176
`
`Federal Register / Vol. 63, No. 2 / Monday, January 5, 1998 / Proposed Rules
`
`and (a)(l)(ii) ofthis AD in accordance with
`the service bulletin. Where there are
`differences between the requirements of this
`AD and the procedures specified in the
`service bulletin, the AD prevails.
`(i) Either repair chafed pipe assemblies or
`replace chafed pipe assemblies with new or
`serviceable pipe assemblies. And
`(ii) Modify the FIREX and the pneumatic
`sense pipe assembly clamp marriage.
`(2) If no chafing is detected, prior to further
`flight, modify the FIREX and the pneumatic
`sense pipe assembly clamp marriage in
`accordance with the service bulletin.
`(b) An alternative method of compliance or
`adjustment of the compliance time that
`provides an acceptable level of safety may be
`used if approved by the Manager, Los
`Angeles Aircraft Certification Office (ACO),
`FAA, Transport Airplane Directorate.
`Operators shall submit their requests through
`an appropriate FAA Principal Maintenance
`Inspector, who may add comments and then
`send it to the Manager, Los Angeles ACO.
`Note 2: Information concerning the
`existence of approved alternative methods of
`compliance with this AD, if any, may be
`obtained from the Los Angeles ACO.
`( c) Special flight permits may be issued in
`accordance with sections 21.197 and 21.199
`of the Federal Aviation Regulations (14 CFR
`21.197 and 21.199) to operate the airplane to
`a location where the requirements of this AD
`can be accomplished.
`Issued in Renton, Washington, on
`December 29, 1997.
`Darrell M. Pederson,
`Acting Manager, Transport Airplane
`Directorate, Aircraft Certification Service.
`[FR Doc. 98- 124 Filed 1- 2- 98; 8:45 am]
`BILLING CODE 4910–13–P
`
`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 (0MB), 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:
`20.16 13.4 milligrams (mg) versus
`1.98 1.44 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
`
`±±
`
`Nexus Ex. 1054
`Page 1 of 10
`
`

`

`Federal Register / Vol. 63, No. 2 / Monday, January 5, 1998 / Proposed Rules
`
`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 ofFDA'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: (I) 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 L VP' s used in TPN
`therapy; (3) require that the maximum
`level of aluminum at expiry be stated on
`the immediate container label ofSVP's
`
`µ
`
`and pharmacy bulk packages used in the
`preparation ofTPN 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§ 201.323(a) would limit the
`aluminum content for all L VP'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
`Proposed§ 201.323(b) would require
`that the package insert for all L VP'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§ 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
`µ
`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
`µ
`instructions, the concentration of
`g/
`aluminum will be no more than
`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
`
`µ
`
`µ
`
`1 The agency has determined that most currently
`marketed L VP 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. L VP and SVP products
`from several manufacturers were tested. All L VP'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 L VP drug products.
`
`µ
`
`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 ofTPN 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§ 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 L VP
`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
`µ
`that the patient was receiving a total of
`7 .99 g/day of aluminum ( calculated
`(0.150x25) + (0.020x2) + (0.002x 100)
`+ (0.010x400)). 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
`
`µ
`
`µ
`
`µ
`
`µ
`
`µ
`
`Nexus Ex. 1054
`Page 2 of 10
`
`

`

`178
`
`Federal Register / Vol. 63, No. 2 / Monday, January 5, 1998 / Proposed Rules
`
`µµ
`
`µ
`
`µ
`
`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§ 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 2ll)(see § 21 l.194(a)).
`Holders of approved applications for
`L VP's used in TPN therapy and SVP's
`used as additives in TPN solutions
`would be required to submit a
`supplement to FDA under§ 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§ 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§ 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 oflntent
`
`µ
`
`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 L VP 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 L VP'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 L VP'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.
`
`µ
`
`µ
`
`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(cid:173)
`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(cid:173)
`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(cid:173)
`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
`
`Nexus Ex. 1054
`Page 3 of 10
`
`

`

`Federal Register / Vol. 63, No. 2 / Monday, January 5, 1998 / Proposed Rules
`
`179
`
`µ
`
`µ
`
`µ
`
`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: (1) 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.
`
`µ
`
`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(cid:173)
`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 ( MIL) or ppb. Two
`comments recommended that the unit of
`measurement be expressed as ppb.
`Other suggestions included: ''ppb ( g/
`L),"" MIL ( 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 L VP '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
`L VP drug products will meet this
`specification (Ref. 17). The notice
`solicited comments regarding acceptable
`levels for parenteral drug products that
`are not required to meet this
`specification, including continuous
`ambulatory peritoneal dialysis drug
`products, hemodialysis drug products,
`antibiotics, and other drug products
`marketed as LVP's. The notice also
`sought additional data and information
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`Nexus Ex. 1054
`Page 4 of 10
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`180
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`Federal Register / Vol. 63, No. 2 / Monday, January 5, 1998 / Proposed Rules
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`regarding both safe levels and unsafe
`levels of aluminum in LVP's.
`10. Four comments supported this
`limit. One comment recommended
`using the following definitions of safe,
`unsafe, and toxic:
`"Safe"-
`the amount of aluminum which
`when administered parenterally that will
`result in neither body or tissue loading nor
`tissue disease or dysfunction; "unsafe"-
`the
`amount of aluminum which when
`administered parenterally will result in
`tissue loading but which cannot be
`definitively determined to produce tissue
`disease or dysfunction; and "toxic"-
`the
`amount of aluminum which when
`administered parenterally will result in
`tissue loading and that can be directly
`associated with tissue disease or dysfunction.
`The comment recommended that these
`terms be made known to physicians and
`pharmacists who prescribe or prepare
`TPN solutions to better estimate the risk
`of aluminum toxicity to the patient.
`Proposed§ 201.323(a) would place an
`upper limit of25 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 L VP's, the
`package insert requirement for L VP'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