Current Good Manufacturing Practice.

Nutrient Content of Infant Formulas.

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 Sec. 107.1 and will amend

Sec. 107.10(a)(2) by requiring that ``any nutrient added by the

manufacturer'' be listed on the label. The proposed regulation amends

Secs. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 unit-by-unit basis.

Proposed Sec. 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 Sec. 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 Sec. 106.3. The

definition of ``manufacturer'' in proposed Sec. 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 Sec. 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 Sec. 106.3 by adding

definitions that are derived from the definitions provided by Congress

in the act.

Proposed Sec. 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 Sec. 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

[[Page 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 Sec. 106.3(b) incorporates into part 106 the definition

for ``final-product-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 Sec. 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 Sec. 106.3(i) defines ``major change''

as it is defined in current Sec. 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 Sec. 106.3(m) revises the definition for ``nutrient'' in

current Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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-

[[Page 36158]]

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 Sec. 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 Sec. 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 Sec. 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

Sec. 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 Sec. 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 Sec. 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 in-process 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 Sec. 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 in-process

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

Sec. 106.35(b)(2), to calibrate, inspect, and check hardware; (2)

specifications, in accordance with proposed Sec. 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 Sec. 106.50(a)(1); and (4) testing procedures,

under proposed Sec. 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

[[Page 36159]]

procedures that are part of the written plan.

Proposed Sec. 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 in-process 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 Sec. 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 Sec. 106.100(e)(3)(i)) that manufacturers make and retain a

list of the standards and specifications that they establish under

proposed Sec. 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

in-process control system.

Proposed Sec. 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 Sec. 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 temperature- recording 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 Sec. 106.30(d)).

Proposed Sec. 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

Sec. 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 Sec. 106.6(c)(4) requires that infant formula

manufacturers review the results of the monitoring required under

proposed Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 106.6(c)(5) requires that infant formula

manufacturers establish recordkeeping procedures, in accordance with

proposed Sec. 106.100(e)(3), that ensure that compliance with the

requirements of proposed Sec. 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 cross-references 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 Sec. 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 Sec. 106.10(a) is consistent with existing

regulations concerning CGMP for foods (Sec. 110.10(c)) and drugs

(Sec. 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.

[[Page 36160]]

Proposed Sec. 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 Sec. 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 Sec. 106.10(b) is consistent with existing

regulations concerning CGMP for foods (Sec. 110.10(b)) and drugs

(Sec. 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 Sec. 106.10(b) enumerates the basic elements

of good personal hygiene. Proposed Sec. 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 Sec. 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 Sec. 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 Sec. 106.10(c) is consistent with existing

regulations concerning CGMP for foods (Sec. 110.10(a)) and drugs

(Sec. 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 Sec. 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 Sec. 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

(Secs. 110.20(b) and 110.35(a)) and drugs (Sec. 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 Sec. 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 (Sec. 110.20(b)(2)) and drugs (Sec. 211.42(c)) and is

consistent with the recommendations made to FDA by the Infant Formula

Council (Ref. 9).

Proposed Sec. 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 Sec. 106.20(b) is consistent with FDA's existing regulations

concerning CGMP for drugs (Sec. 211.42(c)).

Proposed Sec. 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 Sec. 106.20(c) also requires that any lighting fixtures

directly over or adjacent to exposed raw materials, in- process

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 Sec. 106.20(c) is consistent

with FDA's existing regulations concerning CGMP's for food

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

FDA is proposing a requirement in Sec. 106.20(d) for air filtration

systems to improve air quality in production areas

[[Page 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 (Sec. 211.46(c)).

Proposed new requirements in Sec. 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 Sec. 106.20(e) is consistent with FDA's

existing regulations concerning CGMP for food (Sec. 110.35(b)(2)) and

drugs (Sec. 211.56(c)).

Proposed Sec. 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 (Sec. 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 Sec. 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 ready-to-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 Sec. 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 Sec. 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 Sec. 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

Sec. 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 (Sec. 129.35(a)(3)).

Proposed Sec. 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 Sec. 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 Sec. 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 Sec. 106.20(g) is consistent with FDA's regulations

concerning CGMP for food (Sec. 110.37(b)(5)) and drugs

(Sec. 211.48(b)).

Proposed Sec. 106.20(h) requires that steam that comes in direct

contact with infant formula be safe and free of rust

[[Page 36162]]

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 Sec. 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

Sec. 173.310 will ensure that any residue is safe to come in contact

with the infant formula.

Proposed Sec. 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 (Sec. 110.37(d)

and (e)) and drugs (Sec. 211.52). The requirement is also a necessary

adjunct to the requirement in proposed Sec. 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. Hand-washing facilities are not likely to be used in an

appropriate manner by employees if the facilities are not conveniently

located.

Proposed Sec. 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 Sec. 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 Sec. 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 Sec. 106.30(a)

requires that equipment be appropriately designed and installed. This

proposed requirement is consistent with FDA's CGMP regulations for

foods (Sec. 110.40(a)) and drugs (Sec. 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 Sec. 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 Sec. 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 food-

contact 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

Sec. 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 Sec. 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 Sec. 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

[[Page 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 Sec. 106.30(c) regarding substances necessary

for the operation of equipment, such as lubricants or coolants.

Proposed Sec. 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 deg.F, the temperature really is

240 deg.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 Sec. 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 Sec. 106.30(d)(1) also requires that manufacturers make

and retain records of accuracy checks in accordance with the provisions

of proposed Sec. 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 Sec. 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 Sec. 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 Sec. 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

[[Page 36164]]

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 deg.F (4.4

deg.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 Sec. 106.30(e)(2)).

Proposed Sec. 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

Sec. 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 Sec. 106.30(e)(3)(ii) also requires that cold storage

compartments be equipped with either a temperature-recording 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

temperature- recording 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 deg.F. A high-temperature alarm set to go off when the cold

storage compartment goes above 40 deg.F will allow the manufacturer to

make this determination. Likewise, a maximum-indicating thermometer

will remain at the highest temperature that it ever reaches. If the

maximum indicating thermometer indicates a temperature above 40 deg.F,

the infant formula manufacturer must assume that the temperature has

been above 40 deg.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

deg.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 Sec. 106.100(f)(3), of

the temperatures indicated or recorded by these devices (see

Sec. 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 Sec. 106.30(e)(4) requires that for thermal processing,

the temperature-recording 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 temperature-

recording 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 temperature-indicating 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 temperature-recording 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 temperature-recording 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 Sec. 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

[[Page 36165]]

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 Sec. 106.30(f) requires that manufacturers

make and retain records on equipment cleaning, sanitizing, and

maintenance in accordance with proposed Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 106.35(a)(1) is

based on common usage of the term and makes clear that the regulations

in proposed Sec. 106.35 apply to all automatic equipment, whether the

equipment is mechanical or electronic in nature. Proposed

Sec. 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 Sec. 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.

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

\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).

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

The definition of ``system'' in proposed Sec. 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 Sec. 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

[[Page 36166]]

intended to be used in. Therefore in proposed Sec. 106.35(b)(4), FDA is

proposing that all systems be validated ``before their first use to

manufacture commercial product.''

Proposed Sec. 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 Sec. 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 Sec. 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 software-based control system can be configured at

will by the operator or by the system itself. Therefore, proposed

Sec. 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 Sec. 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 Sec. 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 Sec. 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 deg.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

deg.F, an in-process batch of infant formula heated to 261 deg.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 Sec. 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 Sec. 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

[[Page 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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

Sec. 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 Sec. 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

[[Page 36168]]

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 Sec. 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 Sec. 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 Sec. 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

Sec. 106.40(f), to require retesting or reexamination after approved

materials have been exposed to conditions that may adversely affect

them.

Proposed Sec. 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 Sec. 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 Sec. 106.50(a)(1) carries forward and amends the

requirement in current Sec. 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 Sec. 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 Sec. 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

Sec. 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

[[Page 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 Sec. 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 Sec. 107.100 and therefore is not

adulterated, FDA is proposing in Sec. 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 Sec. 107.100 but not unapproved

ingredients that might adulterate the formula.

In proposed Sec. 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 Sec. 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 (Sec. 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 cross-contamination.

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 Sec. 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 Sec. 106.50(d)(3))

and ensure that containers of finished products are properly sealed

(proposed Sec. 106.50(d)(4)), that visible closure and seal defects are

detected (proposed Sec. 106.50(d)(4)(i)), and that destructive tests

are performed to determine closure strength (proposed

Sec. 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 Sec. 106.50(e)). As a result of such monitoring,

the manufacturer will be

[[Page 36170]]

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 Sec. 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

10\5\ 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 Sec. 106.55 requires manufacturers to

establish such controls.

Proposed Sec. 106.55(a) requires that manufacturers of liquid

infant formula comply with the procedures specified in part 113. These

products are thermally-processed 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 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 deg.C for 24 hours in air (Ref. 46).

``Microorganisms'' (as defined in

[[Page 36171]]

proposed Sec. 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 Sec. 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 Sec. 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 Sec. 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.

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

\3\ The 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.''

\4\ The 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.

\5\ The 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.

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

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

[[Page 36172]]

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 Sec. 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 Sec. 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 Sec. 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 Sec. 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,

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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 Sec. 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 Sec. 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 x 106 cells/g within 24

hours at 26 deg.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 hydrolysate-based 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 Sec. 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 Sec. 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 Sec. 106.55(d) requires that manufacturers

make and retain records, in accordance with proposed Sec. 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 Sec. 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 Sec. 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

Sec. 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 Sec. 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

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single infant formula product bearing the same code.

11. Controls on the Release of Finished Infant Formula

Proposed Sec. 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 Sec. 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 Sec. 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 Sec. 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 Sec. 106.70(b) requires that each batch of infant formula

that fails to meet the manufacturer's specifications be rejected.

Although proposed Sec. 106.70(b) recognizes that the formula may be

reprocessed, it requires that the reprocessed product be shown to meet

the requirements of Sec. 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 Sec. 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 Sec. 106.90 requires that manufacturers ensure traceability

by coding all infant formulas in conformity with the coding

requirements in Sec. 113.60(c) for thermally processed low- acid 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 Sec. 113.60(c)

forward in proposed Sec. 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 Sec. 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 Sec. 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 in-process 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

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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

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Current regulation Proposed regulation

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INGREDIEN

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