Federal Register, Volume 65 Issue 17 (Wednesday, January 26, 2000)

[Federal Register Volume 65, Number 17 (Wednesday, January 26, 2000)]
[Rules and Regulations]
[Pages 4103-4111]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 00-1788]

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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 90N-0056]
RIN 0910-AA74

Aluminum in Large and Small Volume Parenterals Used in Total
Parenteral Nutrition

AGENCY: Food and Drug Administration, HHS.

ACTION: Final rule.

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SUMMARY: The Food and Drug Administration (FDA) is amending its
regulations to add certain labeling requirements for aluminum content
in large volume parenterals (LVP's), small

[[Page 4104]]

volume parenterals (SVP's), and pharmacy bulk packages (PBP's) used in
total parenteral nutrition (TPN). FDA is also specifying an upper limit
of aluminum permitted in LVP's and requiring applicants to submit to
FDA validated assay methods for determining aluminum content in
parenteral drug products. The agency is adding these requirements
because of evidence linking the use of parenteral drug products
containing aluminum to morbidity and mortality among patients on TPN
therapy, especially among premature neonates and patients with impaired
kidney function.

DATES: This rule is effective January 26, 2001.

ADDRESSES: Submit written comments to the Dockets Management Branch
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061,
Rockville, MD 20852.

FOR FURTHER INFORMATION CONTACT: Leanne Cusumano, Center for Drug
Evaluation and Research (HFD-7), Food and Drug Administration, 5600
Fishers Lane, Rockville, MD 20857, 301-594-2041.

SUPPLEMENTARY INFORMATION:

I. Background

FDA published a notice of intent in the Federal Register on May 21,
1990 (55 FR 20799) announcing FDA's concerns about toxic aluminum
levels in TPN and requesting comments. As a result of the comments
received, on January 5, 1998, FDA published a proposed rule in the
Federal Register (63 FR 176) in which it proposed to: (1) Establish a
maximum permissible level of aluminum in LVP's used in TPN therapy; (2)
require that the maximum level of aluminum permitted in LVP's used in
TPN therapy be stated on the package insert of all LVP's used in TPN
therapy; (3) require that the maximum level of aluminum at expiry be
stated on the immediate container label of SVP's and PBP's used in the
preparation of TPN solutions; (4) require that the package insert of
all LVP's and SVP's, including PBP's, contain a warning statement about
aluminum toxicity in patients with impaired kidneys and neonates
receiving TPN therapy; and (5) require that applicants and
manufacturers develop validated assay methods for determining the
aluminum content in parenteral drug products used in TPN therapy and
submit the validated assay methods to FDA for approval.
FDA has become increasingly concerned about the aluminum content in
parenteral drug products, which could result in a toxic accumulation of
aluminum in the tissues of individuals receiving TPN therapy. FDA
included specific references in the proposed rule that supported the
following information about aluminum toxicity (63 FR 176). Research
indicates that neonates and patient populations with impaired kidney
function may be at high risk of exposure to unsafe amounts of aluminum.
Many drug products used routinely for TPN may contain levels of
aluminum sufficiently high to cause clinical manifestations. Generally,
when medication and nutrition are administered orally, the
gastrointestinal tract acts as an efficient barrier to the absorption
of aluminum, and relatively little ingested aluminum actually reaches
body tissues. However, parenterally administered drug products
containing aluminum bypass the protective mechanism of the
gastrointestinal tract and aluminum circulates, and it is deposited in
human tissues.
Aluminum toxicity is difficult to identify in neonates because few
reliable techniques are available to evaluate bone metabolism in
premature neonates. Techniques used to evaluate the effects of aluminum
on bone in adults cannot be used in premature neonates. Although
aluminum toxicity is not commonly detected clinically, it can be
serious in selected patient populations, such as neonates, and may be
more common than is recognized.
Classic manifestations of aluminum intoxication in patients with
impaired kidney function include fracturing osteomalacia,
encephalopathy, and microcytic hypochromic anemia. Aluminum may prevent
calcium absorption in premature neonates receiving TPN therapy. In
addition, aluminum loading may be a factor in the bone disease of very
ill neonates with reduced kidney function who have received long-term
parenteral therapy with aluminum-contaminated fluids.
FDA received 21 comments on the proposed rule and addresses each of
those comments in section III of this document. FDA is adopting this
final rule as described below. The agency has also made minor edits to
the final rule in response to the President's June 1, 1998, memorandum
on plain language in Government writing.

II. Highlights of the Final Rule

FDA is implementing this final rule because of evidence linking the
use of parenteral drug products containing aluminum to morbidity and
mortality among patients on TPN therapy, especially premature neonates
and patients with impaired kidney function.
The new regulations added to part 201 ((21 CFR 201) at
Sec. 201.323(a)) limit the aluminum content for all LVP's used in TPN
therapy to 25 micrograms per liter (g/L). This requirement
applies to all LVP's used in TPN therapy, including, but not limited
to, parenteral amino acid solutions, highly concentrated dextrose
solutions, parenteral lipid emulsions, saline and electrolyte
solutions, and sterile water for injection.
New Sec. 201.323(b) requires the package insert for all LVP's used
in TPN therapy to state that the drug product contains no more than 25
g/L of aluminum. This statement must be included in the
``Precautions'' section of the labeling.
New Sec. 201.323(c) requires the product's maximum level of
aluminum at expiry to be stated on the immediate container label of
SVP's and PBP's used in the preparation of TPN solutions. The statement
on the immediate container label must read as follows: ``Contains no
more than ---- g/L of aluminum.'' For those SVP's and PBP's
that are lyophilized powders used in the preparation of TPN solutions,
the maximum level of aluminum at expiry must be printed on the
immediate container label as follows: ``When reconstituted in
accordance with the package insert instructions, the concentration of
aluminum will be no more than ---- g/L.'' The maximum level of
aluminum must be stated as the highest of: (1) The highest level for
the batches produced during the last 3 years; (2) the highest level for
the latest five batches, or (3) the maximum historical level, but only
until completion of production of the first five batches after January
26, 2001. The labeling requirement applies to all SVP's and PBP's used
in the preparation of TPN solutions, including, but not limited to:
Parenteral electrolyte solutions, such as calcium chloride, calcium
gluceptate, calcium gluconate, magnesium sulfate, potassium acetate,
potassium chloride, potassium phosphate, sodium acetate, sodium
lactate, and sodium phosphate; multiple electrolyte additive solutions;
parenteral multivitamin solutions; single-entity parenteral vitamin
solutions, such as vitamin K injection, folic acid, cyanocobalamin, and
thiamine; and trace mineral solutions, such as chromium, copper, iron,
manganese, selenium, and zinc.
New Sec. 201.323(d) requires the package insert for all LVP's,
SVP's, and PBP's used in TPN to contain a warning statement. The
warning statement must be included in the ``Warnings'' section of the
labeling. The warning must contain the following language:

[[Page 4105]]

WARNING: This product contains aluminum that may be toxic.
Aluminum may reach toxic levels with prolonged parenteral
administration if kidney function is impaired. Premature neonates
are particularly at risk because their kidneys are immature, and
they require large amounts of calcium and phosphate solutions, which
contain aluminum.
Research indicates that patients with impaired kidney function,
including premature neonates, who receive parenteral levels of
aluminum at greater than 4 to 5 g/kg/day accumulate
aluminum at levels associated with central nervous system and bone
toxicity. Tissue loading may occur at even lower rates of
administration.

FDA removed the phrase ``intended for patients with impaired kidney
function and for neonates receiving TPN therapy'' from the first
sentence of Sec. 201.323(d) because the phrase duplicated information
contained in the actual warning and because the phrase made the first
sentence of Sec. 201.323(d) unclear.
New Sec. 201.323(e) requires applicants and manufacturers to use
validated assay methods to determine the aluminum content in parenteral
drug products used in TPN therapy. The assay methods must comply with
current good manufacturing practice regulations under part 211 (21 CFR
part 211) (see Sec. 211.194(a)). Holders of approved applications for
LVP's, SVP's, and PBP's used in TPN therapy are required to submit a
supplement to FDA under Sec. 314.70(c) (21 CFR 314.70(c); see also 21
U.S.C. 356a(b)) describing the assay method used for determining the
aluminum content. Applicants must submit the validation method used and
the release data for several batches. In addition, manufacturers of
parenteral drug products not subject to an approved application must
make assay methodology available to FDA during inspections (see 21 CFR
211.160 and 211.180(c)).
New Sec. 201.323 applies to all human drug LVP's, SVP's, and PBP's
used in TPN. Licensed biological products are not covered by this rule.

III. Comments on the Proposed Rule

FDA received 21 comments on the proposed rule from professional
associations, prescription drug manufacturers, Congress, individuals on
TPN, and a hospital. Most comments supported the proposed limit for
aluminum content in LVP's and the labeling requirement for SVP's and
PBP's. Four comments suggested changes to the proposed warning
statement. A summary of the comments received and the agency's
responses follow.

A. Levels of Aluminum Content in LVP's

The agency stated in the proposed rule that it was considering
setting an upper limit of 25 g/L for LVP's used in TPN
therapy. This requirement would apply to all LVP's used in TPN therapy,
including, but not limited to, parenteral amino acid solutions, highly
concentrated dextrose solutions, parenteral lipid emulsions, saline and
electrolyte solutions, and sterile water for injection. The agency also
proposed that the package insert for all LVP's used in TPN therapy
state that the drug product contains no more than 25 g/L.
1. Fifteen comments strongly supported a limit on aluminum of 25
g/L. Two of the comments specifically supported the
accompanying proposal that the package insert state that the drug
product contains no more than 25 g/L of aluminum.
FDA agrees that 25 g/L of aluminum is a reasonable limit.
As stated in the proposed rule, the 25 g/L limit is feasible
and necessary for the safe and effective use of LVP's used in TPN
therapy.
Two comments, one from an LVP manufacturer and the other from a
trade association, stated that 25 g/L is not a reasonable
limit for the varying reasons outlined in comments 2 through 8, in
section III. A of this document.
2. These comments stated that data from production batches show
potential rejections of finished batches at release if a limit of 25
g/L is adopted. One of these comments specified that more than
10 percent of assay results exceed the proposed limit. It also stated
that their current batch analysis showed a 95 percent confidence that
at least 99 percent of the batch contained less than 50.37 g/L
of aluminum at release.
FDA understands that not all current batches of LVP's will meet a
25 g/L level of aluminum. FDA will implement this rule 1 year
after the date of publication to allow companies an opportunity to meet
the specifications in this rule. FDA is not adopting a higher level
because FDA believes a 25 g/L level of aluminum is necessary
to protect the public health.
3. The same two comments said that glass leaching over time
increases aluminum levels so that initial levels cannot be established
low enough to ensure batch acceptability by the end of the expiry
period.
The intention of this rule is to reduce aluminum to an acceptable
level in TPN products. A manufacturer can reduce toxicity by any of
several routes, including using containers made of different materials.
4. One of these comments requested that FDA set the maximum level
of aluminum using the procedure specified in the draft guidance
entitled ``Q6A Specifications: Test Procedures and Acceptance Criteria
for New Drug Substances and New Drug Products: Chemical Substances''
(draft Q6A guidance) (62 FR 62890). This draft guidance states that a
limit on impurities can be determined by (1) Determining the level at
which the impurity is present in relevant batches and then (2)
determining the mean plus upper confidence limit for the impurity where
the upper confidence limit is three times the standard deviation of
batch analysis data.
FDA is not using the procedures specified in the draft Q6A guidance
because it is not appropriate to use current product aluminum levels to
determine upper limits when the goal is to reduce aluminum levels to at
or below the limit defined as safe. Further, the guidances entitled
``Q3A: Impurities in New Drug Substances,'' (January 1996) and ``Q3B
Impurities in New Drug Products,'' (November 1997) address the issue of
quantification of impurities. These guidances state that limits should
be set no higher than the level that can be justified by safety data.
The guidances also state that, for impurities known to be unusually
potent or to produce toxic or unexpected pharmacological effects, the
quantitation and detection limit of the analytical methods should be
commensurate with the level at which the impurities must be controlled.
FDA's primary concern in enacting this rule is ensuring the safety of
the patient population and limiting exposure to the impurity. FDA has
determined that the 25 g/L limit is necessary for the safe and
effective use of LVP's in TPN therapy.
5. These comments also stated that current assay methods cannot
reliably distinguish between 25 g/L and 30 g/L. The
comment did not provide supporting data or evaluation of the specific
methods claimed to lack the required accuracy.
FDA understands that methods are currently available that are
capable of detecting aluminum concentrations at 25 g/L levels.
In particular, FDA is aware that graphite furnace atomic absorption
spectrometometry can be a sufficiently accurate validation method.
However, FDA will accept any validated analytical method to assay
aluminum content in TPN.
6. One of these comments suggested that FDA should require labeling
of LVP's with an average and a range of aluminum values at expiry,
obtained from five production scale batches, instead of requiring a
limit of 25 g/L

[[Page 4106]]

of aluminum in LVP's. The labeling would state ``Approximate average
aluminum value-- g/L. Approximate aluminum range ----
g/L to -- g/L.'' The same comment requested that FDA
apply the same labeling standards to LVP's, SVP's, and PBP's, under the
rationale that some LVP's are identical in composition to PBP's.
FDA notes that if a manufacturer makes a PBP specifically for LVP
use, the PBP should not contain more than 25 g/L of aluminum
so that the LVP manufactured from the PBP does not contain more than 25
g/L of aluminum. FDA is implementing the 25 g/L limit
for LVP's rather than permitting an average or a range of aluminum
levels to be stated for LVP's because the agency believes that it is
more appropriate to set a maximum level due to the large volume of use
of these products. FDA has determined that the 25 g/L limit is
necessary for the safe and effective use of LVP's used in TPN therapy.
FDA's basis for not requiring SVP's and PBP's to be labeled with an
average and a range of aluminum levels is discussed in response to
comment 11 in section III. B of this document.
7. This same comment stated that establishing a 25 g/L
limit on LVP's would not have the desired effect of reducing aluminum
levels in TPN because the majority of aluminum contamination is due to
SVP's, not LVP's. A different comment requested that FDA narrow
coverage of the rule to only those products that contribute significant
amounts of aluminum to TPN: Calcium gluconate, calcium gluceptate,
potassium phosphates, and sodium phosphates. The comment stated that
calcium gluconate alone can contribute 88 percent of the total aluminum
present in a TPN formulation.
FDA recognizes that numerous factors contribute to aluminum
contamination in TPN therapy. Therefore, FDA is addressing the problem
in several different ways in an effort to reduce aluminum
contamination, rather than reducing aluminum from one source.
8. Another comment noted that the United States Pharmacopeia (USP)
has limited aluminum levels in monographs for substances used in
hemodialysis, including: Calcium acetate, calcium chloride, magnesium
chloride, potassium chloride, sodium acetate, sodium bicarbonate, and
sodium chloride. The comment stated that additional steps could be
taken to limit aluminum levels in monographs of substances used in the
manufacture of TPN solutions. Although FDA believes USP's limits add a
valuable contribution to limiting aluminum contamination, FDA believes
the additional measures set forth in this final rule are needed to
prevent an unsafe level of aluminum in TPN.

B. Aluminum Levels in SVP's and PBP's

In the proposed rule, FDA proposed requiring that the maximum level
of aluminum at expiry be stated on the immediate container label of
SVP's and PBP's used in the preparation of TPN solutions. FDA proposed
that the statement on the immediate container label read as follows:
``Contains no more than ---- g/L of aluminum.'' For those
SVP's and PBP's that are lyophilized powders used in the preparation of
TPN solutions, FDA proposed that the maximum level of aluminum at
expiry be printed on the immediate container label as follows: ``When
reconstituted in accordance with the package insert instructions, the
concentration of aluminum will be no more than---- g/L.'' FDA
proposed that the maximum level of aluminum must be expressed as the
highest of: (1) The highest level for the batches produced during the
last 3 years; (2) the highest level for the latest five batches; or (3)
the maximum historical level, but only until completion of production
of the first five batches after the rule takes effect.
9. Two comments supported FDA's proposal. One comment requested
that FDA further specify limitations on aluminum content for SVP's.
FDA plans to implement the labeling requirements for SVP's and
PBP's as proposed. FDA does not consider it appropriate to consider
SVP's as a single category because SVP's are used for many indications
other than TPN and in target populations where aluminum toxicity is not
an issue.
10. One comment asked that FDA set a minimum level below which the
amount of aluminum would not need to be declared.
FDA believes it is important for health care practitioners to know
as much as possible about the aluminum levels being consumed by their
patients. FDA believes the knowledge that a product has a low level of
aluminum is just as important as the knowledge that a product contains
high levels of aluminum. This labeling requirement permits health care
professionals administering the drug to be able to calculate the total
aluminum exposure the patient receives from multiple sources, and to be
able to make appropriate substitutions to prepare ``low aluminum''
parenteral solutions for use in patients who are in high risk groups.
Therefore, FDA believes all LVP's, SVP's, and PBP's used in TPN should
be labeled with their aluminum levels.
11. One comment stated that information about the average amount of
aluminum and its range at expiration for LVP's and SVP's is more useful
than the maximum historical value at expiration, since otherwise a
physician may overestimate the amount of aluminum being delivered to
the patient. Another comment proposed that FDA require labeling of
SVP's and PBP's with an average and a range of aluminum values at
expiry, obtained from five production scale batches, such that the
labeling would state ``Approximate average aluminum value ----
g/L. Approximate aluminum range ---- g/L to----
g/L.''
The agency believes that information about the maximum
concentration of aluminum potentially present at expiry is more useful
to the practitioner. FDA's intention is to limit exposure to aluminum,
and the use of average values or range at expiration would not achieve
this goal as effectively.

C. Applicability to Biologics

In the proposed rule, FDA stated that licensed biological products
were not covered by the proposal.
12. Twelve comments stated that biologics, specifically albumin,
plasminate, and any other colloidal volume expanders, should be
regulated. The Center for Biologics Evaluation and Research at the FDA
is currently considering whether to regulate the levels of aluminum in
licensed biological products. However, such regulation is outside the
scope of this final rule.

D. Statement Regarding Maximum Intake of Aluminum

FDA proposed requiring a statement regarding the maximum daily
aluminum intake recommended for patients. FDA sought comment on whether
adding the language ``Patients should receive no more than 4 to 5
g/kg/day of aluminum'' to the warning statement was
appropriate and on whether a 4 to 5 g/kilogram (kg)/day level
is reasonable and adequate to protect the public health.
13. Two comments stated that FDA should include definitions of
safe, unsafe, and toxic levels of aluminum. Three comments said that
FDA should provide health professionals with a best estimate as to what
constitutes a toxic aluminum load.
One comment stated that proposing to limit aluminum to 4 to 5
g/kg/day would either make TPN formulations unavailable to
neonates or expose doctors to liability, because it is a

[[Page 4107]]

difficult level to meet. Another comment said that 4 to 5 g/
kg/day is too low and may not allow patients to receive adequate
amounts of calcium and phosphates. One comment noted that parenteral
limits are much lower than oral limits, and expressed the belief that
the proposed language did not offer guidance with respect to combined
oral and parenteral daily limits. Another comment noted that the
proposal does not provide a therapeutic alternative to too high
aluminum levels, and asked that FDA include in the statement a
definition of the populations truly at risk.
One comment stated that it would be difficult for health care
professionals to calculate total aluminum intake, particularly for
neonates receiving multiple intravenous infusions. Another comment
stated that the factors that affect plasma aluminum clearance \1\ can
influence sensitivity to aluminum load \2\ at any concentration of
aluminum infused, and therefore aluminum concentration in TPN cannot be
correlated directly to aluminum plasma levels.
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\1\ The clearance rate for aluminum is the rate at which
aluminum is removed from the body by normal body functioning.
\2\ Aluminum load is the amount of aluminum in the body.
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Two comments recommended alternative statements. One suggested
using the following language: ``Daily parenteral intake of greater than
4 to 5 g/kg/day of aluminum has been associated with central
nervous system and bone toxicity.'' Another suggested using the
following warning: ``No aluminum toxicity to the brain or bone of
premature neonates has been documented with intakes below 5 g/
kg/day; however, tissue loading may still occur at that rate of
administration to preterm infants.''
One comment requested that FDA require such a warning statement
only for those SVP's for which aluminum is a significant problem.
Based on these comments, FDA revised the warning to include a
statement on current findings rather than a statement about maximum
safe levels. FDA included specific references in the proposed rule (63
FR 176).

E. Acceptable Assay Methods for Determining Aluminum Levels

FDA proposed permitting applicants and manufacturers to have the
discretion and flexibility to develop their own validated assay methods
as long as the methods are in compliance with current good
manufacturing practices requirements. Holders of approved applications
for LVP's, SVP's and PBP's used in TPN therapy would be required to
submit a supplement under part 314 (21 CFR part 314) in Sec. 314.70(c)
that described the method used for determining aluminum content.
Holders of pending applications would be required to submit an
amendment under Sec. 314.60 or Sec. 314.96. For SVP's not subject to
approved applications, manufacturers would be required to maintain
records for examination by FDA during inspections.
14. One comment stated that the USP provides an established system
and procedure for the development of uniform analytical methods. The
comment asked that FDA request that U.S.P. develop assay methods for
determining aluminum content in parenterals rather than requiring
individual companies to do so.
FDA believes that more than one analytical method may be suitable
or necessary to assay aluminum content in different TPN products. Once
FDA has reviewed several methods, it may evaluate whether it is
appropriate to develop uniform analytical procedures. Individual
companies may provide their validated analytical methods to USP for
publication. Through this process, USP may establish a uniform
analytical method for determining aluminum content in parenterals. FDA
will accept any method that is validated and in compliance with current
good manufacturing practice requirements.
15. One comment supported FDA's proposal. The comment also stated
that analytical methods should be those in general use, such as
flameless atomic absorption spectroscopy with a graphite furnace, and
the method should be sufficiently sensitive to detect aluminum at the
g/L and not the milligram (mg) per liter level.
Again, FDA will accept any method that is validated and in
compliance with current good manufacturing practice requirements. Any
analytical method must be sensitive enough to detect aluminum at the
g/L and not the mg/L level, because the aluminum limits for
LVP's and the required labeling statements for LVP's, SVP's, and PBP's
are measured in g/L.

F. Date of Implementation of the Final Rule

FDA proposed that any final rule that issued based on its proposed
rule would become effective 1 year after the final rule's date of
publication in the Federal Register. After that date, new drug
applications (NDA's) submitted under Sec. 314.50 and abbreviated new
drug applications (ANDA's) submitted under 21 CFR 314.94 would have to
comply with the new requirements under Sec. 201.323.
16. One comment proposed an implementation date of 4 years after
publication of the final rule in the Federal Register to account for
the time necessary to collect and analyze data. Another comment
suggested an implementation date of 31/2 years after publication of the
final rule, or whenever data from five batches of product became
available and the supplement was approved. This comment stated that the
additional time is necessary to collect aluminum levels at expiry by an
appropriate and validated method, since companies do not presently have
such data.
Under the final rule, a manufacturer may use: (1) The highest level
for the batches produced during the last 3 years; (2) the highest level
for the latest five batches, or (3) the maximum historical level, but
only until completion of production of the first five batches after
this rule takes effect. This means that if expiry data under (1) and
(2) of comment 16 in section III. F of this document are not available
within 1 year, data available for the product during that year can be
used under (3) of comment 16. As a manufacturer accrues additional
data, it can then also use methods (1) and/or (2) of comment 16.
17. One comment asked whether FDA expects supplements to be
submitted and approved and labeling changed within 1 year of
publication of the final rule, or simply for supplements to be
submitted within 1 year of publication of the final rule.
FDA expects supplements to be submitted and labeling to be changed
within 1 year of publication of this final rule. Under current
regulations (Sec. 314.70(c)) and the Food and Drug Administration
Modernization Act of 1997 (21 U.S.C. 356a(b)), a manufacturer can file
a changes being effected supplement for immediate implementation of
this change. Thus, FDA believes implementation should take place in 1
year.

G. Cost of Implementing the Rule

FDA estimated in the proposed rule that the annualized cost to
amino acid suppliers to implement the proposed rule would be
$1,416,622. This figure includes first year or one-time costs estimated
at $20 million.
18. One comment stated that wholesale raw material amino acids for
intravenous use is a fraction of the $109 million market cited by FDA,
and is actually much closer to $40 million. The comment went on to
state that this market is shrinking and will continue to

[[Page 4108]]

do so for the foreseeable future. The comment estimated that, in light
of these figures, the annual cost of compliance would represent 3
percent of sales, almost as much as the 4 percent spent by the industry
on research and development. Another comment stated that the proposed
rule underestimated the cost for compliance because validation without
USP guidance would be difficult and because the number of worker hours
required to test products is large.
FDA believes that the benefits of removing the health hazard
outweigh costs to industry. FDA provides additional economic analysis
based on these comments in section VII of this document.
19. The same comment stated that for LVP manufacturers, costs are
even higher. The comment stated that the Eastern Research Group (ERG)
study ``grossly underestimated the expense associated with label copy
changes, non-compliant raw materials, finished product, and did not
consider product recalls, which are inevitable, given the technically
unfeasible 25 g/L limit.''
FDA has reanalyzed these expenses in section VII of this document.

IV. Legal Authority

FDA's rule to regulate the aluminum content of certain parenteral
drug products and to require aluminum content to be stated in the
labeling of certain drug products is authorized by the Federal Food,
Drug, and Cosmetic Act (the act). Section 502(a) of the act (21 U.S.C.
352(a)) prohibits false or misleading labeling of drugs, including,
under section 201(n) of the act (21 U.S.C. 321(n)), failure to reveal
material facts relating to potential consequences under customary
conditions of use. Section 502(f) of the act requires drug labeling to
have adequate directions for use, adequate warnings against use by
patients where its use may be dangerous to health, as well as adequate
warnings against unsafe dosage or methods or duration of
administration, as necessary to protect users. In addition, section
502(j) of the act prohibits the use of drugs that are dangerous to
health when used in the manner suggested in their labeling. Drug
products that do not meet the requirements of section 502 of the act
are deemed to be misbranded.
In addition to the misbranding provisions, the premarket approval
provisions of the act authorize FDA to require that prescription drug
labeling provide the practitioner with adequate information to permit
safe and effective use of the drug product. Under section 505 of the
act (21 U.S.C. 355), FDA will approve a new drug application (NDA) only
if the drug is shown to be safe and effective for its intended use
under the conditions set forth in the drug's labeling. Section 701(a)
of the act (21 U.S.C. 371(a)) authorizes FDA to issue regulations for
the efficient enforcement of the act.
Part 201 sets out FDA's general labeling regulations. Under
Sec. 201.100(d), prescription drug products must bear labeling that
contains adequate information by which licensed practitioners can use
the drugs safely and for their intended purposes. Section 201.57
describes specific categories of information, including information for
drug use in selected subgroups of the general population and warnings
on adverse reactions and potential safety hazards that must be present
to meet the requirements of Sec. 201.100. In addition, under 21 CFR
314.125, an NDA will not be approved unless there is adequate safety
and effectiveness information for the labeled uses and the product
complies with the requirements of part 201.
Any drug product not in compliance with Sec. 201.323 is misbranded
under section 502 of the act and an unapproved new drug under section
505 of the act.

V. Environmental Impact

The agency has determined under 21 CFR 25.30(h) that this action is
of a class of actions that do not individually or cumulatively have a
significant effect on the human environment. Therefore, neither an
environmental assessment nor an environmental impact statement is
required.

VI. Implementation Plan

This final rule is effective on January 26, 2001. After that date,
NDA's submitted under Sec. 314.50 and abbreviated new drug applications
(ANDA's) submitted under Sec. 314.94 must comply with the labeling
requirements under Sec. 201.323. Holders of approved NDA's or ANDA's
must meet the requirements of proposed Sec. 201.323 by submitting
supplements under Sec. 314.70 or Sec. 314.97. Applicants for LVP's used
in TPN therapy and SVP's used as additives in TPN solutions are
required to submit a supplement under Sec. 314.70(c) that describes the
assay method for determining the aluminum content. Applicants must
submit validation of the method used and release data for several
batches. Manufacturers of parenteral drug products not subject to an
approved application must make assay methodology available to FDA
during inspections. Holders of pending applications must submit an
amendment under Sec. 314.60 or Sec. 314.96.

VII. Analysis of Impacts

A. Introduction

FDA has examined the impact of the final rule under Executive Order
12866, under the Regulatory Flexibility Act (5 U.S.C. 601-612), and
under the Unfunded Mandates Reform Act (Pub. L. 104-4). Executive Order
12866 directs agencies to assess all costs and benefits of available
regulatory alternatives and, when regulation is necessary, to select
regulatory approaches that maximize net benefits (including potential
economic, environmental, public health and safety, and other
advantages, distributive impacts and equity). The Regulatory
Flexibility Act requires agencies to examine regulatory alternatives
for small entities, if the rule may have a significant impact on a
substantial number of small entities. The Unfunded Mandates Reform Act
requires agencies to prepare an assessment of anticipated costs and
benefits before enacting any rule that may result in an expenditure in
any one year by State, local and tribal governments, in the aggregate,
or by the private sector, of $100,000,000 (adjusted annually for
inflation). The expected aggregate costs of this final rule, and the
anticipated impact of the rule on small entities, are described in the
analysis below. FDA concludes that this final rule is consistent with
the regulatory philosophy and the principles set forth in the Executive
Order and in these two statutes.

B. Compliance Requirements and Costs

In this final rule, FDA is amending its regulations by establishing
a maximum permissible aluminum limit for LVP's used in TPN, as well as
requiring certain label and package insert information for aluminum
content in LVP's and SVP's used in TPN. The agency is issuing this rule
to lower the risk of aluminum toxicity in light of evidence linking the
use of parenteral drugs containing aluminum to morbidity and mortality
among patients on TPN therapy. FDA estimates total annualized
compliance costs for the final rule at about $23.8 million. Further,
for reasons explained elsewhere in this section of the document, the
agency certifies that this rule will not have a significant economic
impact on a substantial number of small entities. FDA has not
identified any other Federal rules that duplicate, overlap, or conflict
with this final rule.
In the preamble to the proposed rule, FDA relied on the report of
its

[[Page 4109]]

contractor, ERG, for its estimates of compliance cost burdens of the
proposed rule. Total annualized compliance costs were estimated at
$20.1 million. This was composed of a one time cost of $63.8 million
annualized at $9.8 million (over 10 years at a 7 percent discount rate)
plus recurring annual costs of $10.3 million. Over 50 percent of the
total costs would be due to actions undertaken to manufacture LVP
solutions and their components that would comply with the aluminum
limit requirements.
In response to the proposed rule, FDA received many comments, some
of which referred to the cost estimates contained in the ERG report. As
a result of these comments, ERG reanalyzed areas of concern specified
in the comments and made some modifications to its original analysis of
compliance costs. These changes are included in an addendum to the
initial compliance cost analysis (available in the docket). As a
result, FDA concludes that the final rule will impose annualized
compliance costs of about $23.8 million on the affected industries, an
increase of $3.7 million from its cost estimate for the proposed rule.
This is composed of a one time cost of $67.3 million annualized at
$10.6 million (over 10 years at a 7 percent discount rate) plus
recurring annual costs of $13.2 million. The remainder of this section
summarizes the addendum and responds to other comments concerning
economic issues mentioned earlier in this preamble.
One comment to the proposal stated that FDA had underestimated the
costs of label copy changes, noncompliant raw materials, finished
product, and product recalls. As a result, ERG contacted industry to
gain more information and data, where possible, to improve the accuracy
of these estimates. ERG's new research into pharmaceutical labeling
costs shows that compliance costs for the label changes, including
inventory losses occurring at the changeover, are higher for this rule
than previously estimated. Accordingly, FDA has increased its labeling
change estimate to about $588,000 annually.
The original ERG report estimated compliance costs for final
release testing for aluminum in finished LVP products and their raw
material inputs at about $4.5 million annually. After subsequent
discussions with industry, ERG recognized that some LVP production lots
will fail to meet the required aluminum limit, but noted that this loss
of finished product will be reduced by measures to lower the aluminum
level of the raw material inputs. Similarly, ERG found that the cost of
product recalls will be low due to the final release testing of LVP
products, but it could not predict the likely frequency of such
recalls.
The same comment also suggested that dextrose suppliers would incur
compliance costs because some dextrose products contain aluminum at a
level that might exceed the proposed limit. Upon further consideration
of the possible existence of noncompliant raw materials, including
dextrose and amino acids, and discussions between industry and ERG, FDA
adjusted its original cost estimate to include an additional $2.72
million annually due to losses from noncompliant raw materials.
Another comment stated that FDA had underestimated laboratory assay
method validation costs. Following ERG's review of its original
analysis and further discussions with industry, FDA agrees with the
comment as it relates to LVP manufacturers and has increased one-time
assay method validation costs for this sector from $737,000 to $2.1
million. Further research into current compliance rates across all
industry sectors, however, resulted in lowering assay method validation
costs for some other sectors. The net result is a slight increase in
total annualized assay method validation costs to about $1.72 million.
Further, the estimate of annualized equipment purchase costs has been
increased by $350,000.
Another comment referred to a statistic FDA used to show the
relative size of the expected cost impact on amino acid suppliers.
Specifically, the comment disagreed with the FDA statement that annual
compliance costs for raw material amino acid suppliers would represent
only 0.09 percent of sales, having been derived from $1.4 million in
compliance costs and $1.6 billion in total amino acid sales. The
comment proceeded with its own estimate of the relative size of the
compliance cost for these suppliers, calculating it to be 3 1/2 percent
of the $40 million in amino acid sales to TPN solution manufacturers, a
level roughly equivalent to total research and development costs. Upon
further analysis, FDA reaffirms its estimate of the average annual
compliance cost per amino acid manufacturing establishment of about
$1.4 million. However, because there are approximately nine supplier
establishments, the total cost would be about $12.75 million, which
equates to an even greater percentage of total sales of amino acids to
TPN solution manufacturers, about 32 percent, than the comment
suggested. The costs, nevertheless, amount to only about 0.09 percent
of the total $1.6 billion in sales of amino acids to all industries as
stated in the proposal.
As in its original analysis, ERG discussed but could not reliably
forecast the likelihood that some suppliers of amino acids and possibly
dextrose would abandon the TPN solution market, due to the relatively
small percentage of total amino acid and dextrose sales to TPN
manufacturers. Because the industry currently uses nine different
suppliers, FDA does not anticipate product shortages. Nevertheless, the
agency will remain alert to the possibility.
Any professional skills necessary for implementation of this final
rule should already exist within the firms and should not need to be
newly acquired.

C. Affected Entities

If a rule has a significant impact on a substantial number of small
entities, the Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize the significant economic impact
of such a rule on small entities. In the proposed rule, FDA relied on
the estimated compliance costs by type of establishment as projected by
ERG. That analysis determined that very few of the affected companies
are considered small by the standards of the Small Business
Administration (SBA).\3\ Therefore, the agency certified that the
proposed rule would not have a significant economic impact on a
substantial number of small entities.
---------------------------------------------------------------------------

\3\ SBA considers a small business in this context to be one
with fewer than 750 employees (Ref. 2).
---------------------------------------------------------------------------

The agency received no comments specifically directed at this
certification. Nevertheless, due to comments on other aspects of its
estimates and modifications to the original analysis, FDA has
reanalyzed the small business impacts of the final rule.
Fewer than 8 of the 24 companies identified in the ERG report as a
manufacturer or supplier of TPN products or their inputs are small
businesses according to the SBA definitions. No more than four SVP
manufacturers are small under the SBA definitions. Moreover, since the
average annualized cost for these establishments is estimated at about
$51,000 each, the estimated annualized compliance costs for these
companies are expected to account for less than one percent of their
annual revenues. FDA further identified one amino acid supplier that
may be a small business; but again, the annualized compliance costs for
this firm would be less than 1 percent of annual revenues. The size of
one dextrose supplier and one electrolyte

[[Page 4110]]

supplier could not be confidently determined due to the scarcity of
data. Therefore, it was not possible to determine whether the
compliance costs of these firms would represent more than 1 percent of
their revenues. Based on the very few small firms that might incur a
significant impact, the Commissioner of Food and Drugs certifies under
section 605(b) of the Regulatory Flexibility Act that the final rule
will not have a significant economic impact on a substantial number of
small entities. Therefore, under the Regulatory Flexibility Act, no
further analysis is required.

D. Unfunded Mandates Reform Act

The Unfunded Mandates Reform Act requires (in section 202) that
agencies prepare an assessment of anticipated costs and benefits before
establishing any rule that requires expenditures by State, local, and
tribal governments, in the aggregate, or by the private sector of $100
million (adjusted annually for inflation, or about $108 million in
1999) in any one year. The publication of this final rule concerning
the regulation of TPN containing aluminum is not expected to result in
expenditures of funds by State, local, or tribal governments, or the
private sector in excess of $100 million annually. Because the agency
estimates the largest 1-year expenditure to be about $80.5 million
(representing the sum of one-time expenditures and annual
expenditures), no further analysis is warranted according to the
Unfunded Mandates Reform Act.

VIII. Paperwork Reduction Act of 1995

This final rule contains information collection provisions that are
subject to review by the Office of Management and Budget (OMB) under
the Paperwork Reduction Act of 1995 (44 U.S.C. 3501-3520). A
description of these provisions is given below with an estimate of the
annual reporting burden. Included in this estimate is the time for
reviewing instructions, searching existing data sources, gathering and
maintaining the data needed, and completing and reviewing each
collection of information.
Title: Aluminum in Large and Small Volume Parenterals Used in Total
Parenteral Nutrition.
Description: FDA is amending its regulations to add certain
labeling requirements for aluminum content in LVP's, SVP's and PBP's
used in TPN. FDA is also specifying an upper limit of aluminum
permitted in LVP's and requiring manufacturers to submit to FDA for
approval validated assay methods for determining aluminum content in
parenteral drug products. The agency is adding these requirements
because of evidence linking the use of parenteral drug products
containing aluminum to morbidity and mortality among patients on TPN
therapy, especially premature neonates and patients with impaired
kidney function.
Based on data concerning the number of applications for LVP's,
SVP's, and PBP's used in TPN received by the agency, FDA estimates that
the labeling for approximately 200 products will be changed under
Sec. 201.323(b), (c), and (d). FDA estimates that it will take
approximately 14 hours to prepare and submit to FDA each labeling
change. Based on data collected by the Eastern Research Group (Ref. 1)
concerning the number of affected manufacturers, FDA estimates that
approximately 65 respondents will each submit one validated assay
method annually under Sec. 201.323(e). FDA estimates that it will take
approximately 14 hours to prepare and submit to FDA each validated
assay.
Description of Respondents: Persons and businesses, including small
businesses and manufacturers.

Table 1.--Estimated Annual Reporting Burden \1\
----------------------------------------------------------------------------------------------------------------
Annual
21 CFR Section No. of frequency per Total annual Hours per Total hours
respondents response responses response
----------------------------------------------------------------------------------------------------------------
201.323(b), (c), (d) 200 1 200 14 2,800
201.323(e) 65 1 65 14 910
Total 3,710
----------------------------------------------------------------------------------------------------------------
\1\ There are no capital costs or operating and maintenance costs associated with this collection of
information.

FDA did not receive any comments on the paperwork reduction aspects
of the proposed rule.
The information collection provisions of this final rule have been
submitted to OMB for review.
Before this rule becomes effective, FDA will publish a notice in
the Federal Register announcing OMB's decision to approve, modify, or
disapprove the information collection provisions in this final rule. An
agency may not conduct or sponsor, and a person is not required to
respond to, a collection of information unless the information
collection displays a current OMB control number.

IX. Federalism

FDA has analyzed this final rule in accordance with the principles
set forth in Executive Order 13132. FDA has determined that the rule
does not contain policies that have federalism implications as defined
in the order and, consequently, a Federalism summary impact statement
is not required.

X. References

The following references have been placed on display in the Dockets
Management Branch (address above) and may be seen by interested persons
between 9 a.m. and 4 p.m., Monday through Friday.
1. Eastern Research Group, Addendum to Compliance Cost Analysis for
a Regulation for Parenteral Drug Products Containing Aluminum, April
15, 1999.
2. U.S. Small Business Administration, Table of Size Standards,
1996.

List of Subjects in 21 CFR Part 201

Drugs, Labeling, Reporting and recordkeeping requirements.

Therefore, under the Federal Food, Drug, and Cosmetic Act, the
Public Health Service Act, and under authority delegated to the
Commissioner of Food and Drugs, 21 CFR part 201 is amended as follows:

PART 201--LABELING

1. The authority citation for 21 CFR part 201 continues to read as
follows:

Authority: 21 U.S.C. 321, 331, 351, 352, 353, 355, 358, 360,
360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 262, 264.

2. Section 201.323 is added to subpart G to read as follows:

Sec. 201.323 Aluminum in large and small volume parenterals used in
total parenteral nutrition.

(a) The aluminum content of large volume parenteral (LVP) drug
products used in total parenteral nutrition (TPN)

[[Page 4111]]

therapy must not exceed 25 micrograms per liter (g/L).
(b) The package insert of LVP's used in TPN therapy must state that
the drug product contains no more than 25 g/L of aluminum.
This information must be contained in the ``Precautions'' section of
the labeling of all large volume parenterals used in TPN therapy.
(c) The maximum level of aluminum present at expiry must be stated
on the immediate container label of all small volume parenteral (SVP)
drug products and pharmacy bulk packages (PBP's) used in the
preparation of TPN solutions. The aluminum content must be stated as
follows: ``Contains no more than---- g/L of aluminum.'' The
immediate container label of all SVP's and PBP's that are lyophilized
powders used in the preparation of TPN solutions must contain the
following statement: ``When reconstituted in accordance with the
package insert instructions, the concentration of aluminum will be no
more than ---- g/L.'' This maximum level of aluminum must be
stated as the highest of:
(1) The highest level for the batches produced during the last 3
years;
(2) The highest level for the latest five batches, or
(3) The maximum historical level, but only until completion of
production of the first five batches after January 26, 2001.
(d) The package insert for all LVP's, all SVP's, and PBP's used in
TPN must contain a warning statement. This warning must be contained in
the ``Warnings'' section of the labeling. The warning must state:

(e) Applicants and manufacturers must use validated assay methods
to determine the aluminum content in parenteral drug products. The
assay methods must comply with current good manufacturing practice
requirements. Applicants must submit to the Food and Drug
Administration validation of the method used and release data for
several batches. Manufacturers of parenteral drug products not subject
to an approved application must make assay methodology available to FDA
during inspections. Holders of pending applications must submit an
amendment under Sec. 314.60 or Sec. 314.96 of this chapter.

Dated: December 29, 1999.
Margaret M. Dotzel,
Acting Associate Commissioner for Policy.
[FR Doc. 00-1788 Filed 1-25-00; 8:45 am]
BILLING CODE 4160-01-F