[Federal Register Volume 63, Number 2 (Monday, January 5, 1998)]
[Proposed Rules]
[Pages 176-185]
From the Federal Register Online via the Government Publishing Office [www.gpo.gov]
[FR Doc No: 98-76]


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DEPARTMENT OF HEALTH AND HUMAN SERVICES

Food and Drug Administration

21 CFR Part 201

[Docket No. 90N-0056]


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

AGENCY: Food and Drug Administration, HHS.

ACTION: Proposed rule.

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SUMMARY: The Food and Drug Administration (FDA) is proposing to amend 
its regulations to add certain labeling requirements concerning 
aluminum in large volume parenterals (LVP's) and small volume 
parenterals (SVP's) used in total parenteral nutrition (TPN). FDA is 
also proposing to specify an upper limit of aluminum permitted in LVP's 
and to require applicants to develop and to submit to FDA for approval 
validated assay methods for determining aluminum content in parenteral 
drug products. The agency is proposing 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 infants and patients with impaired kidney 
function.

DATES: Submit written comments by April 6, 1998. Submit written 
comments on the information collection requirements by February 4, 
1998.
ADDRESSES: Submit written comments on this proposed rule to the Dockets 
Management Branch (HFA-305), Food and Drug Administration, 12420 
Parklawn Dr., rm. 1-23, Rockville, MD 20857. Submit written comments on 
the information collection requirements to the Office of Information 
and Regulatory Affairs, Office of Management and Budget (OMB), New 
Executive Office Bldg., 725 17th St. NW., rm. 10235, Washington, DC 
20503, ATTN: Desk Officer for FDA.

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

     Aluminum in ionic form is naturally present in all plant and 
animal tissues and in natural bodies of water, although it has no known 
biological function. Human exposure to aluminum also occurs through 
aluminum-containing medications, aluminum cans and cooking utensils, 
drinking water, baking powder, and deodorants (Ref. 1). Aluminum is 
found in public water supplies treated with various clarifiers and in 
food and drink, including infant formulas (Refs. 2, 3, and 4).
     Aluminum is commonly found in dye lakes (coloring agents) and 
sometimes found as an excipient in certain drug products. It is usually 
found in parenteral drugs as a contaminant in the protein source, 
calcium and phosphate salts, albumin, and heparin (Refs. 5 and 6). 
Aluminum also leaches from glass containers and closures during 
autoclaving and storage.
     Changes in the processing and screening of raw materials may 
reduce aluminum contamination of drug products. Aluminum toxicity in 
adults has been reduced by replacing casein hydrolysate with 
crystalline amino acids in TPN solutions (Ref. 7). In addition, the use 
of deionized water in dialysis and the substitution of calcium for 
aluminum-containing oral phosphate binders have reduced dialysis 
osteomalacia and encephalopathy.
     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. 
Research indicates that neonates and patient populations with impaired 
kidney function may be at high risk of exposure to unsafe amounts of 
aluminum (Refs. 2, 5, 6, and 8 through 13). Studies show that aluminum 
may accumulate in the bone, urine, and plasma of infants receiving TPN 
(Refs. 5, 8, and 9). Many drug products used routinely in parenteral 
therapy 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 is 
deposited in human tissues (Refs. 1, 3, 14, and 15).
     Aluminum toxicity is difficult to identify in infants because few 
reliable techniques are available to evaluate bone metabolism in 
premature infants. Techniques used to evaluate the effects of aluminum 
on bone in adults cannot be used in premature infants. 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. One study indicated that premature 
infants who received parenteral therapy had higher than normal plasma 
and urinary aluminum concentrations. The study also indicated that 
aluminum concentration in bone marrow was 10 times higher in infants 
who had received at least 3 weeks of parenteral therapy than in those 
who had received limited parenteral therapy: 20.1613.4 
milligrams (mg) versus 1.981.44 mg per kilogram (kg) of dry 
weight (p < 0.0001) (Ref. 2). Furthermore, there has been at least one 
credible report of measurable aluminum in the brain of a premature 
infant (Ref. 16).
     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 infants receiving TPN therapy (Ref. 9). 
In addition, aluminum loading may be a

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factor in the bone disease of very ill neonates with reduced kidney 
function who have received long-term parenteral therapy with aluminum-
contaminated fluids (Ref. 2).
     FDA has held several meetings to discuss the risks posed by 
aluminum in parenteral drug products. On March 3, 1986, the agency's 
Advisory Committee on Endocrinologic and Metabolic Drug Products met to 
discuss the problems posed by aluminum in parenteral drug products 
(Ref. 22). The committee recommended that parenteral drug products 
intended for repeated use or given in large volumes over a short period 
of time be tested for aluminum levels. The committee also recommended 
that the agency establish an aluminum-contamination limit. On November 
6, 1986, the agency held a public workshop to discuss aluminum toxicity 
in clinical medicine, existing aluminum monitoring, clinical effects of 
aluminum loading, and methodology for quantitative aluminum 
determination in parenteral products (Ref. 23). On June 25 and 26, 
1987, the Allergenic Products Advisory Committee of FDA's Center for 
Biologics Evaluation and Research met to discuss the safety of the 
aluminum component of alum-precipitated allergenic extracts (Ref. 24).
     As a result of the comments received at these meetings and because 
of the overall concern about the risks posed by aluminum content in 
parenteral drug products, FDA published a notice of intent in the 
Federal Register of May 21, 1990 (55 FR 20799). The notice announced 
the regulatory options the agency is considering and requested comments 
and data on the following issues: (l) Safe and unsafe levels of 
aluminum in LVP's, SVP's, and pharmacy bulk packages; (2) assay 
methodology; (3) units of measurement; (4) which drug products should 
be included in any aluminum content disclosure requirement; (5) 
suggestions for any warning statement required on parenteral drug 
product labeling; and (6) information concerning the economic effects 
of these regulatory options. The comments received on the notice of 
intent are discussed in section III of this document.

II. Description of the Proposed Rule

     FDA is proposing 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 pharmacy bulk packages used in the 
preparation of TPN solutions; (4) require that the package insert of 
all LVP's and SVP's, including pharmacy bulk packages, 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 and that 
applicants submit the validated assay methods to FDA for approval.
     Proposed Sec. 201.323(a) would limit the aluminum content for all 
LVP's used in TPN therapy to 25 micrograms per liter (g/L) for 
liquids. 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.\1\
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    \1\ The agency has determined that most currently marketed LVP 
drug products contain less than 25 g/L of aluminum (Ref. 
17). Although aluminum content varied widely among different 
components and the same chemicals could have a different aluminum 
content depending on the manufacturer, lot to lot similarity for a 
specific chemical from a given supplier was found. LVP and SVP 
products from several manufacturers were tested. All LVP's tested, 
except one product, were less than 25 g/L. FDA also bases 
this level on a considerable amount of stability data submitted to 
the agency over several years for LVP drug products.
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     Proposed Sec. 201.323(b) would require that the package insert for 
all LVP's used in TPN therapy state that the drug product contains no 
more than 25 g/L. This statement would be included in the 
``Precautions'' section of the labeling.
     For SVP's and pharmacy bulk packages used in the preparation of 
TPN solutions, proposed Sec. 201.323(c) would require that the 
product's maximum level of aluminum at expiry be stated on the 
immediate container label of the SVP's and pharmacy bulk packages. FDA 
is proposing that the statement on the immediate container label read 
as follows: ``Contains no more than __ g/L.'' For those SVP's 
and pharmacy bulk packages 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 may 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. The labeling requirement 
would apply to all SVP'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.
     Proposed Sec. 201.323(d) would require that the package insert for 
all LVP's and SVP's, including pharmacy bulk packages, contain a 
warning statement about aluminum toxicity in patients with impaired 
kidney function and in neonates receiving TPN therapy. The warning 
statement would be included in the warning section of the labeling and 
would contain the following language:
     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.
    FDA is also concerned about the daily amount of aluminum received 
by patients with impaired kidney function. One study found that 
patients should not receive more than 4 to 5 g/kg/day of 
aluminum (Ref. 20). FDA is considering whether to include in the 
previous warning a statement regarding the maximum daily aluminum 
intake recommended for patients. FDA believes such a recommendation 
would assist health care professionals in determining whether patients 
are receiving toxic levels of aluminum. For example, a health care 
professional administering per day 150 mL of an LVP solution containing 
25 g/L of aluminum to a patient also receiving 20 mL of drug A 
containing 2 g/L of aluminum, 2 mL of drug B containing 100 
g/L of aluminum, and 10 mL of drug C containing 400 
g/L of aluminum, would be able to determine that the patient 
was receiving a total of 7.99 g/day of aluminum (calculated 
(0.150 x 25) + (0.020 x 2) + (0.002 x 100) + (0.010 x 400)). The health 
care professional could then calculate the patient's intake level based 
on the patient's weight. If the patient weighed 2 kg, the patient would 
be receiving

[[Page 178]]

approximately 4 g/kg/day of aluminum (calculated 7.99 
g/2 kg).
    FDA is specifically seeking comment on whether adding the language 
``Patients should receive no more thatn 4 to 5 g/kg/day of 
aluminum'' to the warning statement is appropriate. In addition, FDA is 
seeking comment on whether a 4 to 5 g/kg/day level is 
reasonable and whether the proposed level is adequate to protect the 
public health.
     Proposed Sec. 201.323(e) would require that applicants and 
manufacturers develop validated assay methods to determine the aluminum 
content in parenteral drug products. The assay methods would be 
required to comply with current good manufacturing practice (CGMP) 
regulations under part 211 (21 CFR part 211) (see Sec. 211.194(a)). 
Holders of approved applications for LVP's used in TPN therapy and 
SVP's used as additives in TPN solutions would be required to submit a 
supplement to FDA under Sec. 314.70(c) (21 CFR 314.70(c)) describing 
the assay method used for determining the aluminum content. Under the 
proposed rule, applicants would submit the validation method used and 
the release data for several batches. Manufacturers of parenteral drug 
products not subject to an approved application would be expected to 
make assay methodology available to FDA during inspections.
     Proposed Sec. 201.323 would apply to all human drug LVP's, SVP's, 
and pharmacy bulk packages used in TPN. Licensed biological products 
are not covered by the proposal.
     FDA is also considering codifying the language now proposed for 
Sec. 201.323(a) and (e); however, when this language becomes final it 
may be in subpart E of part 310. These sections would limit the 
aluminum content for all LVP's used in TPN therapy to 25 g/L 
for liquids and would require that applicants and manufacturers develop 
validated assay methods to determine the aluminum content in parenteral 
drug products.

III. Comments on the Notice of Intent

     FDA received 11 comments on the notice of intent from professional 
associations, prescription drug manufacturers, a hospital, and a 
university. Most comments supported the proposed limit for aluminum 
content in LVP's and the labeling requirement for SVP's and pharmacy 
bulk packages. Four comments suggested changes to the proposed warning 
statement. A summary of the comments received and the agency's response 
follows.

A. Drug Products Susceptible to Aluminum Contamination

     1. The notice of intent applied to all human drug LVP's and SVP's 
and pharmacy bulk packages used in TPN therapy. One comment contended 
that nutritional LVP's and nutritional LVP pharmacy bulk packages 
should be considered separate from SVP's and SVP pharmacy bulk 
packages. The comment stated that manufacturers of nutritional LVP 
products, which include amino acids, dextrose concentrations, and lipid 
emulsions, have already taken steps to contain aluminum levels through 
manufacturing processes and testing. Another comment suggested that any 
proposed regulation should apply only to nutritional parenterals and 
not other drug products.
     The agency has concluded that, based on the available data and 
information concerning toxicity resulting from the presence of aluminum 
in parenteral drug products, it is necessary to regulate nutritional 
LVP's and LVP pharmacy bulk packages as well as nutritional SVP's and 
SVP pharmacy bulk packages. The proposal would establish a 25 
g/L limit for LVP's used in TPN therapy, and would require 
that the 25 g/L limit be stated in the package insert of all 
LVP's used in TPN therapy. The proposal would also require that the 
maximum level of aluminum at expiry be stated on the immediate 
container label of SVP's and pharmacy bulk packages used in the 
preparation of TPN solutions.
     The agency agrees that aluminum toxicity is a concern only for 
parenterals used in TPN therapy, and advises that the proposed limit 
for LVP's and the labeling requirement for LVP's, SVP's, and pharmacy 
bulk packages would only apply to LVP's used in TPN therapy and SVP's 
and pharmacy bulk packages used in the preparation of TPN solutions. 
The proposed rule would not apply to LVP's, SVP's, or pharmacy bulk 
packages not used in TPN therapy.

B. Patient Populations at Risk

     In the notice of intent, the agency stated that it was especially 
concerned about three groups of patients at risk for aluminum toxicity: 
(1) Patients with kidney failure on chronic hemodialysis or continuous 
ambulatory peritoneal dialysis; (2) patients of any age receiving long-
term TPN therapy, especially those with compromised kidney function; 
and (3) premature and full-term neonates who require TPN therapy.
     2. One comment agreed with FDA's selection of the three groups 
most at risk, while another comment preferred to limit the regulation 
to premature infants and uremic patients receiving parenteral 
nutrition. Another comment suggested that the agency should first 
conduct indepth studies on aluminum toxicity in TPN patients, as well 
as studies of other populations at risk, such as the elderly, before 
proposing which groups to regulate.
     The agency has considered these comments and the literature 
concerning the patient populations at risk and proposes to apply the 
regulation to products used for patients on TPN therapy who have 
impaired kidney function. Aluminum may accumulate to toxic levels after 
prolonged administration if kidney function is impaired, particularly 
if patients are exposed to other sources of aluminum, such as antacids, 
or if there is a greater than usual requirement for certain parenteral 
nutrition solutions that have a relatively high aluminum content, such 
as calcium and phosphate solutions. This includes patients with 
impaired kidney function receiving long-term parenteral nutrition and 
neonates receiving total parenteral nutrition. Premature neonates would 
be included because of their immature kidneys, their higher intake of 
fluids per unit body weight, and their greater need for calcium and 
phosphate solutions, which may be heavily contaminated with aluminum.
     3. One comment stated that only long-term therapy with TPN 
solutions containing a high level of aluminum has led to clinically 
significant toxicity. Another comment stated that aluminum in TPN 
solutions is a problem for premature infants but not for patients 
receiving continuous ambulatory peritoneal dialysis, except from 
aluminum-containing phosphate gels. The comment added that patients 
with kidney disease who are not undergoing dialysis, but who are 
receiving TPN therapy, accumulate aluminum even when using crystalline 
amino acids. Another comment stated that 5-year followup studies of 
infants on TPN therapy revealed no aluminum loading, and short-term 
therapy had no long-term effects.
     The agency disagrees that the only patients at risk are those on 
long-term therapy with TPN solutions that contain high levels of 
aluminum. The agency advises that the available research has shown that 
all patients with impaired kidney function on short-term or long-term 
TPN therapy are at risk. The agency also disagrees that 5-year studies 
have revealed no aluminum loading in infants. Again, the available 
literature provides sufficient evidence of toxic aluminum loading in 
infants who

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receive TPN therapy (Refs. 2, 5, 6, and 8 through 13).

C. Sources of Aluminum Contamination

     In the notice of intent, the agency stated that aluminum is 
usually found in parenteral drug products as a contaminant and is not 
added deliberately to the drug product. The notice also stated that 
although the drug substance is the main source of aluminum 
contamination in parenteral drug products, it is also leached from 
glass containers and closures during autoclaving and storage. The 
notice stated that additives are the major contributor of aluminum in 
TPN solutions, and that requiring the disclosure of aluminum levels in 
commonly used additives would permit the preparation of parenteral 
solutions lower in aluminum for high-risk patients.
     4. One comment agreed that the sources of aluminum in parenteral 
drug products include raw materials and the glass final container. The 
comment stated that appropriate changes in specifications of raw 
materials would alleviate the problem.
     Another comment stated that aluminum contamination results from 
three main sources: (l) Pharmaceutical ingredients (phosphates, 
gluceptates, gluconates, and some amino acids); (2) the container/
closure system (aluminum content leached from glass container and 
rubber closures increases with shelf life); and (3) the manufacturing 
process (autoclave sterilization and membranes). The comment stated 
that technology does not exist to lessen the presence of aluminum.
     The agency advises that changes in processing and screening of raw 
materials would significantly reduce aluminum contamination of 
parenteral drug products. The agency is proposing to require that the 
aluminum content be stated on the immediate container label of SVP's 
and pharmacy bulk packages so that the health professional preparing 
the TPN solution would be able to determine the aluminum content of the 
final solution. In addition, under the proposed rule, the package 
insert for all LVP's used in TPN therapy would state that the drug 
product contains no more than 25 g/L. This would assist the 
practitioner when calculating the total amount of aluminum being 
administered to a patient with impaired kidney function receiving TPN 
therapy.
     5. One comment suggested that FDA designate orphan drug status for 
parenterals used in infants to account for costs by manufacturers in 
complying with the aluminum content limits discussed in the notice of 
intent.
    The Orphan Drug Act requires that Orphan Drug Designation be 
requested for individual drugs; therefore, the law would not permit 
designation of an entire class of drugs. However, new products intended 
for parenteral use in infants may fit the eligibility criteria for 
Orphan Designation and individual manufactures would be encouraged to 
apply. The Office of Orphan Products Development has a long history of 
encouraging manufacturers to apply for pediatric indications and would 
welcome applications for neonatal indications.
     6. One comment suggested that FDA require parenterals to be 
packaged in plastic containers in order to lessen the aluminum leaching 
associated with glass containers.
     The agency has decided not to require parenterals to be packaged 
only in plastic because not all products used for TPN therapy are 
available in plastic. Under the proposed regulation, health care 
professionals may choose an additive available in a plastic container 
for patients on TPN therapy. It is beyond the intent of this proposed 
rule to require that all drug products used in TPN therapy be packaged 
in plastic containers.
     7. Three comments stated that deionized water has reduced the 
incidence of aluminum in parenteral solutions. One comment stated that 
following the U.S. Pharmacopeia proposed monograph for sterile water 
for dilution of hemodialysis concentrate would minimize aluminum 
toxicity problems. Aluminum toxicity would occur only in those patients 
where the aluminum loading exceeded dialysis capacity.
     The agency advises that aluminum toxicity is not limited to 
patients undergoing dialysis treatment. Furthermore, although deionized 
water may reduce incidence of aluminum toxicity, the use of deionized 
water does not eliminate other sources of aluminum in TPN solutions.
     8. Five comments argued that long-term TPN therapy using products 
containing crystalline amino acids, rather than casein hydrolysates, 
lessens toxic aluminum accumulation.
     Although the agency agrees that replacement of casein hydrolysates 
with crystalline amino acids has reduced the levels of aluminum in 
LVP's, the agency believes that establishing a maximum level of 
aluminum in LVP's used for TPN therapy will contribute to decreasing 
the total amount of aluminum in these solutions. In addition, the 
proposed labeling requirement will permit calculation of total daily 
aluminum intake from all sources.

D. Units of Measure of Aluminum Content

     In the notice of intent, the agency stated that a standard unit of 
measurement (i.e., parts per billion (ppb), parts per million, 
milligrams, or micrograms) should be specified to avoid confusion and 
errors, and that the same unit of measure be used to specify the drug 
being administered, the amount of aluminum present, and the maximum 
exposure permitted each day. The agency recommended that both mass and 
molar concentrations be stated in the labeling.
     9. Three of the eight comments addressing this issue supported the 
g/L unit, and two suggested either micro moles per liter 
(M/L) or ppb. Two comments recommended that the unit of 
measurement be expressed as ppb. Other suggestions included: ``ppb ( 
g/L),'' ``M/L (g/L),'' and ``(g/mL)'' (grams 
per milliliter). One comment specifically recommended ``moles/
L'' as a primary unit and ``g/L'' in parentheses.
     The agency has considered these comments and is proposing 
g/L as the unit of measure. The agency believes that a 
standard unit of measurement will allow health care professionals to 
tailor the parenteral solution to the needs of certain patients. In 
addition, the agency has chosen a unit of measurement by which the 
levels of aluminum administered to patients can be easily calculated.

E. Levels of Aluminum Content in LVP's

     The agency stated in the notice of intent that it was considering 
setting an upper limit of 25 g/L or 25 ppb for LVP's used in 
TPN therapy. This limit is based primarily on a calculation that an 
intake of 3 liters per day would result in a total exposure of under 
100 g per day, which was recommended at the 1986 FDA workshop 
as a safe daily burden for healthy individuals. This limit is also 
based on a study in which patients were treated with long-term TPN 
solutions (Ref. 18). In addition, information provided to the agency 
indicates that most currently marketed LVP drug products will meet this 
specification (Ref. 17). The notice solicited comments regarding 
acceptable levels for parenteral drug products that are not required to 
meet this specification, including continuous ambulatory peritoneal 
dialysis drug products, hemodialysis drug products, antibiotics, and 
other drug products marketed as LVP's. The notice also sought 
additional data and information

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regarding both safe levels and unsafe levels of aluminum in LVP's.
     10. Four comments supported this limit. One comment recommended 
using the following definitions of safe, unsafe, and toxic:
    ``Safe''--the amount of aluminum which when administered 
parenterally that will result in neither body or tissue loading nor 
tissue disease or dysfunction; ``unsafe''--the amount of aluminum 
which when administered parenterally will result in tissue loading 
but which cannot be definitively determined to produce tissue 
disease or dysfunction; and ``toxic''--the amount of aluminum which 
when administered parenterally will result in tissue loading and 
that can be directly associated with tissue disease or dysfunction.
The comment recommended that these terms be made known to physicians 
and pharmacists who prescribe or prepare TPN solutions to better 
estimate the risk of aluminum toxicity to the patient.
     Proposed Sec. 201.323(a) would place an upper limit of 25 
g/L for liquid LVP's used in TPN therapy. The agency is also 
proposing that the package insert for all LVP's used in TPN therapy 
state that the drug product contains no more than 25 g/L. The 
agency has determined that it is unnecessary for the proposed 
regulation to prescribe levels that are ``safe,'' ``unsafe,'' and 
``toxic.'' The agency believes that the proposed limit on aluminum 
content for LVP's, the package insert requirement for LVP's, and the 
immediate container label statement for SVP's and pharmacy bulk 
packages would enable the health care professional to determine which 
drug products are safe for each patient.
     11. One comment stated that proposing a limit for only LVP's 
disregards the fact that SVP's and pharmacy bulk packages contribute a 
large amount of aluminum to TPN solutions. Another comment objected to 
the agency's proposal to require a 25 ppb limit on LVP's but only a 
label statement for SVP's because LVP's provide less than 100 ppb of 
aluminum whereas SVP's can provide over 100,000 ppb of aluminum.
     The agency recognizes that SVP's and pharmacy bulk package 
additives, such as phosphate and calcium solutions, are a major source 
of aluminum toxicity in TPN therapy. However, although the risks 
associated with aluminum toxicity in patients receiving TPN therapy are 
known, an acceptable level of aluminum in SVP's and pharmacy bulk 
package additives has not yet been established.
    FDA is proposing the labeling requirement for SVP's and pharmacy 
bulk packages to permit the health care professional administering the 
drug to calculate the total aluminum exposure the patient receives from 
multiple parenteral sources. This calculation is especially important 
because additives appear to be the major contributor of aluminum to TPN 
solutions. Requiring the disclosure of the maximum level of aluminum 
present at expiry in SVP's and pharmacy bulk packages would also allow 
the user to make appropriate substitutions to prepare ``low aluminum'' 
parenteral solutions for use in patients who are in high-risk groups. 
The user would be unable to make accurate calculations of total 
aluminum exposure if the labeling of SVP's stated only a safe upper 
limit for aluminum rather than stating the exact or maximum amount of 
aluminum actually present.
     12. One comment stated that proper methodology and test procedures 
should be established before an upper limit for the level of aluminum 
in LVP's can be set. Several comments stated that the proposed limit 
was not feasible for the following reasons: (1) It would be very 
difficult to get accuracy and reproducibility at such a low level; (2) 
suppliers of raw materials cannot readily reduce the level of aluminum 
in raw materials and no simple analytical method or technology for 
aluminum determination exists that could be performed outside of a 
research laboratory at detection levels below 100 ppb; (3) aluminum is 
a universal ingredient in essentially all materials, including those 
compounds where there is no practical technique to remove the aluminum; 
(4) some ingredients may leach significant amounts of aluminum from the 
glass containers and/or stoppers used for packaging, processing, and 
storage; (5) technology does not currently exist to prevent parenterals 
with electrolytes or a high pH from accumulating a higher aluminum 
level after autoclaving or to prevent filter membranes from introducing 
aluminum into a parenteral solution; (6) the limit appears too low for 
currently available methodology to measure with a consistent result in 
a manufacturing quality controlled environment; and (7) environmental 
contamination, such as dust particles that may contain over 2,000 ppb 
of aluminum, low levels of aluminum in the purest laboratory reagents, 
and leaching from laboratory supplies, can be a significant source of 
test variation.
     Two comments recommended that FDA should alternatively require a 
limit of 100 ppb or 100 g/L. One comment stated that there is 
essentially no practical risk of adverse health effects at 100 ppb. The 
comment suggested that, as an alternative to a proposed limit, LVP's 
used for nutritional support should include a labeling statement as 
follows: ``Use of this product typically provides not more than 100 ppb 
(g/L) of aluminum. Use of this product, and any other 
additives, should be carefully undertaken if aluminum levels are of 
concern with the patient.''
     One comment stated that because LVP's usually contain less than 
100 ppb at expiration, FDA should not require release testing of every 
lot or establish an upper limit.
     One comment stated that the 25 ppb limit would severely restrict 
availability of products in the LVP market, on which critically ill 
patients depend and for which no other acceptable nutritional 
alternative exists.
     The agency disagrees with these comments. Technology exists to 
detect aluminum levels below 100 ppb and there is a risk of adverse 
health effects with aluminum levels at 100 ppb. The agency has 
determined that a specification of 100 g/L could unnecessarily 
increase the aluminum content of TPN solutions. Increased levels of 
aluminum contamination may result in toxic accumulation of aluminum in 
human tissues. Aluminum intoxication may lead to fracturing 
osteomalacia, encephalopathy, microcytic hypochromic anemia, bone 
disease, and other serious illnesses (Ref. 8). The agency believes that 
the proposed limit of 25 g/L is feasible and is necessary for 
the safe and effective use of LVP's in TPN therapy (Refs. 18 and 19). 
The agency emphasizes that the proposed limit is only applicable to 
LVP's involved in TPN therapy.
     Although the proposed limit of 25 g/L applies to all 
LVP's used in TPN therapy, the agency is identifying the following 
LVP's that are commonly used for prolonged TPN therapy, as those where 
high concentrations of aluminum toxicity are most likely to occur: 
Parenteral amino acid solutions, concentrated dextrose solutions, 
parenteral lipid emulsions, saline and electrolyte solutions, and 
sterile water for injection.

F. Aluminum Content Labeling for SVP's and Pharmacy Bulk Packages

     In the notice of intent, FDA stated that it was considering 
requiring the immediate container labels for each lot of certain SVP's 
and pharmacy bulk packages to state the exact amount of aluminum 
present at the time of release, or alternately, the maximum amount of 
aluminum present. The notice stated that this labeling requirement 
would only apply to solutions intended for use and identified by the 
agency as being commonly used in the preparation of TPN solutions, and 
to all regularly used additives (e.g., vitamins, minerals, and

[[Page 181]]

trace elements), regardless of aluminum levels detected. The notice 
stated that the agency is considering this approach for SVP's and 
pharmacy bulk packages to permit the person administering the drug to 
calculate the total aluminum exposure the patient receives from 
multiple parenteral sources.
     13. Several comments supported a limit on the aluminum content of 
SVP's. One comment recommended that the agency should establish upper 
limits of allowable aluminum content in the near future on the basis of 
lowest aluminum concentrations measured in recently published 
literature. The comment suggested that such limits should reduce 
overall aluminum intake and should be achievable. In addition, the 
comment claimed that the regulation should encourage manufacturers to 
reduce the aluminum content of this class of products even further than 
a proposed upper limit and encourage hospital pharmacists to use 
additives lowest in aluminum concentration.
     The agency has considered the comments and has decided not to 
propose a limit for the aluminum content of SVP's because, among other 
reasons, an acceptable level of aluminum in SVP and pharmacy bulk 
package additives has not yet been established. The proposed rule would 
require that the maximum level of aluminum present at expiry be stated 
on the immediate container label of all SVP's and pharmacy bulk 
packages used in the preparation of TPN solutions. This maximum level 
of aluminum must be expressed as: (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. Although techniques for the analysis of aluminum at the 25 
g/L level exist, the proposed rule would not require that a 
specification for SVP's or pharmacy bulk packages be set at this time.
     14. One comment noted that if no alternatives are available, it 
may be necessary to keep certain SVP's on the market even if they 
exceed the proposed limit. Another comment suggested that manufacturers 
of SVP's should have the opportunity to survey the aluminum content of 
their products before the agency determines the amount of aluminum in 
SVP's and the economic impact of this requirement.
     The agency is not proposing a limit for SVP's in this rulemaking. 
Therefore, it will not be necessary to remove any SVP's from the market 
due to this proposed rule, nor will it be necessary for manufacturers 
of SVP's to survey the aluminum content of their products.
     15. Several comments suggested that a list of drug products or 
components that are commonly used in the preparation of TPN solutions 
should include the salts of calcium, phosphate, and magnesium; trace 
element solutions; multivitamin preparations; and heparin solutions. 
One comment suggested that the products involved include parenteral 
trace minerals, parenteral multivitamins, and parenteral electrolyte 
supplements.
     Another comment stated that the agency should determine what 
products would require aluminum content labeling from the product's 
use. The comment stated that many publications specify the aluminum 
level in products used for TPN therapy and for administration to the 
patient populations at risk cited by the agency.
     Based on these comments, the agency has decided to broaden the 
labeling requirement stated in the notice of intent to apply to all 
SVP's used in TPN therapy. In an effort to assist manufacturers, the 
agency is identifying the following SVP's as those commonly used in the 
preparation of TPN solutions (this list may not be inclusive): 
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.
     16. Five comments agreed with the statement in the notice of 
intent that the immediate container labels of each lot of certain SVP's 
and pharmacy bulk packages must state the exact amount of aluminum 
present at the time of release. One comment stated that the requirement 
should apply to each of the SVP's listed in the response to comment 16 
and in all additive solutions that may contribute to the total aluminum 
content of large volume solutions.
     One comment, which opposed the labeling requirement for SVP's, 
stated that the requirement would not reduce aluminum toxicity and that 
compliance would be difficult. The comment asserted that stating the 
aluminum content at release does not accurately measure aluminum intake 
by the patient because some additives scavenge additional aluminum from 
glass packaging during shelf life. The comment also stated that the 
required labels could not be printed until the product is manufactured 
and testing is completed, and that this would be inconsistent with the 
agency's encouragement of straight-line filling and labeling of 
injectable products to prevent label mixups. The comment stated that 
the analytical technology is not practical for routine release testing 
in the laboratory because stringent control of aluminum contamination 
would be necessary, which would require well-trained, experienced 
personnel in a research setting. As an alternative, the comment 
suggested that the package insert state the potential for aluminum 
toxicity in certain patient populations and provide a range of aluminum 
content in the product that would allow the pharmacist or the physician 
to calculate patient risk based on approximate aluminum content in TPN 
solutions.
     Although it is true that some additives scavenge additional 
aluminum from glass packaging during shelf life, the amount scavenged 
from various sources is generally very small compared with the aluminum 
contamination present in SVP's. In addition, many SVP's are available 
in plastic containers, for which scavenging is nominal. In regard to 
labeling, the agency is not suggesting a change from straight-line 
filling. The proposed rule would not require any change to the 
procedures now employed, since applicants and manufacturers may use 
historical levels of aluminum in their labeling. The use of historical 
data precludes the need for routine release testing. It is true that 
conducting the analytical test will require trained, experienced 
analysts, since all reagents, solvents, and apparatus need to be free 
of aluminum contamination. However, the technology exists and has been 
adapted by a number of manufacturers from which FDA has received data 
for LVP's over the years. Small manufacturers without the facility, 
equipment, or personnel can contract the testing out.
     Accordingly, the agency has determined that proposed 
Sec. 201.323(c) should require that the immediate container label of 
all marketed SVP's used as additives in TPN therapy state the maximum 
level of aluminum at expiry, rather than a range.

G. Aluminum Content/Assay Methods and Validation

     In the notice of intent, the agency asked for comments on whether 
applicants should develop their own validated assay methods and submit 
them to FDA for approval. The notice

[[Page 182]]

stated that the criteria to be considered in the selection of an 
aluminum release assay method would include accuracy, sensitivity, 
specificity, and reproducibility when applied to each of the tested 
drug products. In addition, the notice stated that an aluminum assay 
method should be validated by normal scientific procedures. For 
parenteral drugs that are the subject of an approved application, 
supplements must be submitted to provide the assay methodology to FDA 
for approval. The notice also recommended consultation of the agency's 
``Guideline for Submitting Samples and Analytical Data for Methods 
Validation'' for assistance.
     17. Two comments suggested that FDA provide the appropriate 
methodology to measure aluminum content. One comment stated that assay 
methodology only has a precision of about 10 percent. One 
comment was concerned with the accuracy in measurement if 25 ppb is the 
upper limit, and suggested that FDA wait for methodology to be 
established before setting a limit. Another comment stated that the 
method of analysis should not be specified in the regulation, but that 
each applicant or manufacturer demonstrate under CGMP's that the method 
employed is precise and accurate. The comment noted that equipment 
essential for compliance with an assay methodology for periodic 
analytical testing would be feasible within a research laboratory but 
could not be operated within a manufacturing quality assurance 
laboratory.
     Two comments recommended an assay methodology consisting of 
flameless or electrothermal atomic absorption spectroscopy or 
inductively coupled plasma emission spectroscopy. Manufacturers would 
establish either an in-house method or would contract with a 
laboratory. The comments also recommended that FDA issue specific 
procedures to ensure that manufacturers use appropriate control 
procedures.
     FDA has considered the comments and has concluded that, under 
proposed Sec. 201.323(e), applicants would have the discretion and 
flexibility to develop their own validated assay methods, but would be 
required to submit them to FDA for approval. As required under 21 CFR 
314.50(e)(2)(i), the method of analysis must include a description of 
each sample; the proposed regulatory specifications for the drug; a 
detailed description of the methods of analysis; supporting validation 
data for accuracy, specificity, precision, and ruggedness; and complete 
results of the applicant's tests on each sample. Manufacturers must 
maintain records for examination by FDA during inspections.
     Approved application holders for LVP's and SVP's used in TPN 
therapy must submit a supplement under Sec. 314.70(c) that describes 
the method used for determining aluminum content. Validation methods, 
release data, and historical data at expiry for several batches should 
be submitted. For SVP's not subject to approved applications, 
manufacturers are expected to maintain records for examination by FDA 
during inspections.
     18. One comment recommended that the graphite furnace atomic 
absorption method that is used for a quantitative determination of 
aluminum in parenteral products should be adopted by FDA as an industry 
standard assay method. Another comment recommended graphite furnace 
atomic absorption spectrophotometry with Zeeman background correction 
as an industry standard.
     The agency declines to accept the comments' suggestions. As 
stated, the choice is left to applicants and manufacturers to select 
and properly validate an appropriate methodology.
     19. One comment recommended in determining a limit for aluminum in 
parenteral drugs that the analytical methodology should be capable of 
determining aluminum content in complex matrices, that adherence to 
CGMP's and appropriate documentation should be sufficient for 
compliance, and that routine batch testing should not be required.
     The agency disagrees. Strict adherence to CGMP's, instead of 
routine batch testing, will not fully address the issue of aluminum 
contamination. Routine batch testing is important under the proposed 
rule because the applicants and manufacturers of SVP's and pharmacy 
bulk packages will be expected to assay sufficient lots of products to 
establish the maximum historical level of aluminum present at the 
expiry. The applicant or manufacturer would be expected to monitor the 
aluminum level of their product at the time of release and through the 
expiry of their product.
     20. Another comment stated that an engineering study for an 
assessment of 40 to 60 raw material aluminum analyses would cost 
approximately $150,000 and require 700 man-hours for each plant, and a 
second study for sampling and testing of 25 to 30 unit operations for 
all 24 individual amino acid processes would require a $1.5 million 
commitment. The comment stated further that the cost of implementation 
of aluminum control measures could easily exceed $20 million, and 
continuing costs of analyses and process control could be $1 million 
per year.
     FDA disagrees with the comment's cost estimates. FDA estimates 
that the annualized cost to amino acid suppliers would be $1,416,622. 
This figure includes the first year or one-time costs that the comment 
estimates at $20 million. In addition, FDA notes that the cost of 
compliance represents a small percentage of amino acid revenue. Amino 
acid sales were $1.6 billion in 1996 and are projected to grow at an 
annual rate of 9 percent. ``Commercial Amino Acids,'' Chemical Business 
Newsbase (May 23, 1997). The annualized cost of compliance for amino 
acid suppliers represents just .09 percent of the 1996 annual amino 
acid sales. FDA considers this an acceptable cost.

H. Warning Statement for LVP's and SVP's

     In the notice of intent, FDA stated that it is considering 
requiring the package insert for LVP's to contain a warning statement 
about the potential aluminum toxicity of TPN mixtures.
     21. One comment suggested that LVP products bear a warning 
statement as follows: ``Use of this product typically provides not more 
than 100 ppb (g/L) of aluminum. Use of this product, and any 
other additives, should be carefully undertaken if aluminum levels are 
of concern with the patient * * *.'' Another comment recommended that 
the package insert for LVP's used in TPN state: ``Typically may contain 
up to 100 ppb (mcg/L) of aluminum.'' In addition, the comment stated 
that the package insert for SVP's should state that the potential for 
aluminum toxicity exists in certain patient populations, and that a 
range of aluminum content should be provided.
     Another comment recommended that the package insert of LVP's and 
SVP's state that the product:
    ``contains aluminum of a given quantity which, when given in 
conjunction with other additives as part of a parenteral nutrition 
solution, may result in accumulation of aluminum in bone and other 
tissues and may contribute to the pathogenesis of bone disease.''
The comment also suggested that a special warning be given to uremic 
patients receiving these additives. The warning would state: ``The 
cumulative amount of aluminum administered from this and other 
intravenous additives may cause encephalopathy as well as bone disease. 
Safe amounts of aluminum intake have not been established for uremic 
patients.''
     FDA has determined that, under proposed Sec. 201.323(d), the 
package

[[Page 183]]

insert for LVP's and SVP's must contain the following warning statement 
about aluminum toxicity in patients receiving TPN therapy:
     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.
    The agency has considered the data submitted in response to the 
notice of intent and other available data, and has concluded that a 
specification of 100 g/L is unnecessarily high for LVP's. In 
addition, the agency believes that indicating a range for aluminum 
content of SVP's would not provide health care professionals with 
enough information to calculate the aluminum content of the final TPN 
solution.
     In response to the comment that the proposed rule should include a 
warning statement to uremic patients receiving additives in TPN 
solutions, the agency advises that it examined aluminum toxicity in 
different patient populations and has concluded that the warning 
statement should apply not only to uremic patients but also to all 
patients with impaired kidney function and neonates receiving TPN 
therapy.
     22. One comment suggested that the effects of aluminum on 
individuals should be examined in terms of aluminum intake per kg of 
body weight rather than absolute aluminum intake since an adult and 
infant receiving identical quantities of aluminum would have a vastly 
different body burden of aluminum.
     The agency has considered the option of examining the effects of 
aluminum on individuals in terms of aluminum intake per kg of body 
weight, but has tentatively concluded that setting a limit for LVP's 
and requiring the labeling statement for SVP's would be the best method 
to measure aluminum intake. However, as discussed previously, FDA is 
seeking comment on including language in the warning statement 
concerning maximum aluminum intake per kg of body weight.

IV. Legal Authority

     FDA's proposal 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 both 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.
     Under part 201 (21 CFR part 201) in Sec. 201.100(d) of FDA's 
labeling regulations, prescription drug products must bear labeling 
that contains adequate information under 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.
     If the proposed rule is finalized, any drug product not in 
compliance with Sec. 201.323 would be considered to be misbranded under 
section 502 of the act and an unapproved new drug under section 505 of 
the act.

V. Proposed Implementation Plan

     FDA proposes that any final rule that may issue based on this 
proposal become effective 1 year after its date of publication in the 
Federal Register. After that date, 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 labeling requirements under 
proposed Sec. 201.323. Holders of approved NDA's or ANDA's would meet 
the requirements of proposed Sec. 201.323 by submitting supplements 
under Sec. 314.70 or Sec. 314.97 (21 CFR 314.97). Applicants for LVP's 
used in TPN therapy and SVP's used as additives in TPN solutions would 
also be required to submit a supplement under Sec. 314.70(c) that 
describes the assay method for determining the aluminum content. 
Applicants must submit both 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 
would submit an amendment under 21 CFR 314.60 or 314.96.

VI. Request for Comments

     Interested persons may, on or before April 6, 1998, submit to the 
Dockets Management Branch written comments regarding this proposal. Two 
copies of any comments are to be submitted, except that individuals may 
submit one copy. Comments are to be identified with the docket number 
found in brackets in the heading of this document. Received comments 
may be seen in the office above between 9 a.m. and 4 p.m., Monday 
through Friday. FDA is specifically seeking comments on whether adding 
the language ``Patients should receive no more than 4 to 5 g/
kg/day of aluminum'' to the warning statement is appropriate, and 
whether a 4 to 5 g/kg/day level is reasonable and adequate to 
protect the public health.

VII. Analysis of Impacts

     FDA has examined the impacts of the proposed rule under Executive 
Order 12866 and the Regulatory Flexibility Act (5 U.S.C. 601-612). 
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 agency believes that 
this proposed rule is consistent with the regulatory philosophy and 
principles identified in the Executive Order.
     Based on a study conducted for the agency by the Eastern Research 
Group (ERG), a private consulting firm, FDA has determined the annual 
costs of the proposed regulation to the affected industries. FDA 
estimates total annualized compliance costs at $20.1

[[Page 184]]

million. This estimate is composed of one-time costs annualized to $9.8 
million at a 7 percent discount rate and recurring annual costs of 
$10.3 million. Over 50 percent of the total costs are due to actions 
undertaken to manufacture LVP solutions and their inputs that comply 
with the aluminum requirements. One alternative that would have 
required SVP's to be labeled with the actual aluminum content of each 
batch would have raised these costs (Ref. 21).
     The Regulatory Flexibility Act requires agencies to analyze 
regulatory options that would minimize any significant impact of a rule 
on small entities. The ERG report presents estimated compliance costs 
by type of establishment. The report demonstrates that the largest 
compliance costs will be incurred by amino acid suppliers at about $1.4 
million per establishment, followed by manufacturers of LVP's at about 
$320,000 per establishment, and other suppliers to TPN manufacturers at 
$134,000 per establishment. The data used in this analysis further 
show, however, that very few of the companies involved in these 
manufacturing activities are considered small by the standards of the 
Small Business Administration. Therefore, the agency certifies that the 
proposed rule will not have a significant economic impact on a 
substantial number of small entities and, under the Regulatory 
Flexibility Act, no further analysis is required.

VIII. The Paperwork Reduction Act of 1995

     This proposed 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). 
Therefore, in accordance with 44 U.S.C. 3506(c)(2)(B) and 5 CFR part 
1320, FDA is providing the following title, description, and respondent 
description of the information collection contained in this proposal, 
along with an estimate of the resulting annual collection of 
information burden. This estimate includes the time needed for 
reviewing instructions, gathering and maintaining the data needed, and 
completing and reviewing the collection of information.
     With respect to the following collection of information, FDA 
invites comments on: (1) Whether the proposed collection of information 
is necessary for proper performance of FDA's functions, including 
whether the information will have practical utility; (2) the accuracy 
of FDA's estimate of the burden of the proposed collection of 
information, including the validity of the methodology and assumptions 
used; (3) ways to enhance the quality, utility, and clarity of the 
information to be collected; and (4) ways to minimize the burden of the 
collection of information on respondents, including through the use of 
automated collection techniques, when appropriate, and other forms of 
information technology.
    Title: Aluminum in Large and Small Volume Parenterals Used in Total 
Parenteral Nutrition
     Description: FDA is proposing to amend its regulations to add 
certain labeling requirements concerning aluminum in LVP's and SVP's 
used in TPN. FDA is also proposing to specify an upper limit of 
aluminum permitted in LVP's and to require applicants and manufacturers 
to develop and to submit to FDA for approval validated assay methods 
for determining aluminum content in parenteral drug products.
     Description of Respondents: Persons and businesses, including 
small businesses and manufacturers.

                                   Table 1.--Estimated Annual Reporting Burden                                  
----------------------------------------------------------------------------------------------------------------
                                                      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       
----------------------------------------------------------------------------------------------------------------
There are no capital costs or operating and maintenance costs associated with this collection of information.   

     The agency has submitted a copy of the proposed rule to OMB for 
its review and approval of this information collection. Interested 
persons are requested to send comments regarding this information 
collection to the Office of Information and Regulatory Affairs, OMB 
(address above).

IX. 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. Alfrey, A. C., ``Aluminum,'' Advances in Clinical Chemistry, 
23:69-91, 1983.
     2. Kerr, D. N. S. et al., ``Aluminum-induced Dialysis 
Osteodystrophy: The Demise of `Newcastle Bone Disease'?'' Kidney 
International, 29 (Suppl. 18):S-58-64, 1986.
     3. Sedman, A. B. et al., ``Evidence of Aluminum Loading in 
Infants Receiving Intravenous Therapy,'' The New England Journal of 
Medicine, 312:1337-1343, 1985.
     4. Koo, W. W. K. et al., ``Aluminum Contamination of Infant 
Formulas,'' Journal of Parenteral and Enteral Nutrition, 12:170-173, 
1988.
     5. Sedman, A. B. et al., ``Encephalopathy in Childhood 
Secondary to Aluminum Toxicity,'' The Journal of Pediatrics, 
105:836-838, 1984.
     6. American Academy of Pediatrics Committee on Nutrition, 
``Aluminum Toxicity in Infants and Children,'' Pediatrics, 78:1150-
1154, 1986.
     7. Vargas, J. H. et al., ``Metabolic Bone Disease of Total 
Parenteral Nutrition: Course after Changing from Casein Amino Acids 
in Parenteral Solutions with Reduced Aluminum Content,'' American 
Journal of Clinical Nutrition, 48:1070-1078, 1988.
     8. Klein, G., ``Aluminum in Parenteral Products: Medical 
Perspective on Large and Small Volume Parenterals,'' Journal of 
Parenteral Science and Technology, 43:120-124, 1989.
     9. ASCN/ASPEN Working Group on Standards for Aluminum Content 
of Parenteral Nutrition Solutions, ``Parenteral Drug Products 
Containing Aluminum as an Ingredient or a Contaminant: Response to 
FDA Notice of Intent and Request for Information,'' American Journal 
of Clinical Nutrition, 53:399-402, 1991.
     10. Andreoli, S. P., J. A. Smith, and J. M. Bergstein, 
``Aluminum Bone Disease in Children: Radiographic Features from 
Diagnosis to Resolution,'' Radiology, 156:663-667, 1985.
     11. McGraw, M. et al., ``Aluminum Content of Milk Formulae and 
Intravenous Fluids Used in Infants,'' The Lancet, 1:157, 1986.
     12. Puntis, J. W. L., K. Hall, and I. W. Booth, ``Plasma 
Aluminum and Prolonged Parenteral Nutrition in Infancy,'' The 
Lancet, 2:1332-1333, 1986.
     13. Koo, W. W. K. et al., ``Response to Aluminum in Parenteral 
Nutrition During Infancy,'' Journal of Pediatrics, 109:877-883, 
1986.
     14. Greger, J. L., and M. J. Baier, ``Excretion and Retention 
of Low or Moderate Levels of Aluminum by Human Subjects,'' Food and 
Chemical Toxicology, 21:473-477, 1983.
     15. Gorsky, J. E. et al., ``Metabolic Balance of Aluminum 
Studied in Six Men,'' Clinical Chemistry, 25:1739-1743, 1979.

[[Page 185]]

     16. Bishop, N. J. et al., ``Increased Concentration of Aluminum 
in the Brain of an Infant,'' Archives of Disease in Childhood, 
64:1316-1317, 1989.
     17. Koo, W. W. K. et al.,``Aluminum in Parenteral Nutrition 
Solution--Sources and Possible Alternatives,'' Journal of Parental 
and Enteral Nutrition, 10:591-595, 1986.
     18. Heyman, M. B. et al., ``Aluminum Does Not Accumulate in 
Teenagers and Adults on Prolonged Parenteral Nutrition Containing 
Free Amino Acids,'' Journal of Parenteral and Enteral Nutrition, 
10:86-87, 1986.
     19. Klein, G. L., ``Unusual Sources of Aluminum,'' in Aluminum 
and Renal Failure, edited by M. E. Debroe and J. W. Coburn, Kluwer, 
Boston, 1989.
     20. Bishop, N. J. et al., ``Aluminum Neurotoxicity in Preterm 
Infants Receiving Intravenous Feeding Solutions,'' New England 
Journal of Medicine, 336:1557-1561, 1997.
    21. Eastern Research Group, Compliance Cost Analysis of a 
Regulation for Parenteral Drug Products Containing Aluminum, March 
11, 1996.
    22. March 3, 1986, Meeting Minutes for the Advisory Committee on 
Endocrinologic and Metabolic Drug Products.
    23. November 6, 1986, Meeting Minutes for Public Workshop on 
aluminum toxicity in clinical medicine, existing aluminum 
monitoring, clinical effects of aluminum loading, and methodology 
for quantitative aluminum determination in parenteral products.
    24. June 25 and 26, 1987, Meeting Minutes of the Allergenic 
Products Advisory Committee--available in Docket No. 84N-0387.

 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, it is proposed that 21 CFR part 201 be 
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, 356, 357, 
358, 360, 360b, 360gg-360ss, 371, 374, 379e; 42 U.S.C. 216, 241, 
262, 264.
     2. New Sec. 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 all large volume parenteral (LVP) drug 
products used in total parenteral nutrition (TPN) therapy shall not 
exceed 25 micrograms per liter (g/L).
     (b) The package insert of all LVP's used in TPN therapy shall 
state that the drug product contains no more than 25 g/L. This 
information shall be contained in the ``Precautions'' section of the 
labeling of all LVP's used in TPN therapy.
     (c) The maximum level of aluminum present at expiry shall be 
stated on the immediate container label of all small volume parenteral 
(SVP) drug products and pharmacy bulk packages used in the preparation 
of TPN solutions. The aluminum content shall be stated as follows: 
``Contains no more than ______ g/L.'' The immediate container 
label of all SVP drug products and pharmacy bulk packages that are 
lyophilized powders used in the preparation of TPN solutions shall 
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 shall 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 this rule takes effect.
     (d) The package insert for all LVP's, SVP's, and pharmacy bulk 
packages shall contain the following warning statement, intended for 
patients with impaired kidney function and for neonates receiving TPN 
therapy. This information shall be contained in the ``Warnings'' 
section of the labeling of all SVP's and LVP's as follows:
     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.
     (e) Applicants and manufacturers shall develop validated assay 
methods to determine the aluminum content in parenteral drug products. 
The assay methods shall comply with current good manufacturing practice 
requirements. Applicants shall submit to the Food and Drug 
Administration (FDA) both validation of the method used and release 
data for several batches. Manufacturers of parenteral drug products not 
subject to an approved application shall make assay methodology 
available to FDA during inspections. Holders of pending applications 
shall submit an amendment under Sec. 314.60 or Sec. 314.96 of this 
chapter.

    Dated: December 5, 1997.
William K. Hubbard,
Associate Commissioner for Policy Coordination.
[FR Doc. 98-76 Filed 1-2-98; 8:45 am]
BILLING CODE 4160-01-F