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3 Regulatory Report: FDA’s FCS Notification Program

3 Regulatory Report: FDA’s FCS Notification Program

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demonstrating that the substance that is the subject

of the notification is safe for the intended use.

FDA’s fiscal year 2000 budget contained an appropriation to fund the FCN program, and in October

1999 the Office of Food Additive Safety began converting approximately 120 in-house food additive

petitions and threshold of regulation submissions for

review under the new amended requirements.

(Threshold of regulation for substances used in food

contact articles can be found in 21 CFR 170.39.) On

January 18, 2000, the Agency began accepting new

food contact notifications, and in July 2000 FDA

published proposed regulations for the program. The

regulations were finalized in May 2002 and codified

in 21 CFR Part 170.100À106.



Scope

Food contact notifications are required only for

new uses of FCSs that are food additives. Although

a notification is not required for a FCS that is

GRAS or prior sanctioned for its intended use in

contact with food, some companies do choose to

notify the Agency in order to clarify the regulatory

status of such substances. Manufacturers may also

use FCNs to notify FDA of new uses of FCSs that

are GRAS or prior sanctioned.

Unlike food additive regulations and threshold of

regulation exemptions, approvals under the FCN

process are proprietary. This is because Section 409

(h)(1)(C) of the FD&C Act states that an FCN is

effective only for the manufacturer and substance

identified in the notification. Thus, any person wishing to rely on an FCN needs to demonstrate that the

FCS being marketed has been manufactured or supplied by the manufacturer identified in the FCN and

is being used under the conditions that are the subject of the FCN. This may seem a trivial point, but it

is important since the manufacturer for whom the

FCN is effective does not need to be the actual manufacturer of the FCS but can also be a supplier who

is purchasing the substance and distributing it for

the intended use. If a notifier is not careful in defining the entities for which the FCN is effective, the

proprietary approval received in a successful FCN

may not be applied to the intended company.



16.3.2 The Notification Process

Anyone may submit a food contact notification

to FDA. (Although the FD&C Act refers to



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manufacturers or suppliers submitting a notification, FDA interprets the term “supplier” broadly to

include persons who could previously have

requested authorization under the food additive

petition process. This ensures that no one was

unfairly excluded by the transition to the FCN process.) The FCN process is initiated when a submission, prepared by the notifier, arrives at the Office

of Food Additive Safety. A notification control

assistant logs the submission and assigns it a notification number. The submission is then distributed

to a review team for assignment. The review team

consists of a consumer safety officer, a chemist, a

toxicologist, and an environmental scientist. During

the initial month of the review period, FDA does

not ordinarily contact the notifier; however, the

notifier is free to contact the consumer safety officer in charge of the notification.

A “phase one” review meeting is held within the

first 3 weeks after receipt of the FCN to ensure that

the basic data and informational elements are present and that the submission meets the administrative requirements set forth in the FD&C Act and

FDA’s regulations. If the submission is complete, it

is accepted and FDA sends the notifier an acknowledgment letter. The acknowledgment letter initiates

formal communication between FDA and the notifier and gives the notifier an opportunity to comment on the Agency’s understanding of the identity

and intended use of the FCS that is the subject of

the notification. Notifiers who disagree with FDA’s

description of the FCS should respond as quickly as

possible to this acknowledgment letter. The

acknowledgment letter also establishes the date of

receipt of the notification, which indicates when the

120-day FCN review period began, and that the

review team is entering into “phase two” review.

During “phase two”, the team evaluates the

safety of the FCS as it is proposed for use. If there

are no concerns during the “phase two” review, the

FCN automatically becomes effective on the 120day date, and the consumer safety officer sends a

letter to the notifier confirming the effective date.

Information about the notification is then added to

the Inventory of Effective Premarket Notifications

for Food Contact Substances posted on CFSAN’s

web page.

If after “phase one” review the notification is

deemed “not acceptable” and FDA must request

additional information, the date of receipt of the

additional information may be considered the date



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of receipt of the complete notification, and the 120day review period would begin on that date. This

determination is based on the nature of the additional information received, i.e. whether it is substantive or nonsubstantive in nature. Since the time

for review of FCNs is short, requests for and

receipt of additional information must be handled

in a timely manner, as one of several scenarios may

play out this point. If the requested information is

not received within approximately 2 weeks and the

notifier does not withdraw the submission, FDA

may deem the notification incomplete and a nonacceptance letter may be issued to the notifier indicating termination of FDA’s review. If FDA does

receive the additional information within 2 weeks

but still deems the notification to be incomplete,

the notifier may be given the option of withdrawing

the submission without prejudice before receiving a

nonacceptance letter. (About one in four FCNs are

withdrawn because of deficiencies.) If the information adequately completes the submission, it is

accepted, an acknowledgment letter is sent, and the

“phase two” review begins. Provided that there are

no safety concerns during “phase two” review, a

final letter is sent to the notifier confirming the

FCN effective date, and the notification is added to

the Inventory of Effective Premarket Notifications

for Food Contact Substances posted on the internet.

What happens if there are safety concerns during

the “phase two” review? If safety concerns emerge,

the notifier is given the option of withdrawing the

submission without prejudice to a future submission. If the notifier does not withdraw the notification, an objection letter is sent to the notifier.

Under 21 CFR 170.100 (c), FDA may also issue a

nonacceptance letter for the following reasons: (1)

FCS uses that increase the cumulative estimated daily

intake (CEDI) of the FCS to a level equal to or greater

than 3 mg per person per day for a substance that is

not a biocide (e.g. it is intended to exert microbial

toxicity), and 0.5 mg per person per day for a biocide;

and/or (2) where a bioassay exists on the FCS,

FDA has not reviewed the bioassay, and the bioassay

is not clearly negative for carcinogenic effects.



Threshold of Regulation

Some FCNs are for uses that qualify for review

under FDA’s “threshold of regulation” process. The

threshold of regulation process is an abbreviated

review process for uses of indirect food additives



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that result in exposures below 1.5 μg per person per

day. The threshold of regulation process can result

in a faster approval; however, that approval is not

proprietary.



Confidentiality

A common concern of many notifiers is the

availability of information submitted in an FCN.

The FD&C Act prohibits FDA from disclosing

information in an FCN during the 120-day review

period. In addition, FDA has issued regulations

establishing that information in FCNs withdrawn

before FDA issues an objection letter or before the

FCN becomes effective will not be disclosed. FDA

also considers information in an FCN that is “not

accepted” to be confidential commercial information protected from disclosure.

Some notifiers seek to protect information by

including it in a food additive master file. Such

information is protected only if it is not used as the

basis of an FDA safety decision or if it is not otherwise publicly available. In these scenarios, the information in the food master file is treated as if it was

in the FCN. In short, information in an FCN is protected from disclosure during review, if the FCN is

withdrawn, or if a nonacceptance letter is issued, but

it is not protected from disclosure after an FCN

becomes effective or if FDA objects to the FCN,

unless it is trade secret or confidential information.



16.3.3 Increasing the Odds of

Success

FDA encourages notifiers to participate in a prenotification consultation to facilitate the development

of a complete FCN submission. Prenotification consultations are interactions between the Office of

Food Additive Safety and industry prior to submission of an FCN, a food additive petition, or a threshold of regulation exemption request. They are

particularly advisable in situations where current

guidance is not completely applicable. There are

three circumstances in which FDA specifically

recommends a prenotification consultation. The first

specific circumstance is when the notifier believes

that an FCN is not sufficient and a food additive petition is required for the use of an FCS. Such a meeting

may be used to verify that a petition is required and

that an appropriate level of information is supplied in

the petition. The second specific circumstance for



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which FDA recommends a prenotification consultation is when different interpretations of available

data would result in different conclusions, which in

turn could affect whether it is appropriate to submit a

notification or a petition, e.g. if different interpretations of data in a bioassay could change the conclusion regarding the likely carcinogenicity of the

substance. The third specific circumstance for which

a prenotification consultation is recommended is

when there are uncertainties about how specific data

may be interpreted and those uncertainties are of

such magnitude that they may affect the outcome of

the overall safety determination; e.g. if the estimated

daily intake (EDI) is close enough to the

acceptable daily intake that different choices for the

no-effect level may cause the resulting

acceptable daily intake to be larger or smaller than

the EDI. A prenotification consultation request may

be sent via e-mail, facsimile, or letter and should be

addressed to the notification control assistant.



16.3.4 FCS Formulations

Occasionally, individuals may wish to verify

compliance of the components of a particular food

contact material. In such instances, they may submit

a notification for a FCS formulation. Such notifications are only meant to verify that components of a

food contact material may legally be used and not to

authorize a new FCS. Notifications for formulations

do not require resubmission of the information supporting the safety of the intended use of each FCS in

the formulation. A notifier for a formulation need

only submit a completed FDA Form 3479 and any

additional documentation required to establish that

each of the components of the formulation is authorized for its intended use. In cases where the basis

for compliance of an individual FCS in a formulation is an effective notification, a notifier of the formulation should establish that he can rely on the

notification cited and that such notification is effective for the intended use in the formulation.

When checking compliance of components of a

food contact material, remember that substances

that are reasonably expected to migrate to food

because of their intended use in contact with food

should be one of the following: (1) approved indirect food additives used in compliance with 21

CFR Parts 174À179, (2) GRAS for use in or on

contact with food, (3) substances whose use in contact with food are the subject of a prior sanction



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issued by FDA or USDA before 1958, used under a

threshold of regulation exemption by FDA since

October of 1999, or the subject of an effective

FCN. If the substance does not fall into one of

these categories, the FCN process or the threshold

of regulation process are the preferred methods of

providing for the safe use of the substance.

Individuals wishing to determine if FDA has a

regulation for a specific food additive can view a

list of food additives and their corresponding regulations at www.fda.gov. The individual regulations

for food additives and GRAS substances listed for

use in the United States are located in Title 21 CFR

Parts 182À186 and can be accessed through

CFSAN’s web site. However, not all substances

that are GRAS are listed in FDA’s regulations.

FDA has instituted a procedure whereby companies

may inform FDA of their own GRAS determination

(GRAS notification procedure). A list of these

GRAS notices, with FDA’s response letter to the

notifier, can be found at www.fda.gov.

It is important to remember that the use of any

chemicals to fabricate food contact articles is done

with the understanding that it is the responsibility

of the manufacturer to ensure that any resultant

food contact articles comply with the specifications

and limitations in all applicable regulations. When

reviewing composite formulations to determine

compliance, consider each regulation or notification

to be composed of three parts: the identity of the

substance; specifications, including purity or physical properties; and limitations on the conditions of

use. In order for your products to be suitable for

use in contact with food in the United States, each

chemical component must comply with all three

criteria.



16.4 Preservation of Foods by

Irradiation

Food-borne diseases are a source of concern for

every person who consumes food. These are the illnesses contracted from eating contaminated foods or

beverages. The illnesses include food-borne intoxications and infections and are often incorrectly

referred to as food poisoning (McKeen, 2012).

There are more than 250 different food-borne diseases caused by viruses, bacteria, parasites, toxins,

metals, and prions. According to the US Center for



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Disease Control (CDC), 31 pathogens are known to

cause 20% of the food-borne illnesses, with 80%

being caused by unknown agents (Scallan et al.,

2011).

Concern over food safety dates back thousands

of years. Many techniques have been devised over

the centuries to keep food safe, including drying,

pickling, salting, sugaring, cold storage, smoking,

canning, and blanching. Every one of these techniques has limitations such as preservation of freshness, applicability, scalability, and cost. Worldwide

population growth and the demand for food grown

in distant locations have resulted in a complex

global distribution system, increasing the challenge

of keeping foods safe. Ionizing irradiation has been

recognized as a convenient technique for food preservation for over a century.

Present-day food processors prefer that food be

prepackaged in its final packaging form before irradiation to prevent recontamination and to expedite

shipment to market after irradiation. Prepackaged

food could potentially be contaminated by the by-



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products formed if the packaging materials are

degraded by irradiation. This may lead to a safety

concern and, therefore, testing of packaging materials after exposure to irradiation is an integral

part of the premarket safety assessment of packaging materials irradiated in contact with food

(Packaging for Foods Treated with Ionizing

Radiation, 2007). A partial preventive measure is to

limit the radiation used to treat the packaged food

(Table 16.1).



16.4.1 FDA Regulations for

Treatment of Foods with Radiation

There are different reasons for the irradiation of

foodstuff. Many foods are irradiated to kill bacteria

and parasites that pose health risks to humans. This

makes the food safer, and is comparable to pasteurizing milk. Irradiation at lower dose levels also

extends shelf life and can be used to control insects.

Food is also irradiated to destroy bacteria, fungi, or

parasites that cause human disease or cause food to



Table 16.1 FDA Food Radiation Specifications (Packaging for Foods Treated with Ionizing Radiation, 2007)

Food Type



Purpose



Radiation Dose



Fresh, nonheated processed pork



Control of Trichinella

spiralis



0.3 kGy minimum

to 1 kGy

maximum



Fresh food



Growth and maturation

inhibition



1 kGy maximum



Foods



Arthropod disinfection



10 kGy maximum



Dry or dehydrated enzyme preparations



Microbial disinfection



1 kGy maximum



Dry or dehydrated spices/seasonings



Microbial disinfection



30 kGy maximum



Fresh or frozen, uncooked poultry products



Pathogen control



3 kGy maximum



Frozen packaged meats (solely used in the

National Aeronautics and Space Administration

(NASA) space flight programs)



Sterilization



44 kGy minimum



Refrigerated, uncooked meat products



Pathogen control



4.5 kGy

maximum



Frozen, uncooked meat products



Pathogen control



7 kGy maximum



Fresh shell eggs



Control of Salmonella



3.0 kGy

maximum



Seeds for sprouting

Fresh or frozen molluscan shellfish (per FDA 2005)



8.0 kGy

maximum

Control of Vibrio species

and other food-borne

pathogens



5.5 kGy

maximum



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spoil. Irradiation kills harmful bacteria such as

Escherichia coli O157:H7, Salmonella, Listeria,

Campylobacter, and Vibrio, which are main contributors to the illnesses and deaths caused by foodborne poisoning (Feed Irradiation, 2012; Sommers

and Fan, 2006). Moreover, parasites such as

Cryptosporidium sp., Cyclospora sp., Toxoplasma

gondii, and Trichinella are eliminated.

When used in this manner, irradiation is comparable to pasteurizing milk, in that the product is left

fresh, but is much safer. Irradiation also extends the

shelf life of food by retarding maturation in

vegetables and reducing spoilage organisms that

can even grow under refrigeration. Irradiated strawberries can last weeks in the refrigerator without

developing mold. Irradiation can also be used in

place of fumigants and other quarantine procedures

to allow fruits and vegetables to be imported or

exported without risking the introduction of

harmful insects to the receiving country (Feed

Irradiation, 2012).

The primary regulation that covers irradiation in

the production, processing, and handling of food is

21 CFR 179. It is divided into subparts and sections

and is summarized in Table 16.2. Subpart B of 21

CFR 179 describes the type of radiation and its

sources; they include gamma ray, electron beam,

and X-ray. The general provisions for food irradiation are described. Subpart B also describes other

radiation methods such as radio-frequency radiation, ultraviolet, and pulsed light. Subpart C of 21



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CFR 179 describes packaging materials for irradiated foods. The regulations listed in Part 179 are

due to the approved food additive petitions via the

codified process of 21 CFR 171. The actual content

of each section in Table 16.2 has been described in

this chapter.



16.4.2 Title 21 CFR 179. Subpart B:

Radiation and Radiation

Sources

Section 179.21: Sources of Radiation

Used for Inspection of Food, for

Inspection of Packaged Food, and for

Controlling Food Processing

Sources of radiation for the purposes of inspection of foods, for inspection of packaged food, and

for controlling food processing may be safely used

under the following conditions:

a. The radiation source is one of the following:

1. X-ray tubes producing X-radiation from

operation of the tube source at a voltage

of 500 kV peak or lower.

2. Sealed units producing radiation at energy

levels of not more than 2.2 million electron volts (MeV) from one of the following isotopes: americium-241, cesium-137,

cobalt-60, iodine-125, krypton-85, radium226, and strontium-90.



Table 16.2 Title 21, Part 179: Irradiation in the Production, Processing, and Handling of Food

Regulation Section



Regulation Coverage



Subpart B—radiation and

radiation sources

179.21



Sources of radiation used for inspection of food, for inspection of

packaged food, and for controlling food processing



179.25



General provisions for food irradiation



179.26



Ionizing radiation for the treatment of food



179.30



Radio frequency radiation for the heating of food, including

microwave frequencies



179.39



Ultraviolet radiation for the processing and treatment of food



179.41



Pulsed light for the treatment of food



Subpart C—packaging materials

for irradiated foods

179.45



Packaging materials for use during the irradiation of prepackaged

foods



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3. Sealed units producing neutron radiation

from the isotope californium-252 (CAS

Reg. No. 13981-17-4) to measure moisture

in food.

4. Machine sources producing X-radiation at

energies no greater than 10 MeV.

5. Monoenergetic neutron sources producing

neutrons at energies not less than 1 MeV

but no greater than 14 MeV.

b. To assure safe use of these radiation sources:

1. The label of the sources shall bear, in

addition to the other information required

by the Act:

i. appropriate and accurate information

identifying the source of radiation

ii. the maximum energy of radiation

emitted by X-ray tube sources

iii. the maximum energy of X-radiation

emitted by machine source

iv. the minimum and maximum energy of

radiation emitted by neutron source

2. The label or accompanying labeling shall

bear:

i. adequate directions for installation

and use

ii. a statement that no food shall be

exposed to radiation sources listed in

Paragraph (a) (1) and (2) of this section so as to receive an absorbed dose

in excess of 10 Gy

iii. a statement that no food shall be

exposed to a radiation source listed in

Paragraph (a)(3) of this section so as

to receive an absorbed dose in excess

of 2 mGy

iv. a statement that no food shall be

exposed to a radiation source listed in

Paragraph (a)(4) of this section so as

to receive a dose in excess of 0.5 Gy

v. a statement that no food shall be

exposed to a radiation source listed in

Paragraph (a)(5) of this section so as

to receive a dose in excess of 0.01 Gy



Section 179.25: General Provisions for

Food Irradiation

For the purposes of 179.26, current good

manufacturing practice is defined to include the following restrictions:



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a. Any firm that treats foods with ionizing radiation shall comply with the requirements of

Part 110 of this chapter and other applicable

regulations.

b. Food treated with ionizing radiation shall

receive the minimum radiation dose reasonably required to accomplish its intended technical effect and not more than the maximum

dose specified by the applicable regulation

for that use.

c. Packaging materials subjected to irradiation

incidental to the radiation treatment and processing of prepackaged food shall be in compliance with 179.45, shall be the subject of

an exemption for such use under 170.39 of

this chapter, or shall be the subject of an

effective premarket notification for a FCS for

such use submitted under 170.100 of this

chapter.

d. Radiation treatment of food shall conform to

a scheduled process. A scheduled process

for food irradiation is a written procedure

that ensures that the radiation dose range

selected by the food irradiation processor is

adequate under commercial processing conditions (including atmosphere and temperature) for the radiation to achieve its intended

effect on a specific product and in a specific

facility. A food irradiation processor shall

operate with a scheduled process established by qualified persons having expert

knowledge in radiation processing requirements of food and specifically for that food

and for that irradiation processor’s treatment

facility.

e. A food irradiation processor shall maintain

records as specified in this section for a

period of time that exceeds the shelf life of

the irradiated food product by 1 year, or up

to a maximum of 3 years, whichever period

is shorter, and shall make these records available for inspection and copying by authorized

employees of the FDA. Such records shall

include the food treated, lot identification,

scheduled process, evidence of compliance

with the scheduled process, ionizing energy

source, source calibration, dosimetry, dose

distribution in the product, and the date of

irradiation.



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