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

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

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

sis

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 g/L) for

liquids

enteral 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 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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arity 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

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)

ion 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

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

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

r

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

oxicity 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

on 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

ty. 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

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

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

e 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

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)

ency 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

ug 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

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

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

s. 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

h 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

grees 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

acy 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

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

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

ested 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

ice 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

atient 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

ould 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

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

hat 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

eral 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

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

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

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

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

nts 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

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

pproved 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

. 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

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

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

lection 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

apital 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

`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.

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.

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

, 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.

m 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

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