[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]
=======================================================================
-----------------------------------------------------------------------
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.
-----------------------------------------------------------------------
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="" [[page="" 177]]="" 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\
---------------------------------------------------------------------------
\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.
---------------------------------------------------------------------------
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
[[Page 179]]
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
[[Page 180]]
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
