[Federal Register Volume 60, Number 32 (Thursday, February 16, 1995)]
[Proposed Rules]
[Pages 8989-8993]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 95-3970]



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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Parts 101, 111, 170, and 310

[Docket Nos. 91P-0186 and 93P-0306]


Iron-Containing Supplements and Drugs; Label Warning Statements 
and Unit-Dose Packaging Requirements

AGENCY: Food and Drug Administration, HHS.

ACTION: Supplemental proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is issuing a 
supplemental proposed rule to set forth its legal authority, after the 
passage of the Dietary Supplement Health and Education Act (DSHEA), to 
require unit-dose packaging of iron-containing dietary supplements that 
contain 30 milligrams (mg) or more iron per dosage unit. On October 6, 
1994, the agency proposed this packaging requirement as part of a 
broader proposal to require unit-dose packaging of all iron-containing 
products in solid oral dosage form containing 30 mg or more iron per 
dosage unit and to require label warning statements on all iron-
containing products in solid oral dosage form. The agency's authority 
to establish the labeling requirements and the packaging requirements 
for iron-containing products other than dietary supplements (i.e., 
iron-containing drugs) is unaffected by the DSHEA. To ensure that there 
is adequate time to comment on this supplemental proposed rule, as well 
as on the issues raised by the initial proposal, FDA is reopening the 
comment period for this rulemaking until April 17, 1995.

DATES: Written comments to the initial proposal (published at 59 FR 
51030, October 6, 1994) and this supplemental proposal by April 17, 
1995. The agency is proposing that any final rule that may be issued 
based upon this proposal become effective 180 days after its 
publication in the Federal Register.

ADDRESSES: Submit written comments to the Dockets Management Branch 
(HFA-305), Food and Drug Administration, rm. 1-23, 12420 Parklawn Dr., 
Rockville, MD 20857.

FOR FURTHER INFORMATION CONTACT: John N. Hathcock, Center for Food 
Safety and Applied Nutrition (HFS-465), Food and Drug Administration, 
8301 Muirkirk Rd., Laurel, MD 20708, 301-594-6006.

SUPPLEMENTARY INFORMATION:

I. Background

    In the Federal Register of October 6, 1994 (59 FR 51030), FDA 
issued a proposal on actions that it tentatively concluded were 
necessary to stem the recent epidemic of pediatric poisonings from 
accidental overdoses of iron-containing products. The available 
evidence shows that since the mid 1980's, there has been an upsurge in 
reported accidental pediatric poisonings from ingestion of iron-
containing products (59 FR 51030). This upsurge in poisonings, and the 
many resultant injuries and deaths of children, have created a dilemma 
with respect to how to ensure that iron sources are available while 
still minimizing the risks to children.
    To protect children, FDA proposed two new requirements: First, to 
ensure that consumers are fully informed about the consequences of 
consuming iron-containing products, FDA proposed to require a warning 
statement about the adverse effects of acute, high-dose iron ingestion 
by children to be included in the labeling of all iron-containing 
products in solid oral dosage form. FDA found that the fact that 
poisonings continue to occur, even though there have been at least 37 
deaths from accidental iron ingestion, strongly suggests that many 
adults are not aware of the potential for serious harm or death in 
young children from accidental ingestion of iron-containing products. 
Support for this finding is provided by statements made by the parents 
of the victims in several of the poisoning incidents, described in the 
case reports obtained from the U.S. Consumer Product Safety Commission 
(CPSC). FDA proposed that this requirement apply to iron-containing 
drugs and dietary supplements based on its authority under sections 
201(n), 403(a)(1), 502(a), and 701(a) of the Federal Food, Drug, and 
Cosmetic Act (the act) (21 U.S.C. 321(n), 343(a)(1), 352(a), and 
371(a)). Under section 403(a)(1) of the act, a food is misbranded if 
its labeling is false or misleading in any particular. Section 502(a) 
of the act establishes the same rule for drugs. Section 201(n) of the 
act states:
    If an article is alleged to be misbranded because the labeling 
or advertising is misleading, then in determining whether the 
labeling or advertising is misleading there shall be taken into 
account (among other things) not only representations made or 
suggested by statement, word, design, device, or any combination 
thereof, but also the extent to which the labeling or advertising 
fails to reveal facts material in the light of such representations 
or material with respect to consequences which may result from the 
use of the article to which the labeling or advertising relates 
under the conditions of use prescribed in the labeling or 
advertising thereof or under such conditions of use as are customary 
or usual.
These statutory provisions, combined with section 701(a) of the act, 
which grants the agency authority to issue regulations for the 
efficient enforcement of the act, clearly authorize FDA to issue a 
regulation designed to ensure that persons using iron-containing drugs 
and dietary supplements will receive information that is material with 
respect to consequences that may result from the use of the product. 
[[Page 8990]] 
    The circumstances involved with the iron poisonings parallel in 
many significant respects those that led the agency to require a 
warning on protein products. The use of iron-containing products in 
households where children are present is in no way an unusual practice. 
Multi-vitamin/mineral supplements with iron are taken routinely by 
children, and products of this type specifically intended for use by 
children are widely available and commonly sold. Iron supplements and 
iron-containing drug products are frequently recommended by physicians 
for pregnant women (often with a prescription) and other women of 
child-bearing age to meet their dietary requirement (these groups 
require more iron than other adults). Yet, the evidence on poisonings 
and deaths shows that the presence of iron-containing products in 
households with young children can lead to accidental injury or death 
if the children gain access to the products. Thus, FDA tentatively 
concluded that a warning about the risk of accidental pediatric 
poisoning from iron-containing products in solid oral dosage form is 
necessary in the labeling of all iron-containing products.
    Second, FDA proposed to require that all iron-containing drugs and 
dietary supplements in solid oral dosage form that contain 30 mg or 
more iron per dosage unit be packaged in unit-dose packaging. In the 
proposal, FDA tentatively concluded that full compliance with CPSC's 
child resistant packaging requirements, even if there are warning 
statements in labeling of iron-containing products and appropriate 
educational programs, is not adequate to ensure the safe use of certain 
iron-containing drugs and dietary supplements if bottle and closure 
packaging were to continue as the predominant means of packaging such 
products. FDA recognizes that each of these measures either has been 
successful in limiting the number of poisonings or can be reasonably 
expected to be effective in reducing the number of poisonings. However, 
given the potentially fatal outcome that can result from pediatric iron 
poisoning, FDA stated that it is not persuaded that these measures are 
adequate to ensure the safety of the use of certain iron-containing 
drugs and dietary supplements. To reduce the incidence of pediatric 
iron poisonings to a level that would permit the agency to conclude 
that the use of these products is safe, or generally recognized as safe 
(GRAS), FDA tentatively concluded that it was necessary to require a 
specific type of physical barrier to access dietary supplements that 
contain 30 mg or more of iron. Therefore, FDA tentatively concluded 
that an additional packaging requirement was necessary.
    FDA proposed this packaging requirement for iron-containing dietary 
supplements based on its authority under the act, with the provisions 
available at that time, to ensure that food ingredients are safe. In 
particular, the act requires, in sections 402 and 409 (21 U.S.C. 342 
and 348), that the safety of each food ingredient be established, 
either because the ingredient is GRAS, or because it is listed under 
the food additive or other relevant provisions, before it is added to 
food.
    Section 409(a) of the act deems a food additive to be unsafe unless 
its use conforms to the conditions specified in the listing regulation. 
These conditions include, but are not limited to, specifications as to 
the particular food or classes of food to which the additive may be 
added, the manner in which the additive may be added to such food, and 
any directions or other labeling or packaging requirements for such 
additive deemed necessary to assure the safety of such use (section 
409(c)(1)(A) of the act). Thus, under the act, the agency is authorized 
to specify packaging requirements for a food additive when it finds 
that use of such packaging is necessary to ensure the safe use of the 
additive.
    Section 201(s) of the act provides an exemption to the ``food 
additive'' definition for substances that are GRAS under the conditions 
of their intended use. FDA has issued regulations delineating 
conditions under which the use of certain substances is GRAS. In the 
proposal, FDA tentatively concluded that those conditions could include 
packaging. Thus if a dietary supplement contained an iron salt whose 
use would be GRAS except for the fact that its packaging would not 
ensure that its use would be safe, the product would be considered to 
contain an unsafe food additive and thus to be adulterated.
    FDA proposed the packaging requirement for iron-containing drugs 
based on its authority under section 501(a)(2)(B) of the act (21 U.S.C. 
351(a)(2)(B)). This section states that a drug shall be deemed to be 
adulterated if the methods used in, or the facilities or controls used 
for, its manufacture, processing, packing, or holding do not conform 
to, or are not operated or administered in conformity with, current 
good manufacturing practice (CGMP) to assure that such drug meets the 
requirements of the act as to safety and has the identity and strength, 
and meets the quality and purity characteristics, which it purports or 
is represented to possess.
    Under section 501(a)(2)(B) of the act, manufacturers are 
responsible for preventing intentional misuse of a drug product. For 
example, in 1982, in response to a series of capsule tamperings, FDA 
issued a regulation (Sec. 211.132), under the authority of this 
section, that requires tamper-resistant packaging for all over-the-
counter (OTC) human drug products except dermatologics, dentifrices, 
and insulin (47 FR 50442, November 5, 1982). The agency's action 
assured greater package integrity and product security beyond the point 
of manufacture.
    The recent data available to FDA demonstrate that the current 
manner of holding iron-containing drug products until their use by the 
intended consumer fails to ensure that the drug products will be safe 
because large numbers of children are ingesting such products and 
suffering serious injuries or death. Existing technology permits 
additional safeguards, such as child-resistant blister packs, to be 
used for holding iron-containing drug products. Given the known dangers 
and the ability to minimize or eliminate such dangers through the use 
of existing technology, FDA tentatively concluded that CGMP dictates 
that unit-dose packaging be used.

II. The Dietary Supplement Health and Education Act

    On October 25, 1994, President Clinton signed into law the DSHEA 
(Pub. L. 103-417). The DSHEA contains two provisions that bear on FDA's 
packaging proposal with respect to dietary supplements. First, section 
3(b) of the DSHEA added section 201(s)(6) to the act. This provision 
excludes minerals, such as iron, that are used in dietary supplements 
from the definition of a ``food additive.'' Second, section 9 of the 
DSHEA added section 402(g) to the act. Under this provision, a dietary 
supplement is adulterated unless it has been prepared, packed, and held 
under conditions that comply with the CGMP (section 402(g)(1) of the 
act). Under section 402(g)(2), the Secretary (and, by delegation, FDA) 
is authorized to prescribe CGMP's for dietary supplements by 
regulation.
    The DSHEA does not bear on any aspect of this rulemaking other than 
the proposed packaging requirement for dietary supplements. Dietary 
supplements are deemed to be food and thus are subject to sections 
201(n), 403(a), and 701(a) of the act (see section 201(ff) of the act). 
Thus, the proposed labeling requirement for iron-containing dietary 
supplements is not affected by [[Page 8991]] the DSHEA. Moreover, the 
DSHEA does not bear on how drugs are regulated. Thus, the proposed 
requirements for iron-containing drugs are also unaffected by the new 
law. Even with the DSHEA, however, FDA continues to have authority to 
require that dietary supplements that contain 30 mg or more of iron per 
dosage unit be unit-dose packed.

III. Discussion

A. Effect of Section 201(s)(6) of the Act

    In the proposal, FDA explained the basis for its tentative 
conclusion that it had authority to impose packaging requirements on 
iron-containing dietary supplements, FDA stated:
    Should FDA determine that a particular type of packaging is 
necessary to ensure the safe use of iron substances in dietary 
supplements, either as GRAS substances or as listed food additives, 
then any use of iron substances in dietary supplements that does not 
involve use of that type of packaging would constitute a use of an 
unapproved food additive and render the dietary supplements 
adulterated under the act.
See 59 FR 51047.
    This argument is deprived of its legal validity by new section 
201(s)(6) of the act. The use of iron ingredients in dietary 
supplements is not subject to section 409 of the act, even if the 
conditions of use of the iron ingredients are not those that are GRAS. 
Thus, FDA cannot rely on section 409 of the act for authority to 
require unit-dose packaging of dietary supplements.

B. Effect of Section 402(g) of the Act

    While, on the one hand, the DSHEA deprives the agency of the 
authority that it relied on in the proposal to require unit-dose 
packaging, on the other it added a new provision to the act that gives 
the agency authority to establish such a requirement.
    Section 402(g)(2) of the act provides that CGMP's for dietary 
supplements shall be modeled after the CGMP's for food. The current 
food CGMP regulations provide that food is to be packaged in a way that 
ensures that it is safe and sanitary (Secs. 110.5(a)(2) and 
110.80(b)(13)). As explained in the preamble to the October 6, 1994, 
proposal, FDA has tentatively concluded that unit-dose packaging is 
necessary to ensure the safety of dietary supplements that contain 30 
mg or more of iron per dosage unit.
    As discussed in the proposal, the recent data available to FDA 
demonstrate that iron-containing products with 30 mg or more iron per 
dosage unit are associated with a significant number of pediatric 
illnesses and deaths. As FDA stated with respect to drugs in the 
proposal, to ensure that these products are safe, CGMP requires that 
manufacturers respond to this new information, and take advantage of 
advances in technology, to alter, adapt, or change their manufacturing 
processes to ensure that all possible measures have been taken to 
eliminate known dangers from their products.
    Existing technology permits safeguards, specifically unit-dose 
packaging, to be used for iron-containing products, including dietary 
supplements. Unit-dose packaging limits a child's ability to gain 
access to enough dosage units to provide a harmful amount of iron. 
Given the known dangers posed by dietary supplements that contain 30 mg 
or more iron per dosage unit, and the ability to minimize or eliminate 
such dangers through the use of unit-dose packaging, FDA tentatively 
concludes that the CGMP dictates that unit-dose packaging be used for 
these products.
    Thus, FDA tentatively concludes that, to ensure that dietary 
supplements that contain 30 mg of iron or more per dosage unit are 
safe, CGMP requires that they be packaged in unit-dose packaging.
    The agency will consider conducting a more complete rulemaking on 
what CGMP requirements for dietary supplements under section 402(g) of 
the act are. However, considering the hazard presented to young 
children by iron-containing products, FDA tentatively concludes that it 
is appropriate to effect this aspect of its CGMP authority in advance 
of any broader rulemaking.
    To reflect the shift in the agency's authority with respect to 
packaging of dietary supplements, FDA is codifying the proposed CGMP 
requirements for iron-containing dietary supplements in new part 111, 
rather than in part 170 (21 CFR part 170). Proposed Sec. 170.55 is 
being removed in this supplemental proposal and replaced by Sec. 111.1. 
The agency is also making conforming amendments to part 101 to reflect 
new part 111 rather than part 170. For the convenience of the reader, 
FDA is republishing the amendments to parts 101 and 310 in their 
entirety. Thus, the codified portion of this document will also reflect 
the changes proposed in the October 6, 1994, proposed rule and thereby 
supersedes that codified material.
    In proposing the unit-dose packaging requirement under new part 
111, the agency is removing the provision from the packaging regulation 
in the original proposal that also would have required the proposed 
warning labels as a condition of safe use (i.e., as food additives or 
GRAS ingredients) for iron and iron salts in iron-containing 
supplements. The authority for this requirement was also derived from 
section 409 of the act, which permits the agency to consider any 
necessary labeling requirements in establishing conditions of safe use 
for a food additive. New section 201(s)(6) of the act also invalidates 
the legal authority that FDA relied upon for this proposed provision 
because the use of iron ingredients in dietary supplements is no longer 
subject to section 409 of the act.

IV. Comments

    Because of the change in the law and issuance of this supplemental 
proposal, FDA will allow an additional 60 days for comment on the 
entire proposed action. This additional time will provide an 
opportunity for the submission of all views on the issues in the 
rulemaking.
    Interested persons may, on or before April 17, 1995, submit to the 
Dockets Management Branch (address above) written comments regarding 
this proposal. Two copies of any comments are to be submitted, except 
that individuals may submit one copy. Comments are to be identified 
with the docket number found in brackets in the heading of this 
document. Received comments may be seen in the office above between 9 
a.m. and 4 p.m., Monday through Friday.

V. Environmental Impact

    The agency previously considered the environmental effects of its 
action to require unit-dose packaging for iron-containing products, in 
the proposed rule that was published in the Federal Register of October 
6, 1994 (59 FR 51030). The changes in legal authority being proposed in 
this document will not affect the agency's previously proposed 
requirement for unit-dose packaging for iron-containing products and, 
therefore, will not affect the agency's previous determination that 
there is no significant impact on the human environment and that an 
environmental impact statement is not required.

VI. Analysis of Impacts

    FDA previously examined the impact of the proposed rule as 
published in the Federal Register of October 6, 1994 (59 FR 51030), in 
accordance with Executive Order 12866 and the Regulatory Flexibility 
Act, and determined that it is not an economically significant rule. 
The discussion of the legal authority contained in this supplemental 
proposed rule does not alter the [[Page 8992]] agency's conclusions. 
The rule will result in total costs of approximately $53 million and 
discounted benefits of between $315 million and $653 million over the 
next 20 years (discounted at 7 percent).

List of Subjects

21 CFR Part 101

    Food labeling, Nutrition, Reporting and recordkeeping requirements.

21 CFR Part 111

    Current good manufacturing practices, Dietary supplements.

21 CFR Part 170

    Administrative practice and procedure, Food additives, Reporting 
and recordkeeping requirements.

21 CFR Part 310

    Administrative practice and procedure, Drugs, Labeling, Medical 
Devices, Reporting and recordkeeping requirements.
    Therefore, under the Federal Food, Drug, and Cosmetic Act and under 
authority delegated to the Commissioner of Food and Drugs, the codified 
text as proposed in the Federal Register of October 6, 1994 (59 FR 
51030), is republished in its entirety and is thereby superseded by 
this document. It is further proposed that Title 21, Chapter I be 
amended as follows:

PART 101--FOOD LABELING

    1. The authority citation for 21 CFR part 101 continues to read as 
follows:

    Authority: Secs. 4, 5, 6 of the Fair Packaging and Labeling Act 
(15 U.S.C. 1453, 1454, 1455); secs. 201, 301, 402, 403, 409, 701 of 
the Federal Food, Drug, and Cosmetic Act (21 U.S.C. 321, 331, 342, 
343, 348, 371).

    2. Section 101.17 is amended by adding a new paragraph (e) to read 
as follows:


Sec. 101.17  Food labeling warning and notice statements.

* * * * *
    (e) Dietary supplements containing iron or iron salts. (1) The 
labeling of any dietary supplement in solid oral dosage form (e.g., 
tablets or capsules) that contains iron or iron salts for use as an 
iron source shall bear the following statement:
    (i) If the product is packaged in unit-dose packaging as defined in 
Sec. 111.1 of this chapter:

    WARNING--Keep away from children. Keep in original package until 
each use. Contains iron, which can harm or cause death to a child. 
If a child accidentally swallows this product, call a doctor or 
poison control center immediately.

    (ii) If the product contains less than 30 milligrams of iron per 
dosage unit and is packaged by the manufacturer in other than unit-dose 
packaging as defined in Sec. 111.1 of this chapter, e.g., a container 
with a child-resistant closure, its label shall bear the following 
statement:

    WARNING--Close tightly and keep away from children. Contains 
iron, which can harm or cause death to a child. If a child 
accidentally swallows this product, call a doctor or poison control 
center immediately.

    (2) The statement required by paragraph (e)(1)(i) of this section 
shall appear prominently and conspicuously on the immediate container 
labeling in such a way that the warning is intact until all of the 
dosage units to which it applies are used. The statement required by 
paragraph (e)(1)(ii) of this section shall appear prominently and 
conspicuously on the immediate container labeling. In all cases where 
the immediate container is not the retail package, the warning 
statement shall also appear prominently and conspicuously on the 
principal display panel of the retail package. In addition, the warning 
statement shall appear on any labeling that contains warnings.
    3. Part 111 is added to read as follow:

PART 111--CURRENT GOOD MANUFACTURING PRACTICE FOR DIETARY 
SUPPLEMENTS

    Authority: Secs. 201, 402, 701 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 342, 371).


Sec.  111.1  Iron and iron salts in dietary supplements.

    The use of iron and iron salts as iron sources in dietary 
supplements offered in solid oral dosage form (e.g., tablets or 
capsules), and containing 30 milligrams or more of iron per dosage 
unit, is safe and in accordance with current good manufacturing 
practice only when such supplements are packaged in unit-dose 
packaging. ``Unit-dose packaging'' means a method of packaging a 
product into a nonreusable container designed to hold a single dosage 
unit intended for administration directly from that container, 
irrespective of whether the recommended dose is one or more than one of 
these units. The term ``dosage unit'' means the individual physical 
unit of the product (e.g., tablets or capsules).

PART 170--FOOD ADDITIVES

    3. The authority citation for 21 CFR part 170 continues to read as 
follows:

    Authority: Secs. 201, 401, 402, 408, 409, 701 of the Federal 
Food, Drug, and Cosmetic Act (21 U.S.C. 321, 341, 342, 346a, 348, 
371).

Sec. 170.55  [Removed]

    4. Section 170.55 Iron and iron salts in dietary supplements not in 
conventional food form (as proposed in at 59 FR 51030, October 6, 1994) 
is removed.

PART 310--NEW DRUGS

    5. The authority citation for 21 CFR part 310 continues to read as 
follows:

    Authority: Secs. 201, 301, 501, 502, 503, 505, 506, 507, 512-
516, 520, 601(a), 701, 704, 705, 721 of the Federal Food, Drug, and 
Cosmetic Act (21 U.S.C. 321, 331, 351, 352, 353, 355, 356, 357, 
360b-360f, 360j, 361(a), 371, 374, 375, 379e; secs. 215, 301, 
302(a), 351, 354-360F of the Public Health Service Act (42 U.S.C. 
216, 241, 242(a), 262, 263b-263n).

    6. New Sec. 310.518 is added to subpart E to read as follows:


Sec. 310.518  Drug products containing iron or iron salts.

    Drug products containing elemental iron or iron salts as an active 
ingredient in solid oral dosage form (e.g., capsules or tablets) shall 
meet the following requirements:
    (a) Packaging. If the product contains 30 milligrams or more of 
iron per dosage unit, it shall be packaged in unit-dose packaging. 
``Unit-dose packaging'' means a method of packaging a product into a 
nonreusable container designed to hold a single dosage unit intended 
for administration directly from that container, irrespective of 
whether the recommended dose is one or more than one of these units. 
The term ``dosage-unit'' means the individual physical unit of the 
product, e.g., tablets or capsules.
    (b) Labeling. (1) If the product is packaged by the manufacturer in 
unit-dose packaging, its label shall bear the following statement:

    WARNING--Keep away from children. Keep in original package until 
each use. Contains iron, which can harm or cause death to a child. 
If a child accidentally swallows this product, call a doctor or 
poison control center immediately.

    (2) If the product contains less than 30 milligrams of iron and is 
packaged by the manufacturer in other than unit-dose packaging, e.g., a 
container with a child-resistant closure, its label shall bear the 
following statement:

    WARNING--Close tightly and keep away from children. Contains 
iron, which can harm or cause death to a child. If a child 
accidentally swallows this product, call a doctor or poison control 
center immediately.

    (3) The statement required by paragraph (b)(1) of this section 
shall appear prominently and conspicuously on the immediate container 
labeling in [[Page 8993]] such a way that the warning is intact until 
all of the dosage units to which it applies are used. The statement 
required by paragraph (b)(2) of this section shall appear prominently 
and conspicuously on the immediate container labeling. In all cases 
where the immediate container is not the retail package, the warning 
statement shall also appear prominently and conspicuously on the 
principal display panel of the retail package. In addition, the warning 
statement shall appear on any labeling that contains warnings.

    Dated: February 10, 1995.
David A. Kessler,
Commissioner of Food and Drugs.
[FR Doc. 95-3970 Filed 2-15-95; 8:45 am]
BILLING CODE 4160-01-F