**OMB INFORMATION COLLECTION - SUPPORTING STATEMENT**

**ALUMINUM IN LARGE AND SMALL VOLUME PARENTERALS**

**USED IN TOTAL PARENTERAL NUTRITION - 21 CFR 201.323**

**OMB \# 0910-0439**

**Docket No. 02N-0496**

**[Justification]{.underline}**

**1. [Circumstances of Information Collection]{.underline}**

**The Food and Drug Administration (FDA) is requesting OMB approval
under the Paperwork Reduction Act (44 USC 35) for the labeling
requirements for aluminum content in large volume parenterals, small
volume parenterals, and pharmacy bulk packages used in total parenteral
nutrition. As explained in the final rule on aluminum content labeling
requirements published in the Federal Register of January 26, 2000 (65
FR 4103), aluminum content in parenteral drug products could result in a
toxic accumulation of aluminum in the tissues of individuals receiving
total parenteral nutrition therapy. Research indicates that neonates and
patient populations with impaired kidney function may be at high risk of
exposure to unsafe amounts of aluminum. Studies show that aluminum may
accumulate in the bone, urine, and plasma of infants receiving TPN. 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. 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.**

**FDA amended its regulations to add labeling requirements for aluminum
content in LVPs, SVPs, and PBPs used in TPN. FDA specified an upper
limit of aluminum permitted in LVPs and required applicants to submit to
FDA validated assay methods for determining aluminum content in
parenteral drug products. The agency added 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.**

**The information collection reporting requirements resulting from this
rulemaking are as follows:**

**21 CFR 201.323(b) Requires that the package insert of all large volume
parenterals used in total parenteral nutrition therapy state that the
drug product contains no more than 25 ug/L. This information must be
contained in the \_Precautions\_ section of the labeling of all large
volume parenterals used in total parenteral nutrition therapy.**

**21 CFR 201.323(c) Requires that the maximum level of aluminum present
at expiry be stated on the immediate container label of all small volume
parenteral drug products and pharmacy bulk packages used in the
preparation of total parenteral nutrition solutions. The aluminum
content must be stated as prescribed in the regulation. The immediate
container label of all small volume parenteral drug products and
pharmacy bulk packages that are lyophilized powders used in the
preparation of total parenteral nutrition solutions must contain the
statement prescribed in the regulation.**

**21 CFR 201.323(d) Requires that the package insert for all large
volume parenterals, small volume parenterals, and pharmacy bulk packages
used in TPN contain a warning statement, prescribed in the regulation,
intended for patients with impaired kidney function and for neonates
receiving total parenteral nutrition therapy. This information must be
contained in the \"Warnings\" section of the labeling.**

**21 CFR 201.323(e) Requires that applicants and manufacturers must use
validated assay methods to determine the aluminum content in parenteral
drug products. The assay methods must comply with current good
manufacturing practice requirements. Applicants must submit to FDA 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 must submit an amendment to
the application.**

**2. [Purpose and Use of Information]{.underline}**

**As explained in the final rule on aluminum content labeling
requirements published in the Federal Register of January 26, 2000 (65
FR 4103), aluminum content in parenteral drug products could result in a
toxic accumulation of aluminum in the tissues of individuals receiving
total parenteral nutrition therapy. Research indicates that neonates and
patient populations with impaired kidney function may be at high risk of
exposure to unsafe amounts of aluminum. Studies show that aluminum may
accumulate in the bone, urine, and plasma of infants receiving TPN. Many
drug products used routinely in parenteral therapy may contain levels of
aluminum sufficiently high to cause clinical manifestations.**

**3. [Use of Improved Information Technology]{.underline}**

**The information collection results mainly from the submission to FDA
of revised labeling. In the Federal Register of May 3, 2002 (67 FR
22367), FDA published a proposed rule to require that certain labeling
content be submitted electronically in a form that FDA can process,
review, and archive. FDA is now preparing to finalize this rulemaking.**

**4. [Efforts to Identify Duplication]{.underline}**

**Because of the unique nature of the information to be collected,
duplication of information is unlikely.**

**5. [Involvement of Small Entities]{.underline}**

**If a rule has a significant impact on a substantial number of small
entities, the Regulatory Flexibility Act requires agencies to analyze
regulatory options that would minimize the significant economic impact
of such a rule on small entities. In the proposed rule, FDA relied on
the estimated compliance costs by type of establishment as projected by
Eastern Research Group. That analysis determined that very few of the
affected companies are considered small by the standards of the Small
Business Administration. Therefore, the agency certified that the
proposed rule would not have a significant economic impact on a
substantial number of small entities. The agency received no comments
specifically directed at this certification. Nevertheless, due to
comments on other aspects of its estimates and modifications to the
original analysis, FDA, in the final rule, reanalyzed the small business
impacts of the final rule.**

**Fewer than 8 of the 24 companies identified in the ERG report as a
manufacturer or supplier of TPN products or their inputs are small
businesses according to the Small Business Administration (SBA)
definitions. It is possible that four SVP manufacturers are small under
the SBA definitions. However, since the average annualized cost for
these establishments is estimated at about \$51,000 each, the estimated
annualized compliance costs for these companies are expected to account
for less than one percent of their annual revenues. FDA further
identified one amino acid supplier that may be a small business; but
again, the annualized compliance costs for this firm would be less than
1 percent of annual revenues. The size of one dextrose supplier and one
electrolyte supplier could not be confidently determined due to the
scarcity of data. Therefore, it was not possible to determine whether
the compliance costs of these firms would represent more than 1 percent
of their revenues. Based on the very few small firms that might incur a
significant impact, the agency certified under section 605(b) of the
Regulatory Flexibility Act that the final rule will not have a
significant economic impact on a substantial number of small entities.**

**6. [Consequences if Information Collected Less
Frequently]{.underline}**

**As discussed above, these requirements are necessary 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.**

**7. [Consistency with the Guidelines in 5 CFR
1320.5(d)(2)]{.underline}**

**The collection methods are consistent with the guidelines of 5 CFR
1320.5(d)(2), except that applicants are required to submit 12 copies of
labeling to FDA under the supplement regulations in 21 CFR 314.70. This
is necessary to facilitate FDA review of these supplements in a timely
manner. This is already approved by OMB under Control Number
0910-0001.**

**8. [Consultation Outside the Agency]{.underline}**

**In developing the proposed rule, FDA 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. 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. 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. 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.
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
responses were discussed in the proposed rule.**

**In the Federal Register of January 5, 1998 (63 FR 176), FDA published
the proposed rule requesting comments on the proposed collections of
information and received 21 comments 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 the comments received and the agency\'s responses are
discussed in the final rule.**

**In the Federal Register of December 19, 2002 (67 FR 77792), FDA
published a notice requesting public comment and an extension of the
approval of this information collection. No comments were received.**

**9. [Remuneration of Respondents]{.underline}**

**FDA has not provided and has no intention to provide any payment or
gift to respondents under this provision.**

**10. [Assurance of Confidentiality]{.underline}**

**Trade secret information collected under section 505 of the act is
protected by statute and regulation (21 U.S.C. 331(j) and 21 CFR part
20).**

**11. [Questions of a Sensitive Nature]{.underline}**

**This rulemaking does not contain questions pertaining to sex,
behavior, attitude, religious beliefs, or any other matters that are
commonly considered private or sensitive in nature.**

**12. [Estimates of Annualized Hour Burden]{.underline}**

**FDA regulations add certain labeling requirements for aluminum content
in LVP\'s, SVP\'s and PBP's used in TPN. FDA regulations also specify an
upper limit of aluminum permitted in LVP\'s and require manufacturers to
submit to FDA for approval validated assay methods for determining
aluminum content in parenteral drug products. These requirements are
necessary because of evidence linking the use of parenteral drug
products containing aluminum to morbidity and mortality among patients
on TPN therapy, especially premature neonates and patients with impaired
kidney function. Compliance with the information collection burdens
under 21 CFR 201.323(b), (c), and (d) consists of submitting application
supplements to FDA containing the revised labeling for each product.
Based on data concerning the number of applications for LVPs, SVPs, and
PBPs used in TPN received by the agency, FDA estimates that the labeling
for approximately 200 products will be changed under section 201.323(b),
(c), and (d). FDA estimates that it will take approximately 14 hours to
prepare and submit to FDA each labeling change. FDA estimates that
approximately 65 respondents will each submit one validated assay method
annually under section 201.323(e). FDA estimates that it will take
approximately 14 hours to prepare and submit to FDA each validated
assay.**

**The burdens can be charted as follows:**

  -----------------------------------------------------------------------

  -----------------------------------------------------------------------