Federal Register / Vol. 65, No. 17 / Wednesday, January 26, 2000 I Rules and Regulations
`
`4103
`
`rule that was published in the Federal
`Register on January 10, 2000, (65 FR
`1309). Airspace Docket No. 99- ASO-27.
`EFFECTIVE DATE: January 26, 2000.
`FOR FURTHER INFORMATION CONTACT:
`Nancy B. Shelton, Manager. Airspace
`Branch, Air Traffic Division, Federal
`Aviation Admin istration, P.O. Box
`20636, Atlanta, Georgia 30320;
`telephone (404) 305- 5627.
`SUPPLEMENTARY INFORMATION:
`History
`Federal Register Document DOCID:
`frl0ja00-6, Airspace Docket No. 99-
`ASO- 27, published on January 10, 2000,
`(65 FR 1309), amended Class D surface
`area airspace at Jacksonville Whitehouse
`NOLF, FL. An error was discovered in
`the amendalory language identifying the
`airspace description. This action
`corrects that error.
`Correction to Final Rule
`Accordingly, pursuant lo the
`authority delegated to me, the
`publication for describing Jacksonville
`Whitehouse NOLF, FL, Class D surface
`area airspace al Jacksonville Whitehouse
`NOLF, FL, as published in the Federal
`Register on January 10, 2000, (65 FR
`1309), (Federal Register Document
`DOCID: frl0ja00-6; page 1309), is
`corrected as follows:
`
`[Corrected]
`
`Section 71 .1
`*
`ASO FL D Jacksonville Whitehouse
`NOLF, FL [Corrected)
`By removing "be effective during the
`specific dates and limes established in
`advance by a Notice to"
`*
`
`Issued in College Park, Georgia, on January
`10, 2000.
`Nancy B. Shelton,
`A cting Manager, Air Traffic Division,
`Southern Region.
`[FR Doc. 00-1815 Filed 1-25-00; 8:45 aml
`BILLING CODE 4910-13-M
`
`DEPARTMENT OF TRANSPORTATION
`
`Federal Aviation Administration
`
`14 CFR Part 71
`[Airspace Docket No. 99-ANE-92]
`
`Establishment of Class E Airspace;
`Burlington, VT
`
`AGENCY: Federal Aviation
`Administration (FAA), DOT.
`ACTION: Direct final rule; correction;
`confirmation of effective date.
`
`Correction to the Direct Final Rule
`Accordingly, pursuant to the
`authority delegated lo me, the
`establishment of Class E airspace al
`Burlington, VT as published in the
`Federal Register on December 6, 1999
`(64 FR 68008), Federal Register
`document 99-31518: page 68009,
`column 2; and the description in FAA
`Order 7400.9G, dated September 1,
`1999, and effective September 16, 1999,
`which is incorporated by reference in 14
`CFR 71.7; are corrected to read as
`follows:
`
`Subpart E-Class E Airspace
`
`Issued in Burlington, MA, on January 13,
`2000.
`William C. Yuknewicz,
`Acting Manager, Air Traffic Division, New
`England Region.
`[FR Doc. 00- 1814 Filed 1- 25-00 8:45 am]
`BILLING CODE 491~13-M
`
`SUMMARY: This notice confirms the
`effective date of a direct final rule that
`establishes Class E airspace area at
`Burlington, VT (KBTV) to provide for
`adequate cont.rolled airspace for aircraft
`executing instrument approaches lo the
`Burlington International Airport at
`times when the Burlington Air Traffic
`Control Tower is closed. This action
`also corrects a typographical error in the
`docket number and changes the
`longitude and latitude of the Burlington
`International Airport to reflect North
`American Datum (NAD) 1983.
`EFFECTIVE DATE: The direct final rule
`published al 64 FR 68008 is effective
`0901 UTC, February 24, 2000.
`**
`FOR FURTHER INFORMATION CONTACT:
`Paragraph 6002-Class E Airspace
`David T. Bayley, Air Traffic Division,
`Areas Designated as Extending Upward
`Airspace Branch , ANE-520.3, Federal
`From the Surface of the Earth
`Aviation Administration, 12 New
`England Executive Park, Burlington , MA *
`01803- 5299; telephone (781) 238-7586; ANE VT EZ Burlington, VT [New)
`fax (781) 238-7596.
`Burlington International Airport, VT
`SUPPLEMENTARY INFORMATION:
`(Lat. 44°28'23" N, long. 73°09'01" W.)
`The FAA published this direct final
`Within a 5-mile radius of Burlington
`rule with a request for comments in the
`International Airport. This Class E
`Federal Register on December 6, 1999
`airspace is effective during the specific
`(64 FR 68008). The FAA uses the direct
`dates and limes established in advance
`final rulemaking procedure for a non(cid:173)
`by a Notice lo Airman. The effective
`controversial rule where the FAA
`dates and times will thereafter be
`believes that there will be no adverse
`continuously publish ed in the Airport/
`public comment. This direct final rule
`Facility Directory.
`advised the public that n o adverse
`comments were anticipated, and that
`unless a written adverse comment, or a
`wrillen notice of intent to submit such
`an adverse comment, were received
`within the comment period, the
`regulation would become effective on
`February 24, 2000. No adverse
`comments were received, and thus this
`notice confirms that this direct final rule
`will become effective on that date.
`This direct final rule also corrects the
`docket number for this act.ion lo 99-
`ANE- 92. The docket number used for
`the publication of the direct final rule
`was previously used for another
`airspace action. Thal other action,
`however, was issued from FAA
`Headquarters, while this action was
`issued from the New England Region.
`Therefore, the FAA has determined th at
`the error in the docket number caused
`no confusion lo interested persons
`w ishing lo comment on this proposal
`and corrects the docket number in this
`action.
`Lastly, the longitude and latitude
`coordinates published in the direct final
`rule must be updated to re11ect North
`American Datum (NAD) 1983. The FAA
`has determined that neither of these
`corrections expands the scope of the
`direct final rule.
`
`DEPARTMENT OF HEAL TH AND
`HUMAN SERVICES
`
`Food and Drug Administration
`
`21 CFR Part 201
`[Docket No. 90N-0056]
`
`RIN 0910-AA74
`
`Aluminum in Large and Small Volume
`Parenterals Used in Total Parenteral
`Nutrition
`AGENCY: Food and Drug Administration ,
`HHS.
`ACTION: Final rule.
`
`SUMMARY: The Food and Drug
`Administration (FDA) is amending its
`regulations lo add certain labeling
`requirements for aluminum content in
`large volume parenterals (LVP's), small
`
`Nexus Ex. 1055
`Page 1 of 9
`
`

`

`4104
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`Federal Register / Vol. 65, No. 17 / Wednesday, January 26, 2000 I Rules and Regulations
`
`volume parenterals (SVP's). and
`pharmacy bulk packages (PBP's) used in
`total parenteral nutrition (TPN). FDA is
`also specifying an upper limit of
`aluminum permitted in LVP's and
`requiring applicants to submit to FDA
`validated assay methods for determining
`aluminum content in parenteral drug
`products. The agency is adding these
`requirements because of evidence
`linking the use of parenteral drug
`products containing aluminum to
`morbidity and mortality among patients
`on TPN therapy, especially among
`premature neonates and patients with
`impaired kidney function.
`DATES: This rule is effective January 26,
`2001.
`ADDRESSES: Submit written comments
`to the Dockets Management Branch
`(HFA-305). Food and Drug
`Administration, 5630 Fishers Lane, rm.
`1061, Rockville, MD 20852.
`FOR FURTHER INFORMATION CONTACT:
`Leanne Cusumano, Center for Drug
`Evaluation and Research [HFD-7), Food
`and Drug Administration, 5600 Fishers
`Lane, Rockville, MD 20857, 301-594-
`2041.
`SU PPLEMENTARY INFORMATION:
`I. Background
`FDA published a notice of intent in
`the Federal Register on May 21 , 1990
`(55 FR 20799) announcing FDA's
`concerns about toxic aluminum levels
`in TPN and requesting comments. As a
`result of the comments received, on
`January 5, 1998, FDA published a
`proposed rule in the Federal Register
`(63 FR 176) in which it proposed to: (1)
`Establish a maximum permissible level
`of aluminum in L VP's used in TPN
`therapy; (2) require that the maximum
`level of aluminum permitted in L VP's
`u sed 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 of SVP's
`and PBP's used in the preparation of
`TPN solutions; (4) require that the
`package insert of all L VP's and SVP's,
`including PBP's, contain a warning
`statement about aluminum toxicity in
`patients with impaired kidneys and
`neonates receiving TPN therapy; and (5)
`require that applicants and
`manufacturers develop validated assay
`methods for determining the aluminum
`content in parenteral drug products
`used in TPN therapy and submit the
`validated assay methods to FDA for
`approval.
`FDA has become increasingly
`concerned about the aluminum content
`in parenteral drug products, which
`could result in a toxic accumulation of
`
`aluminum in the tissues of individuals
`receiving TPN therapy. FDA included
`specific references in the proposed rule
`that supported the following
`information about aluminum toxicity
`(63 FR 176). Research indicates that
`neonates and patient populations with
`impaired kidney function may be at
`high risk of exposure to unsafe amounts
`of aluminum. Many drug products used
`routinely for TPN may contain levels of
`aluminum su fficiently high to cause
`clinical manifestations. Generally, when
`medication and nutrition are
`administered orally, the gastrointestinal
`tract acts as an efficient barrier to the
`absorption of aluminum, and relatively
`little ingested aluminum actually
`reaches body tissues. However,
`parenterally administered drug products
`containing aluminum bypass the
`protective mechanism of the
`gastrointestinal tract and aluminum
`circulates, and it is deposited in human
`tissues.
`Aluminum toxicity is difficult to
`identify in neonates because few
`reliable techniques are available to
`evaluate bone metabolism in premature
`neonates. Techniques used to evaluate
`the effects of aluminum on bone in
`adults cannot be used in premature
`neonates. Although aluminum toxicity
`is not commonly detected clinically, it
`can be serious in selected patient
`populations, such as neonates, and may
`be more common than is recognized.
`Classic manifestations of aluminum
`intoxication in patients with impaired
`kidney function include fracturing
`osteomalacia, encephalopathy, and
`microcytic hypochromic anemia.
`Aluminum may prevent calcium
`absorption in premature neonates
`receiving TPN therapy. In addition,
`aluminum loading may be a factor in the
`bone disease of very ill neonates with
`reduced kidn ey function who have
`received long-term parenteral therapy
`with aluminum-contaminated fluids.
`FDA received 21 comments on the
`proposed rule and addresses each of
`those comments in section III of this
`document. FDA is adopting this final
`rule as described below. The agency has
`also made minor edits to the final rule
`in response to the President's June 1,
`1998, memorandum on plain language
`in Government writing.
`II. Highlights of the Final Rule
`FDA is implementing this final rule
`because of evidence linking the use of
`parenteral drug products containing
`aluminum lo morbidity and mortality
`among patients on TPN therapy,
`especially premature neonates and
`patients with impaired kidney function.
`
`The new regulations added to part
`201 ((21 CFR 201) at§ 201.323(a)) limit
`the aluminum content for all LVP's used
`in TPN therapy lo 25 micrograms per
`liter (µg/L). This requirement applies to
`all LVP's used in TPN therapy,
`includi ng, but not limited to, parenteral
`amino acid solutions, highly
`concentrated dextrose solutions,
`parenteral lipid emulsions, saline and
`electrolyte solutions, and sterile water
`for injection.
`New § 201.323(b) requires the package
`insert for all LVP's used in TPN th erapy
`lo state that the drug product contains
`no more than 25 µg/L of aluminum. This
`statement must be included in the
`"Precautions" section of the labeling.
`New§ 201.323(c) requires the
`product's maximum level of aluminum
`at expiry to be stated on the immediate
`container label of SVP's and PBP's u sed
`in the preparation ofTPN solutions. The
`statement on the immediate container
`label must read as follows: "Contains no
`more than - - µg/L of aluminum." For
`those SVP's and PBP's that are
`lyophilized powders used in the
`preparation of TPN solu tions, the
`maximum level of aluminum at expiry
`must be printed on the immediate
`contain er label as follows: "When
`reconstituted in accordance with the
`package insert instructions, the
`concentration of aluminum will be no
`more than -
`- µg/ L." The maximum
`level of aluminum must be slated as the
`highest of: (1) The highest level for the
`batches produced during the last 3
`years; (2) the highest level for the latest
`five batches, or (3) the maximum
`historical level, but only until
`completion of production of the first
`five batches after January 26, 2001. The
`labeling requirement applies to all
`SVP's and PBP's used in the preparation
`ofTPN solutions, including, but not
`limited lo: 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 solu tions; 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, a nd zinc.
`New § 201 .323(d) requires the package
`insert for all LVP's, SVP's, and PBP's
`used in TPN to contain a warning
`statement. Th e warning statement must
`be included in the "Warn ings" section
`of the labeling. Tho warning must
`con tain the following language:
`
`Nexus Ex. 1055
`Page 2 of 9
`
`

`

`Federal Register / Vol. 65, No. 17 / Wednesday, January 26, 2000 I Rules and Regulations
`
`4105
`
`WARNING: This product contains
`aluminum that may be toxic. Aluminum may
`reach toxic levels with prolonged parenteral
`administration if kidney function is
`impaired. Premature neonates are
`particularly at risk because their kidneys are
`immature. and they require large amounts of
`calcium and phosphate solutions, which
`contain aluminum.
`Research indicates that patients with
`impaired kidney function, including
`premature neonates, who receive parenteral
`levels of aluminum at greater than 4 to 5 µg/
`kg/day accumulate aluminum at levels
`associated with central nervous system and
`hone toxicity. Tissue loading may occur at
`even lower rates of administration.
`FDA removed the phrase "intended
`for patients with impaired kidney
`function and for neonates receiving TPN
`therapy" from the first sentence of
`§ 201.323(d) because the phrase
`duplicated information contained in the
`actual warni ng and because the phrase
`made the first sentence of § 201.323(d)
`unclear.
`New§ 201.323(e) requires applicants
`and manufacturers to use validated
`assay methods to determine the
`aluminum content in parenteral drug
`products used in TPN therapy. The
`assay methods must comply with
`current good manufacturing practice
`regulations under part 211 (21 CFR part
`211) (see § 211.194(a)J. Holders of
`approved applications for LVP's, SVP's,
`and PBP's used in TPN therapy are
`required to submit a supplement to FDA
`under§ 314. 70(c) (21 CFR 314. 70(c); see
`also 21 U.S.C. 356a(b)) describing the
`assay method used for determining the
`aluminum content. Applicants must
`submit the validation method used and
`the release data for several batches. In
`addition, manufacturers of parenteral
`drug products not subject to an
`approved application must make assay
`methodology available to FDA during
`inspections (see 21 CFR 211 .160 and
`211.180(c)).
`New§ 201.323 applies to all human
`drug LVP's, SVP's, and PBP's used in
`TPN. Licensed biological products are
`not covered by this rule.
`III. Comments on the Proposed Rule
`FDA received 21 comments on the
`proposed rule from professional
`associations, prescription drug
`manufacturers, Congress, individuals on
`TPN, and a hospital. Most comments
`supported the proposed limit for
`aluminum content in LVP's and the
`labeling requirement for SVP's and
`PBP's. Four comments suggested
`changes to the proposed warning
`statement. A summary of Lhe comments
`received and the agency's responses
`follow.
`
`A. Levels of Aluminum Content in LVP's
`The agency stated in the proposed
`rule that it was considering setting an
`upper limit of 25 µg/L for L VP's used in
`TPN therapy. This requirement would
`apply to all LVP's used in TPN therapy,
`including, but not limited lo, parenteral
`amino acid solutions, highly
`concentrated dextrose solutions,
`parenteral lipid emulsions, saline and
`electrolyte solutions, and sterile water
`for injection. The agency also proposed
`that the package insert for all L VP's
`used in TPN therapy state that the drug
`product contains no more than 25 µg/1.
`1. Fifteen comments strongly
`supported a limit on aluminum of 25
`µg/1 . Two of the comments specifically
`supported the accompanying proposal
`that the package insert state that the
`drug product contains no more than 25
`µg/L of aluminum.
`FDA agrees that 23 µg/L of aluminum
`is a reasonable limit. As stated in the
`proposed rule, the 25 µg/L limit is
`feasible and necessary for the safe and
`effective use of LVP's used in TPN
`therapy.
`Two comments, one from an L VP
`manufacturer and the other from a trade
`association , staled that 25 µg/L is not a
`reasonable limit for the varying reasons
`outlined in comments 2 through 8, in
`section III. A of this document.
`2. These comments staled that data
`from production batches show potential
`rejections of finished batches al release
`if a limit of 25 µg/L is adopted . One of
`these comments specified that more
`than 10 percent of assay results exceed
`the proposed limit. IL also stated that
`their current batch analysis sh owed a 95
`p ercent confidence that at least 99
`percent of the batch contained less than
`50.37 µg/L of aluminum al release.
`FDA understands that not all current
`batches of LVP's will meet a 25 µg/L
`level of aluminum. FDA will implement
`this rule 1 year after the date of
`publication lo allow companies an
`opportunity to meet the specification s
`in this rule. FDA is not adopting a
`higher level because FDA believes a 25
`µg/L level of aluminum is necessary to
`protect the public health.
`3. The same two comments said that
`glass leaching over lime increases
`aluminum levels so that initial levels
`cannot be established low enough lo
`ensure batch acceptability by the end of
`the expiry period.
`The intention of this rule is to reduce
`aluminum lo an acceptable level in TPN
`products. A manufacturer can reduce
`toxicity by any of several routes,
`including using containers made of
`different materials.
`4. One of these comments requested
`that FDA set the maximum level of
`
`aluminum using the procedure specified
`in the draft guidance entitled "Q6A
`Specifications: Test Procedures and
`Acceptance Criteria for New Drug
`Substances and New Drug Products:
`Ch emical Substances" (draft Q6A
`guidan ce) (62 FR 62890). This draft
`guidance states that a limit on
`impurities can be determined by (1)
`Determining the level at which the
`impurity is present in relevant batches
`and then (2) determining the mean plus
`upper confidence limit for the impurity
`where the upper confidence limit is
`three times the standard deviation of
`batch analysis data.
`FDA is not using the procedures
`specified in the draft Q6A guidance
`because it is not appropriate to use
`current product aluminum levels to
`determine upper limits when the goal is
`lo reduce aluminum levels to at or
`below the limit defined as safe. Further,
`the guidances entitled "Q3A: Impurities
`in New Drug Substances," Oanuary
`1996) and " Q3B Impurities in New Drug
`Products," (November 1997) address the
`issue of quantification of impurities.
`These guidan ces stale that limits should
`be set no higher than the level that can
`be justified by safety data. The
`guidances also state that, for impurities
`known to be unusually potent or to
`produce toxic or unexpected
`pharmacological effects, the
`quantitation and detection limit of the
`analytical methods should be
`commensurate with the level at which
`the impurities must be controlled.
`FDA's primary concern in enacting this
`rule is ensuring the safety of the patient
`population and limiting exposure lo the
`impurity. FDA has determined that the
`25 µg/L limit is necessary for the safe
`and effective use of LVP's in TPN
`therapy.
`5. These comments also stated that
`current assay methods cannot reliably
`distinguish between 25 µg/L and 30 µg/
`L. The comment did not p rovide
`supporting data or evaluation of the
`specific methods claimed to lack the
`required accuracy.
`FDA understands that methods are
`currently available that are capable of
`detecting aluminum concentrations al
`25 µg/L levels. In particular, FDA is
`aware that graphite furnace atomic
`absorption spectrometometry can be a
`sufficiently accurate validation method.
`However, FDA will accept any validated
`analytical method to assay aluminum
`content in TPN.
`6. One of these comments suggested
`that FDA sh ould require labeling of
`LVP's w ith an average and a range of
`aluminum values al expiry, obtained
`from five production scale batches,
`instead of requiring a limit of 25 µg/L
`
`Nexus Ex. 1055
`Page 3 of 9
`
`

`

`4106
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`Federal Register / Vol. 65, No. 17 / Wednesday, January 26, 2000 / Rules and Regulations
`
`of aluminum in LVP's. The labeling
`would state "Approximate average
`aluminum value- µg/L. Approximate
`aluminum range --µ g/L to - µg/L."
`The same comment requested that FDA
`apply the same labeling standards lo
`LVP's, SVP's, and PBP's, under the
`rationale that some LVP's are identical
`in composition to PBP's.
`FDA notes that if a manufacturer
`makes a PBP specifically for L VP use,
`the PBP should not contain more than
`25 µg/L of aluminum so that the L VP
`manufactured from the PBP does not
`contain more than 25 µg/L of aluminum.
`FDA is implementing the 25 µg/L limit
`for LVP's rather than permitting an
`average or a range of aluminum levels
`to be stated for L VP's because the
`agency believes that it is more
`appropriate to set a maximum level due
`to the large volume of use of these
`products. FDA has determined that the
`25 µg/L limit is necessary for the safe
`and effective use of L VP's used in TPN
`therapy. FDA's basis for not requiring
`SVP's and PBP's to be labeled with an
`average and a range of aluminum levels
`is discussed in response to comment 11
`in section III. B of this document.
`7. This same comment stated that
`establishing a 25 µg/L limit on LVP's
`would not have the desired effect of
`reducing aluminum levels in TPN
`because the majority of aluminum
`contamination is due lo SVP's, not
`LVP's. A different comment requested
`that FDA narrow coverage of the rule lo
`only those products that contribute
`significant amounts of aluminum to
`TPN: Calcium gluconale, calcium
`gluceptate, potassium phosphates, and
`sodium phosphates. The comment
`stated that calcium gluconate alone can
`contribute 88 percent of the total
`aluminum present in a TPN
`formulation.
`FDA recognizes that numerous factors
`contribute lo aluminum contamination
`in TPN therapy. Therefore, FDA is
`addressing the problem in several
`different ways in an effort to reduce
`aluminum contamination, rather than
`reducing aluminum from one source.
`8. Another comment noted that the
`United States Pharmacopeia (USP) has
`limited aluminum levels in monographs
`for substances used in hemodialysis,
`including: Calcium acetate, calcium
`chloride, magnesium chloride,
`potassium chloride, sodium acetate,
`sodium bicarbonate, and sodium
`chloride. The comment stated that
`additional steps could be taken to limit
`aluminum levels in monographs of
`substances used in the manufacture of
`TPN solutions. Although FDA believes
`USP's limits add a valuable contribution
`to limiting aluminum contamination,
`
`FDA believes the additional measures
`set forth in this final rule are needed to
`prevent an unsafe level of aluminum in
`TPN.
`B. Aluminum Levels in SVP's and PBP's
`In the proposed rule, FDA proposed
`requi ring that the maximum level of
`aluminum at expiry be slated on the
`immediate container label of SVP's and
`PBP's used in the preparation of TPN
`solutions. FDA proposed that the
`statement on the immediate container
`label read as follows: "Contains no more
`than - - µg/L of aluminum." For those
`SVP's and PBP's that are lyophilized
`powders used in the preparation of TPN
`solutions, FDA proposed t11at the
`maximum level of aluminum al expiry
`be printed on the immediate container
`label as follows: "When reconstituted in
`accordance with the package insert
`instructions, the concentration of
`aluminum will be no more than-- µg/
`L." FDA proposed that the maximum
`level of aluminum must be expressed as
`the highest of: (1 ) The highest level for
`the batches produced during the last 3
`years; (2) the highest level for t1ie latest
`five batches; or (3) the maximum
`h istorical level , but only until
`completion of production of the first
`five batches after the rule takes effect.
`9. Two comments supported FDA's
`proposal. One comment requested that
`FDA further specify limitations on
`aluminum content for SVP's.
`FDA plans to implement the labeling
`requirements for SVP's and PBP's as
`proposed. FDA does not consider it
`appropriate to consider SVP's as a single
`category because SVP's are used for
`many indications other than TPN and in
`target populations where al uminum
`toxicity is not an issue.
`10. One comment asked that FDA set
`a minimum level below which the
`amount of aluminum would not need to
`be declared.
`FDA believes it is important for health
`care practitioners to know as much as
`possible about the aluminum levels
`being consumed by their patients. FDA
`believes the knowledge that a product
`has a low level of aluminum is just as
`important as the knowledge that a
`product contains high levels of
`aluminum. This labeling requirement
`permits health care professionals
`administering the drug to be able lo
`calculate the total aluminum exposure
`the patient receives from multiple
`sources, and lo be able to make
`appropriate substitutions to prepare
`"low aluminum" parenteral solutions
`for use in patients who are in h igh risk
`groups. Therefore, FDA believes all
`LVP's, SVP's, and PBP's used in TPN
`
`should be labeled with their aluminum
`levels.
`11. One comment stated that
`information about the average amount of
`aluminum and its range at expiration for
`LVP's and SVP's is more useful than the
`maximum historical value at expiration,
`since otherwise a physician may
`overestimate the amount of aluminum
`being delivered to the patient. Another
`comment proposed that FDA require
`labeling of SVP's and PBP's with an
`average and a range of aluminum values
`at expiry, obtained from five production
`scale batches, such that the labeling
`would stale "Approximate average
`aluminum value - - µg/L.
`Approximate al uminum range - - µg/
`L lo-- µg/L."
`The agency believes that information
`about the maximum concentration of
`aluminum potentially present at expiry
`is more useful lo the practitioner. FDA's
`intention is to limit exposure lo
`aluminum, and the use of average
`values or range al expiration would not
`achieve th is goal as effectively.
`C. Applicability to Biologics
`In the proposed rule, FDA slated that
`licensed biological products were not
`covered by the proposal.
`12. Twelve comments stated that
`biologics, specifically albumin,
`plasminate, and any other colloidal
`volume expanders, should be regulated.
`The Center for Biologics Evaluation and
`Research at the FDA is curren tly
`considering whether lo regulate the
`levels of al uminum in licensed
`biological products. However, such
`regulation is outside the scope of this
`final rule.
`D. Statement Regarding Maximum
`Intake of Aluminum
`FDA proposed requiring a statement
`regarding the maximum daily aluminum
`intake recommended for patients. FDA
`sought comment on whether adding the
`language "Patients should receive no
`more than 4 to 5 µg/kg/day of
`aluminum" to the warning statement
`was appropriate and on whether a 4 to
`5 µg/kilogram (kg)/day level is
`reasonable and adequate lo protect the
`public health.
`1 3. Two comments stated that FDA
`should include definitions of safe,
`unsafe, and toxic levels of aluminum.
`Three comments said that FDA should
`provide health professionals w ith a best
`estimate as to what constitutes a toxic
`aluminum load.
`One comment stated that proposing to
`limit aluminum to 4 to 5 µg/kg/day
`would either make TPN formulations
`unavailable to neonates or expose
`doctors lo liability, because ii is a
`
`Nexus Ex. 1055
`Page 4 of 9
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`Federal Register /Vol. 65, No. 17 /Wednesday, January 26, 2000/Rules and Regulations
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`4107
`
`difficult level to meet. Another
`comment said th at 4 to 5 µg/kg/day is
`too low and may not allow patients to
`receive adequate amounts of calcium
`and phosphates. One comment noted
`that parenteral limits are much lower
`than oral limits, and expressed the
`belief that the proposed language did
`not offer guidance with respect to
`combined oral and parenteral daily
`limits. Another comment noted that the
`proposal does not provide a therapeutic
`alternative to too high aluminum levels,
`and asked that FDA include in the
`statement a definition of the
`popu lations truly at risk.
`One comment stated that it would be
`difficult for health care professionals lo
`calculate total aluminum intake,
`particularly for neonates receiving
`multiple intravenous infusions. Another
`comment staled that the factors that
`affect plasma aluminum clearance 1 can
`influence sen sitivity to aluminum load 2
`at any concentration of aluminum
`infused, and therefore aluminum
`concentration in TPN cannot be
`correlated directly to aluminum plasma
`levels.
`Two comments recommended
`alternative statements. One suggested
`using the following language: "Daily
`parenteral intake of greater than 4 to 5
`µg/kg/day of aluminum has been
`associated with central nervous system
`and bone toxicity." Another suggested
`usi ng the following warning: "No
`aluminum toxicity to the brain or bone
`of premature neonates has been
`documented with intakes below 5 µg/
`kg/day; however, tissue loading may
`still occur at that rate of administration
`to preterm infants."
`One comment requested that FDA
`requ ire such a warning statement only
`for those SVP's for which aluminum is
`a significant problem.
`Based on these comments, FDA
`revised the warning to include a
`statement on current findings rather
`than a statement about maximum safe
`levels. FDA included specific references
`in the proposed rule (63 FR 176).
`E. Acceptable Assay Methods for
`Determining Aluminum Levels
`FDA proposed permitting applicants
`and manufacturers to have the
`discretion and flexibility lo develop
`their own validated assay methods as
`long as the methods are in compliance
`with current good manufacturing
`practices requirements. Holders of
`approved applications for LVP's, SVP's
`
`1 The clearance rate for aluminum is the rate al
`which aluminum is removed from the body by
`normal body functioning.
`'Aluminum load is lhe amount of aluminwn in
`tl10 body.
`
`and PBP's used in TPN therapy would
`be required to submit a supplement
`under part 314 (21 CFR part 314) in
`§ 314.70(c) that described the method
`used for determining al uminum content.
`Holders of pending applications would
`be required to submit an amendment
`under§ 314.60 or§ 314.96. For SVP's
`not subject to approved applications,
`manufacturers would be required lo
`maintain records for examination by
`FDA during inspections.
`14. One comment stated that the USP
`provides an established system and
`procedure for the development of
`uniform analytical methods. The
`comment asked that FDA request that
`U.S.P. develop assay methods for
`determining aluminum content in
`parenterals rather than requiring
`individual companies to do so.
`FDA believes that more than one
`analytical method may be suitable or
`necessary to assay aluminum content in
`different TPN products. Once FDA has
`reviewed several methods, it may
`evaluate whether it is appropriate lo
`develop uniform analytical procedures.
`Individual companies may provide their
`validated analytical methods lo USP for
`publication. Through this process, USP
`may establish a uniform analytical
`method for determining aluminum
`content in parenterals. FDA will accept
`any method that is validated and in
`compliance with current good
`manufacturing practice requirements.
`15. One comment supported FDA's
`proposal. The comment also stated that
`analytical methods should be those in
`general use, such as flameless atomic
`absorpt