[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:

    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.

    (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