[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
