Small Volume Parenteral 
Drug Products and 
Pharmacy Bulk Packages 
for Parenteral Nutrition: 
Aluminum Content and 
Labeling Recommendations 
Guidance for Industry 
 
 
 
DRAFT GUIDANCE 
 
  This guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit electronic comments to https://www.regulations.gov.  Submit written 
comments to the Dockets Management Staff (HFA-305), Food and Drug Administration, 5630 
Fishers Lane, Rm. 1061, Rockville, MD  20852.  All comments should be identified with the 
docket number listed in the notice of availability that publishes in the Federal Register. 
 
For questions regarding this draft document, contact (CDER) Thao Vu at 240-402-2690.  
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2022 
Clinical/Medical 
26805550dft.docx 
11/30/2022   
Small Volume Parenteral 
Drug Products and 
Pharmacy Bulk Packages 
for Parenteral Nutrition:  
Aluminum Content and 
Labeling Recommendations 
Guidance for Industry 
 
Additional copies are available from: 
 
Office of Communications, Division of Drug Information 
Center for Drug Evaluation and Research 
Food and Drug Administration 
10001 New Hampshire Ave., Hillandale Bldg., 4th Floor  
Silver Spring, MD  20993-0002  
Phone: 855-543-3784 or 301-796-3400; Fax: 301-431-6353; Email: druginfo@fda.hhs.gov 
https://www.fda.gov/drugs/guidance-compliance-regulatory-information/guidances-drugs 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Drug Evaluation and Research (CDER) 
 
December 2022 
Clinical/Medical 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
TABLE OF CONTENTS 
 
I.  INTRODUCTION............................................................................................................. 1 
II.  BACKGROUND ............................................................................................................... 3 
III.  STEPS TO DERIVE THE RECOMMENDED ALUMINUM CONCENTRATION 
LIMIT IN THE SVP DRUG PRODUCT ....................................................................... 4 
A.  Determination of the IAE of Individual SVP Drug Products .................................................... 5 
B.  Determination of the ACL in an SVP Drug Product .................................................................. 7 
IV.  EXAMPLES OF DETERMINATION OF IAE AND ACL .......................................... 7 
A.  Determination of IAE  of SVP Drug Products with Known or Labeled Aluminum 
SVP
Concentration ................................................................................................................................. 7 
1. Potassium Acetate ............................................................................................................................ 8 
2. Zinc Chloride ................................................................................................................................... 9 
3. Multiple Vitamins Injection .............................................................................................................. 9 
4. Cysteine Hydrochloride ................................................................................................................... 9 
B.  Determination of ACL from IAE  for SVP Drug Product Under Development .................. 9 
SVP
1. Potassium Acetate .......................................................................................................................... 10 
2. Cysteine Hydrochloride ................................................................................................................. 11 
V.  MANUFACTURING CONSIDERATIONS FOR THE CONTROL OF 
ALUMINUM CONTENT IN SVP DRUG PRODUCTS ............................................. 12 
VI.  LABELING CONSIDERATIONS ................................................................................ 14 
A.  Prescribing Information .............................................................................................................. 14 
1. Limitations of Use in the Indications and Usage Section .............................................................. 14 
2. Warnings and Precautions Section ................................................................................................ 14 
3. Pediatric Use Subsection in the Use in Specific Populations Section ........................................... 16 
4. Description Section ........................................................................................................................ 16 
B.  Container Label and Carton Labeling ....................................................................................... 17 
GLOSSARY................................................................................................................................. 19 
ABBREVIATIONS AND ACRONYMS ................................................................................... 20 
REFERENCES ............................................................................................................................ 21 
  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
1  Small Volume Parenteral Drug Products  
2  and Pharmacy Bulk Packages for Parenteral Nutrition:  
3  Aluminum Content and Labeling Recommendations 
4  Guidance for Industry1 
5   
6   
7   
8   
9  This draft guidance, when finalized, will represent the current thinking of the Food and Drug 
10  Administration (FDA or Agency) on this topic. It does not establish any rights for any person and is not 
11  binding on FDA or the public. You can use an alternative approach if it satisfies the requirements of the 
12  applicable statutes and regulations. To discuss an alternative approach, contact the FDA staff responsible 
13  for this guidance as listed on the title page.   
14   
15   
16   
17   
18  I.  INTRODUCTION 
19   
20  Aluminum toxicity in parenteral nutrition (PN)2 represents a major safety concern, necessitating 
21  that PN products meet the requirements in 21 CFR 201.323 for aluminum content and labeling. 
22  Per the regulation, aluminum content of large volume parenteral (LVP) drug products3 used in 
23  total parenteral nutrition (TPN) therapy must not exceed 25 micrograms per liter (mcg/L).4 In 
24  contrast, the limits for the aluminum content of small volume parenteral (SVP) drug products 
25  and pharmacy bulk packages (PBPs)5 used in PN are not specified by statute or regulation. 
 
1 This guidance has been prepared by the Division of Hepatology and Nutrition in cooperation with the Labeling 
Policy Team within the Office of New Drugs, the Office of Pharmaceutical Quality, and the Office of Generic Drugs 
in the Center for Drug Evaluation and Research at the Food and Drug Administration.  
 
2 Parenteral nutrition encompasses both total parenteral nutrition and peripheral parenteral nutrition, administered 
via central or peripheral veins. FDA understands that 21 CFR 201.323 refers only to total parenteral nutrition; 
however, based on current clinical practice, the Agency believes that it is appropriate to treat the terms total 
parenteral nutrition, peripheral parenteral nutrition, and parenteral nutrition interchangeably for the purposes of 
this guidance. 
 
3 For the purposes of this guidance, a large volume parenteral drug product has the same meaning as in 21 CFR 
310.509(b): a terminally sterilized aqueous drug product packaged in a single-dose container with a capacity of 100 
milliliters or more and intended to be administered or used intravenously in a human. 
 
4 21 CFR 201.323(a). 
 
5 PBPs are sterile preparations for dispensing of single doses to many patients in a pharmacy admixture program. 
PBPs are either used to prepare admixtures for infusion or for the filling of empty sterile syringes (through a sterile 
transfer device). PBPs are limited to injection, for injection, or to injectable emulsion dosage forms. See USP 
General Chapters <7> Labeling and <659> Packaging and Storage Requirements. 
  1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
26  Further, the International Council for Harmonisation (ICH) has not established a permitted daily 
27  exposure (PDE) for aluminum.6 
28   
29  To address this lack of information, this guidance clarifies the key factors in determining the  
30  aluminum content in an SVP drug product7 and/or a PBP intended as a component of PN and 
31  provides FDAs recommendations regarding the aluminum concentration limits in SVP drug 
32  products8 and PBPs for PN. 
33   
34  Additionally, this guidance is intended to assist applicants in determining the appropriate content 
35  and placement of information on aluminum in SVP and PBP human prescription drug product 
36  labeling,9 including the Prescribing Information and container label and carton labeling. The 
37  intent of this guidance is to help assure that the information is clear and accessible to health care 
38  practitioners and guides the safe and effective use of the drug product.   
39   
40  The recommendations in this guidance apply to the evaluation of aluminum content and 
41  establishment of a recommended aluminum concentration limit in an SVP drug product or PBP 
42  for PN.10   
43   
44  The guidance does not alter labeling considerations or recommended concentration limits for 
45  aluminum content in LVP drug products for TPN as those are already addressed in 21 CFR 
46  201.323. However, because LVP and SVP drug products can be used together in PN therapy, this 
 
6 PDE is defined as the maximum acceptable intake of elemental impurity in pharmaceutical products per day. See 
the ICH guidance for industry Q3D(R1) Elemental Impurities (March 2020). The ICH guidance does not provide a 
PDE for aluminum because of differences in regulations and practices among geographic regions. We update 
guidances periodically. To make sure you have the most recent version of a guidance, check the FDA guidance web 
page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents.  
 
7 For the purposes of this guidance, references to drug products include drug products approved under section 505 of 
the Federal Food, Drug, and Cosmetic Act (FD&C Act) (21 U.S.C. 355) that are subject to section 503(b)(1) of the 
FD&C Act (21 U.S.C. 353(b)(1)).  
 
8 For the purposes of this guidance, use of the term SVP drug products includes both SVP drug products and SVP 
drug products packaged as PBPs, unless otherwise noted. 
 
9 See 21 CFR 201.56(d) and 21 CFR 201.57. The labeling examples in this guidance are for prescription SVP and 
PBP drug products with labeling that meets the requirements of 21 CFR 201.56(d) and 21 CFR 201.57 (physician 
labeling rule (PLR) format). FDA recommends that the applicant discuss incorporating aluminum toxicity 
information for SVP drug products with labeling that meets the requirements of 21 CFR 201.56(e) and CFR 201.80 
(old format) with the FDA prescription drug review division. For new drug applications that are not required to have 
labeling in PLR format, applicants can consider voluntarily converting the labeling to PLR format because the PLR 
format represents a more useful and modern approach for communicating information on the safe and effective use 
of drug products and makes Prescribing Information more accessible for use with electronic prescribing tools and 
other electronic information resources. 
 
10 The recommendations in this guidance apply to all prescription drug products that are the subject of new drug 
applications (NDAs), abbreviated new drug applications (ANDAs), and future supplements to those applications; 
however, the labeling recommendations in section VI. of this guidance only apply to NDAs and supplemental 
NDAs. The recommendations in this guidance do not apply to compounded drug products or nonprescription drug 
products. 
  2  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
47  guidance does consider the aluminum content in LVP drug products when calculating the 
48  recommended aluminum concentration limit in an SVP drug product. 
49   
50  In general, FDAs guidance documents do not establish legally enforceable responsibilities.  
51  Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
52  as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
53  the word should in Agency guidances means that something is suggested or recommended, but 
54  not required. 
55   
56   
57  II.  BACKGROUND 
58   
59  Parenteral drug products are those intended for injection through the skin or other external 
60  boundary tissue, rather than through the alimentary canal, so that the drug products active 
61  substances are administered directly into a blood vessel, organ, tissue, or lesion. SVP drug 
62  products for PN are used as additives to PN admixtures. 
63   
64  Aluminum, one of the most abundant metallic elements on earth, occurs naturally in several 
65  minerals, ores, oxides, and silicates. Humans are exposed to aluminum through drinking water, 
66  foods, and drugs. Aluminums oral bioavailability is poor, so healthy individuals typically face 
67  little risk of toxicity. The gastrointestinal tract allows less than 1 percent of ingested aluminum to 
68  be absorbed into the bloodstream, and renal excretion removes 99 percent of that aluminum. 
69  Despite that, aluminum toxicity has been documented in medical literature for more than 30 
70  years,11 with manifestations that include osteomalacia and reduced bone mineralization, 
71  neurological dysfunction and dialysis encephalopathy, microcytic hypochromic anemia, and 
72  cholestasis. 
73   
74  A long-implicated, major source of aluminum exposure is PN, resulting from contamination of 
75  ingredients. PN ingredients are contaminated with aluminum in raw materials as well as through 
76  byproducts from the manufacturing process and packaging system, during which aluminum may 
77  leach from the manufacturing equipment and/or container closure components (e.g., glass vials, 
78  stoppers) during autoclave terminal sterilization and shelf-life storage. Patients with underlying 
79  renal impairment who receive prolonged courses of PN support are at greatest risk of exposure to 
80  toxic levels of aluminum from PN. Preterm neonates and infants12 who have immature kidneys 
81  that are incapable of excreting aluminum efficiently and often require many days of PN support 
82  are at particularly high risk. 
83   
84  Research indicates that patients with renal impairment, including preterm neonates, who receive 
85  parenteral levels of aluminum at greater than 4 to 5 micrograms/kilogram/day (mcg/kg/day) 
86  accumulate aluminum at levels associated with central nervous system and bone toxicity. Tissue 
 
11 See, for example, Boyce BF, GS Fell, HY Elder, BJ Junor, HL Elliot, G Beastall, I Fogelman, and IT Boyle, 1982, 
Hypercalcaemic Osteomalacia Due to Aluminium Toxicity, Lancet, 2(8306):10091013, doi: 10.1016/s0140-
6736(82)90049-6. PMID: 6127501. 
 
12 The term neonate includes the age range from birth to up to 1 month of age, and the term infant includes the age 
range from 1 month to up to 2 years of age. The terms preterm infant and premature infant include birth before 37 
weeks of gestation. 
  3  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
87  loading may occur at even lower rates of administration.13 Despite these potential risks and the 
88  variability of each SVP drug product added to PN for individual patients, patients with renal 
89  impairment benefit from PN. Because patients with renal impairment, including all preterm 
90  neonates, comprise a major portion of those requiring PN support, FDA recommends that the 
91  total aluminum exposure (TAE) from PN uniformly should not exceed 5 mcg/kg/day to protect 
92  the safety of all patients. 
93   
94  Multiple sources of LVP and SVP drug products comprise PN, and each drug product may 
95  contribute to the total aluminum content of PN, which should not exceed 5 mcg/kg/day (see 
96  Figure 1). Applicants should consider the recommended limit of aluminum in individual SVP 
97  drug products as the drug products contribution to the total daily aluminum dose from PN to 
98  determine whether the total daily exposure exceeds 5 mcg/kg/day. 
99   
100  Figure 1. Schematic of Aluminum Contributions in PN 
101   
102   
103  PN = parenteral nutrition, LVP = large volume parenteral, SVP = small volume parenteral, TAE = total aluminum 
104  exposure, NMT = no more than; mcg = microgram; kg = kilogram. 
105   
106   
107  III.  STEPS TO DERIVE THE RECOMMENDED ALUMINUM CONCENTRATION 
108  LIMIT IN THE SVP DRUG PRODUCT 
109   
110  There are two major steps in deriving the aluminum concentration limit (ACL) in an SVP drug 
111  product for PN. First, the applicant needs to determine the individual aluminum exposure (IAE) 
112  of the individual SVP drug product (see section IV. A., Determination of IAE  of Drug 
SVP
113  Products with Known or Labeled Aluminum Concentration); then, the applicant can use the IAE 
114  to calculate the ACL (see section IV. B., Determination of ACL from IAE  for SVP Drug 
SVP
115  Product Under Development) for each specific SVP drug product. 
 
13 21 CFR 201.323(e). 
  4  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
116   
117  A.  Determination of the IAE of Individual SVP Drug Products 
118   
119  The first step in the derivation of the ACL in the specific SVP drug product is the determination 
120  of the IAE for the individual SVP drug product. 
121   
122  The determination of the IAE from each individual LVP and SVP drug product combined into 
123  the final PN is needed to determine whether the total daily aluminum dose from the PN therapy 
124  exceeds 5 mcg/kg/day (see Figure 2 and examples below). 
125   
126  Figure 2. Contribution of IAE to TAE for PN  
127   
128   
129  IAE = individual aluminum exposure; TAE = total aluminum exposure; PN = parenteral nutrition; LVP = large 
130  volume parenteral; SVP = small volume parenteral; IAE  = individual aluminum exposure from LVP drug 
LVP
131  product; IAE  = total aluminum exposure from LVP drug products; IAE  = individual aluminum exposure 
LVPtotal SVP
132  from SVP drug product; IAE = total aluminum exposure from SVP drug products 
SVPtotal 
133   IAE  = 0.025 micrograms/milliliters (mcg/mL) times (mL of LVPs/kilograms (kg)/day). Actual measured 
LVPtotal
134  aluminum concentration in the LVP drug product may be lower than 25mcg/liter (L), but the aluminum 
135  concentration in the LVP drug product is assumed as 25 mcg/L per 21 CFR 201.323.  
136   IAE = Y mcg/kg/day divided by the number of SVP drug products intended for use in the PN therapy. When 
SVP 
137  dividing the total aluminum contribution from SVP drug products (Y mcg/kg/day) by the number of SVP drug 
138  products intended for use in the PN therapy, an equal contribution of IAE from each SVP drug product is assumed 
139  when the IAE  for the drug products are unknown. This calculation can be modified based on known or 
SVP
140  established values of IAE  for a given drug product, and the number of SVP additives in a typical PN prescription 
SVP
141  (e.g., four to six) can be justified for each SVP drug product indication. 
142   
  5  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
143    TAE from LVP drug product (X mcg/kg/day or IAE ) 
LVPtotal
144   
145   The IAE of each LVP drug product (in mcg/kg/day) is calculated from the daily dose 
146  volume (milliliter/kilogram/day (mL/kg/day)) of the LVP drug product and its 
147  aluminum concentration (mcg/L).  
148   
149   The aluminum concentration in each LVP component used in a TPN therapy must not 
150  exceed 25 mcg/L.14 Therefore, this guidance assumes a maximum aluminum 
151  concentration of 25 mcg/L (or 0.025 mcg/mL) to determine each IAE . 
LVPtotal
152   
153  Example: For a 3 kg infant on daily dose volume of 80 mL/kg/day of LVP the 
1+2+n, 
154  total aluminum contribution from an LVP drug product (X mcg/kg/day or IAE ) 
LVPtotal
155  would be 2 mcg/kg/day (i.e., 0.025 mcg/mL times 80 mL/kg/day). The infant will 
156  receive 6 mcg/day (i.e., IAE  times 3 kg) of aluminum from the LVP drug 
LVPtotal
157  product. 
158   
159    TAE from SVP drug product (Y mcg/kg/day or IAE ) 
SVPtotal
160   
161   TAE from SVP drug products can be calculated by subtracting the IAE  
LVPtotal
162  aluminum contribution from the TAE for the total amount of PN therapy (e.g., 5 
163  mcg/kg/day) or Y mcg/kg/day equals 5 mcg/kg/day minus X mcg/kg/day. 
164   
165  Example: If TAE from the LVP drug product (IAE ) is X equals 2 mcg/kg/day, 
LVPtotal
166  given that the TAE for the total amount of PN is 5 mcg/kg/day, Y should be 3 
167  mcg/kg/day (IAE ). 
SVPtotal
168   
169   SVP drug products in PN therapy can be used alone or in combination with other 
170  SVP drug products as additives (i.e., electrolytes, trace elements, vitamins, amino 
171  acids), which will all contribute toward the IAE .  
SVPtotal
172   
173   IAE from an individual SVP drug product (IAE ) should take into consideration the 
SVP
174  number of SVP drug products intended to be used in the PN therapy, and the known 
175  IAE  of other individual SVP drug products intended for use in the PN therapy. If 
SVP
176  the aluminum content of an individual SVP drug product is not known, the applicant 
177  should consider equal contribution of IAE from each indivudal SVP drug product. 
178  Based on current FDA experience, a typical PN prescription can include 
179  approximately four to six SVP additives, but this can vary depending on the specific 
180  SVP drug product indication and/or PN prescription practice trends. The applicant 
181  should provide a rationale or justification for the number of SVP additives used in 
182  determining the IAE.  
183   
184  Example: If total aluminum exposure from SVP drug products (Y) is 3 mcg/kg/day 
185  (IAE ), and if six SVP additives are used, IAE for each individual SVP drug 
SVPtotal
 
14 See 21 CFR 201.323(a). 
  6  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
186  product should not exceed 0.5 mcg/kg/day assuming an equal contribution of IAE 
187  from each individual SVP drug product.  
188   
189   When the specific IAE  is known for a given SVP drug product, the calculation can 
SVP
190  be adjusted to ensure that the Y does not exceed 3 mcg/kg/day.  
191   
192  Example: Table 1 lists the known IAE  for potassium acetate as less than or equal 
SVP
193  to 0.6 mcg/kg/day. By subtracting the known IAE  of potassium acetate (i.e., 0.6 
SVP
194  mcg/kg/day) from the IAE  (or Y mcg/kg/day, i.e., 3 mcg/kg/day), the total 
SVPtotal
195  aluminum contribution from the remaining five individual SVP drug products would 
196  be 2.4 mcg/kg/day. Individual IAE  for the five remaining SVP drug products can 
SVP
197  be estimated as less than or equal to 0.48 mcg/kg/day. 
198   
199  B.  Determination of the ACL in an SVP Drug Product 
200   
201  Once the IAE for an individual SVP drug product is determined and adequately justified, the 
202  proposed IAE can be used to calculate the ACL in mcg/L for each specific SVP drug product as 
203  shown in the formula below.  
204   
mL IAE mcg/kg/day x SVP conc. mg/ 15
205  SVP ACL  mcg/L =1000 x ( ) 
L SVP max.  dos e (mg/kg/day)
 ( )   ( mL)
206   
( )
207  The acceptance criteria of the aluminum concentration in dthaeil yS VP adgrug product specification 
208  should not exceed the ACL. This will ensure that the total aluminum the patients receive from 
209  PN will not exceed 5 mcg/kg/day. 
210   
211   
212  IV.  EXAMPLES OF DETERMINATION OF IAE AND ACL 
213   
214  This section provides examples of the determination of IAE  and/or SVP ACL of SVP drug 
SVP
215  products to include known or existing SVP drug products with known aluminum concentrations. 
216  Section A addresses the determination of IAE  of SVP Drug Products with Known or Labeled 
SVP
217  Aluminum Concentration (Table 1), and Section B addresses the determination of ACL from 
218  IAE  for an SVP Drug Product Under Development.  
SVP
219   
220  A.  Determination of IAE  of SVP Drug Products with Known or Labeled 
SVP
221  Aluminum Concentration 
222   
223  When there is an SVP drug product with a known or labeled aluminum concentration (Al conc. 
224  in formulas) (e.g., potassium acetate, multivitamins, zinc chloride, cysteine hydrochloride) (see 
225  Table 1 below), the projected aluminum exposure from the SVP drug product (mcg/kg/day) or 
 
15 Note that the concentration of the drug (i.e., SVP conc. (milligram/milliliter (mg/mL)) in formulas) and the 
prescribed maximum daily dosage of the drug product (i.e., SVP max. dosage (mg/kg/day) in formulas) should be 
expressed consistently in the same form, e.g., active moiety, salt, or inorganic counter ion (see examples in Table 1, 
Section IV. A.). 
  7  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
226  IAE  of an individual drug product can be calculated (right column of Table 1) using the 
SVP
227  following formula when specific SVP maximum dose is expressed in milligram (mg)/kg/day: 
228   
mcg
Al conc.   x SVP max.  dos e (m /kg/day)
L
229  IAE (mcg/kg/day)=  
m mg
 1000   x SVP dcaoinlyc.   ag g
L mL
   
230    L
 
231   
232  or 
233   
234  When a specific SVP maximum dose is expressed in mL/kg/day (dose volume), the IAE  of a 
SVP
235  specific drug product with a known or labeled aluminum concentration can be calculated (right 
236  column of Table 1) using the following formula: 
237   
mcg
Al onc.   x SVP  ax. os e (m /kg/day)
L
238  IAE (mcg/kg/day)=  
m
 c   1m000  daily d ag L
L
   
239    L
240  Table 1. Examples of IAE  from Individual SVP Drug Products with Known Aluminum 
SVP
241  Concentration 
242   
Labeled 
Drug Product  Drug Product  Maximum Daily  Aluminum  IAE  
SVP
Name  Concentration  Dosage  Concentration  (mcg/kg/day) 
Limit* (mcg/L) 
2 mEq/mL of 
Potassium Acetate  6 mEq/kg/day  NMT 200  0.6 
Potassium 
Zinc Chloride  1 mg/mL of Zinc  0.3 mg/kg/day  NMT 150  0.045 
Multiple Vitamins  Multiple vitamins 
3.25 mL/kg/day  NMT 30  0.1 
Injection   (not applicable)** 
15 mg cysteine /g 
Cysteine  34.5 mg/mL of   
of AA***  NMT 120 
Hydrochloride  cysteine  0.21 
 
243  IAE = individual aluminum exposure; SVP = small volume parenteral; IAE  = individual aluminum contribution 
SVP
244  from SVP drug product; mcg = microgram; L = liter; kg = kilogram; mEq = milliequivalent; mL = milliliter; mg = 
245  milligram; g = gram; NMT= no more than, AA = amino acid. 
246  * Known aluminum concentrations have been demonstrated to be no more than the labeled limit.  
247  ** Multivitamins injections are fixed-dose combination products, and the volume-based dosage is derived from the 
248  known concentrations of each component. 
249  *** Maximum amino acid dose of 4 grams AA/kg/day. 
250   
251  1.  Potassium Acetate 
252   
253  Potassium acetate (KOAc) injection contains 2 milliequivalents/milliliter (mEq/mL) potassium. 
254  The recommended dosage ranges are 40 to 80 mEq/day in adults, 2 to 3 mEq/kg/day in older 
255  pediatric patients, and 2 to 6 mEq/kg/day in neonates. The maximum weight-based dose (6 
  8  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
256  mEq/kg/day) should be used for calculations to support establishment of aluminum acceptance 
257  criteria. The derived aluminum exposure (IAE of potassium acetate) from the known labeled 
258  aluminum concentration (i.e., less than or equal to 200 mcg/L) is as follows: 
259   
260  IAE  (mcg/kg/day) = (200 mcg/L x 6 mEq/kg/day)  (1000 mL/L x 2 mEq/mL) = 0.6 mcg/kg/day  
KOAC
261   
262  2.  Zinc Chloride  
263   
264  Zinc chloride (ZnCl ) injection, United States Pharmacopeia (USP) contains 1 mg/mL zinc. The 
2
265  recommended maximum daily dosage is 0.3 mg/kg/day. The aluminum concentration is less than 
266  or equal to 150 mcg/L.  
267   
268  The derived aluminum exposure (IAE of zinc chloride) is calculated as the following: 
269   
270  IAE  (mcg/kg/day) = (150 mcg/L x 0.3 mg/kg/day)  (1000 mL/L x 1 mg/mL) = 
ZnCl2
271  0.045 mcg/kg/day 
272     
273  3.  Multiple Vitamins Injection  
274   
275  The following example pertains to multiple vitamins injection intended for pediatric patients.  
276   
277  The recommended dosage levels are expressed as mL/day and are weight based. Among the 
278  range of body weights for pediatric patients in the dosing instructions, the maximum potential 
279  dosage is 3.25 mL/kg/day. The derived aluminum exposure (IAE of multiple vitamins injection) 
280  from the known labeled aluminum concentration (i.e., less than or equal to 30 mcg/L) is as 
281  follows: 
282   
283  IAE  (mcg/kg/day) = (30 mcg/L x 3.25 mL/kg/day)   1000 mL/L =  
multiple vitamins injection 
284  0.1 mcg/kg/day 
285    
286  4.  Cysteine Hydrochloride  
287   
288  Cysteine hydrochloride (cysteine HCl) injection, USP contains 34.5 mg/mL of cysteine. The 
289  recommended maximum daily dosage is 15mg cysteine/gram of amino acid (AA), with 4 g 
290  AA/kg/day in pediatric patients. The aluminum concentration is less than or equal to 120 mcg/L. 
291  The derived aluminum exposure (IAE of cysteine hydrochloride) from the known labeled 
292  aluminum concentration (i.e., less than or equal to 120 mcg/L) is calculated as follows: 
293   
294  IAE  (mcg/kg/day) = (120 mcg/L x 15 mg/g AA x 4 g AA/kg/day)    
cysteine HCl
295  (1000 mL/L x 34.5 mg/mL) = 0.21 mcg/kg/day 
296  
297  B.  Determination of ACL from IAE  for SVP Drug Product Under 
SVP
 
298  Development 
299   
300  For SVP drug products in development, the ACL in the drug product can be calculated using an 
301  estimated or known IAE .  
SVP
302   
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303  Unless IAE  of all drug products in the final PN admixture is known, sponsors should make 
SVP
304  assumptions for the IAE  of the SVP drug product in development to determine ACL. The 
SVP
305  hypothetical examples below use marketed SVP drug products but assume that the aluminum 
306  concentration is not known to illustrate the calculation that would be conducted during 
307  development.   
308   
309  Depending on the assumptions made regarding the IAE , such as the number and the 
SVP
310  proportion of aluminum content of other concomitantly administered SVP PN components, ACL 
311  in a given drug product can vary widely. For the premarket development phase, the cysteine 
312  hydrochloride example (see section IV. B. 2., Cysteine Hydrochloride) illustrates the effect of 
313  the assumptions made regarding the number of and aluminum content of other individual SVP 
314  drug products administered together with PN.   
315   
316  1.  Potassium Acetate 
317   
318  Potassium acetate injection contains 2 mEq/mL potassium.  The recommended dosage ranges are 
319  40 to 80 mEq/day in adults, 2 to 3 mEq/kg/day in older pediatric patients, and 2 to 6 mEq/kg/day 
320  in neonates. The safety assessment of aluminum in PN is based on aluminum dose expressed as 
321  mcg/kg/day.16 For potassium acetate, the highest recommended potassium dosage on a body 
322  weight basis (expressed as mEq/kg/day) will deliver the highest aluminum dosage on a body 
323  weight basis (mcg/kg/day). Therefore, the applicant should use the maximum weight-based 
324  dosage of potassium (6 mEq/kg/day) for calculations to support the establishment of the ACL.   
325   
326  As described in section IV. A., Determination of IAE  of Drug Products with Known or 
SVP
327  Labeled Aluminum Concentration, the IAE  is calculated to be 3 mcg/kg/day, as follows: 
SVPtotal
328   
329  TAE  IAE  = IAE (or TAE  X = Y) 
LVPtotal SVPtotal 
330  5 mcg/kg/day  2 mcg/kg/day = 3 mcg/kg/day 
331   
332  Based on the assumption that up to five SVP drug products (including potassium acetate) may be 
333  added to TPN therapy, with equal contribution of aluminum among the SVP drug products, the 
334  IAE for potassium acetate is calculated as follows: 
335   
336  IAE   5 SVPs = IAE for individual SVP 
SVPtotal
337  3 mcg/kg/day  5 SVPs = 0.6 mcg/kg/day for individual SVP (potassium acetate) 
338 
339  Therefore, the assumed IAE  of potassium acetate equals 0.6 mcg/kg/day. 
SVP
 
340   
341  The ACL is calculated as follows: 
342 
 
0.6 mcg
343 
1000 mL kg
 x (  x 2 mEq of potassium/mL)
L day
ACL (mcg/L)= 6 mEq  = 200mcg/L 
/day
  kg  
16 See 21 CFR 201.323(e). 
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344   
345  2.  Cysteine Hydrochloride 
346   
347  The clinical dose of cysteine is determined by amino acid dose (e.g., mg cysteine/gram AA), 
348  therefore the formula below accommodates the amino acid dose: 
349   
mcg
kg
1000 IAE   x  ysteine  onc.17 
day (mg/mL)
350  ACL  mcg/L =  x    c c  
mg grams
  ax.  os e  x  ose 
AA AA ( /day)
gram kg
( )
351   
cysteine m daily d ag   d
352  The formula includes the following assumptions: 
353   
354    IAE  cysteine hydrochloride = 0.6 mcg/kg/day 
SVP
355    Clinical dose of cysteine base = 15 mg cysteine/gram AA 
356    Clinical dosage of amino acid = 4 grams/kg/day 
357    Cysteine conc. = 34.5 mg/mL 
358   
0.6mcg
m kg 34.5
mg
1000  x  x 
mcg L day
mL
359  ACL  = =  345 mcg/L 
L   L mg  x 4grams
15
gramAA kg
360     
361  Table 2 is the illustration of ACL in cysteine hydrochloride injection using the formula above 
362  with different IAE  assumptions and cysteine hydrochloride concentrations (5 percent or 7.25 
SVP
363  percent). Because the TAE is fixed a priori, increasing the IAE of each SVP drug product 
364  decreases the number of SVP additives that can be assumed. 
365   
366  On the other hand, the higher the concentration of cysteine, the higher ACL because it is 
367  proportional to the concentration of cysteine in the drug product.  
368   
 
17 Cysteine conc. is the concentration of the cysteine base in the drug product. 
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369  Table 2. An Illustration of Calculation of Recommended ACL in Cysteine Hydrochloride 
370  Injection Based on the Maximum Daily Clinical Dose of Cysteine and Variations of IAEs, 
371  Drug Product Concentrations of Cysteine (5 percent or 7.25 percent), and Maximum 
372  Number of SVP Drug Products Allowed  
373   
ACL in Cysteine  N* (Max. 
Hydrochloride Injection  number of 
Amino  IAE of Each  5%**  7.25%**  SVP 
Cysteine Daily  Acid Daily  SVP  (34.5 mg/mL  (50 mg/mL  Additives) 
Dosage  Dosage  Additive  of Cysteine)  of Cysteine)   
(mg cysteine/g 
AA)/ day)  (g/kg/day)  (mcg/kg/day)  (mcg/L)  (mcg/L)   
15  4  0.1  58  83  30 
15  4  0.6  345  500  5 
15  4  1  575  833  3 
15  4  3  1725  2500  1 
374  Calculated numbers with a decimal place are rounded to the next integer. 
375  ACL = aluminum concentration limit; IAE = individual aluminum exposure; SVP = small volume parenteral; AA = 
376  amino acid; mg = milligram; mL = milliliter; g = gram; kg = kilogram; mcg = microgram; L = liter; PN = parenteral 
377  nutrition; IAE  = total aluminum exposure from SVP drug products. 
SVPtotal
378  *Assuming the total aluminum from SVP drug products in PN therapy, (IAE ), is 3 mcg/kg/day. 
SVPtotal
379  ** Concentration based on amount of cysteine hydrochloride monohydrate. 
380   
381   
382  V.  MANUFACTURING CONSIDERATIONS FOR THE CONTROL OF 
383  ALUMINUM CONTENT IN SVP DRUG PRODUCTS 
384   
385  Control of elemental impurities to ensure that the levels do not exceed the PDE is one part of the 
386  overall control strategy for a drug product. The International Council for Harmonisation (ICH) 
387  guidance for industry Q3D(R1) Elemental Impurities (March 2020) (ICH Q3D(R1)) provides 
388  general recommendations for risk assessment and control of elemental impurities. ICH Q3D(R1) 
389  does not provide recommendations of the actual values of the established PDE for some 
390  elemental impurities including aluminum because of several reasons, including the differences in 
391  regulations and practices among geographic regions. FDA recommends that applicants establish 
392  the tests for the aluminum content (i.e., concentration) with validated analytical methods and an 
393  appropriate acceptance criterion and include those in the specifications of SVP drug products for 
394  PN at release and at expiry. Applicants should establish the appropriate acceptance criterion of 
395  the aluminum content in an SVP drug product based on the following two factors:  
396   
397  1)  The historical experience of the manufacturing capability, such as pharmaceutical 
398  development, batch records, and results from release and stability studies of the 
399  registration batches; and  
400   
401  2)  The dosing regimen for patients with renal impairment including preterm neonates.  
402   
403  For each SVP drug product intended to be added to the PN, the aluminum exposure to patients 
404  with renal impairment should not exceed the IAE. Therefore, the concentration of the aluminum 
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405  impurity of each SVP drug product should be controlled at or below the recommended ACL (see 
406  the determination of ACL in section IV.B., Determination of ACL from IAE  for SVP Drug 
SVP
407  Product Under Development). This information can be used to guide the establishment of the 
408  acceptance criterion for aluminum content in the SVP drug product specification. If the 
409  historically observed maximum level of aluminum exceeds the calculated safety level per this 
410  guidance, FDA recommends developing mitigation and control strategies to reduce the 
411  aluminum content in a drug product (e.g., formulation design optimization, manufacturing 
412  process improvement, selection of appropriate container and closure system).  
413   
414  If there is adequate justification, the differences in the acceptance criterion of the aluminum 
415  content in the drug product specifications between the proposed abbreviated new drug 
416  application (ANDA) and the reference listed drug (RLD) product may be considered as 
417  permissible as part of the Agencys overall benefit-risk analysis of the ANDA at issue. 
418   
419  Some special consideration should be given in the control of aluminum impurities in SVP drug 
420  products during the drug product development and product life cycle. For example, minerals are 
421  commonly added into USP Type I glass as modifiers and stabilizers to produce glass containers 
422  with desired physical properties and durability. Aluminum and other elemental impurities could 
423  leach into the SVP drug product from the glass containers over time, especially for drug products 
424  with a formulation at extreme pH. Therefore, the pH of the formulation should be considered 
425  when performing risk assessment to identify the source and control of aluminum and other 
426  elemental impurities in SVP drug products. As part of the risk mitigation, the control of 
427  aluminum should be considered in the proposed quality target product profile (e.g., route of 
428  administration, patient population, drug product formulation design, strength, primary packaging 
429  materials). As illustrated in the SVP ACL calculation formula in section III.B., the ACL is 
430  proportional to the API concentration for an individual SVP drug product if the maximum daily 
431  dose of the SVP drug product and its IAE remain unchanged. Under such circumstance, a higher 
432  aluminum concentration resulting from a higher ACL will be anticipated when an applicant has 
433  selected a higher API concentration during the SVP drug product formulation design. FDA 
434  encourages the applicant to discuss aluminum control strategy with FDAs review divisions 
435  when developing SVP drug products intended to be a component for TPN therapy.18 Finally, the 
436  applicant should also implement an adequate control strategy for postapproval changes that could 
437  affect aluminum content in the drug product during the drug products life cycle.  
438   
439   
 
18 When the submission is for an NDA, the applicant should contact the specific drug product review division with 
questions. When the submission is for an ANDA, the applicant should submit questions as a general correspondence 
to the application, via the controlled correspondence pathway or via the pre-ANDA meeting request pathway. See 
the guidances for industry Formal Meetings Between FDA and ANDA Applicants of Complex Products Under 
GDUFA (November 2020) and Controlled Correspondence Related to Generic Drug Development (December 
2020). 
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440  VI.  LABELING CONSIDERATIONS 
441   
442  A.  Prescribing Information 
443   
444  1.  Limitations of Use in the Indications and Usage Section  
445   
446  If there is a reasonable concern or uncertainty about the use of the SVP drug products for PN 
447  solutions in a subpopulation because of the risk of aluminum toxicity, the INDICATIONS AND 
448  USAGE section can include limitations of use.19 The following is an example: 
449   
450  Limitations of Use  
451  The use of DRUG-X for parenteral nutrition in pediatric patients less than 1 year old is 
452  not recommended due to the risk of aluminum toxicity [see Warnings and Precautions 
453  (5.x) and Use in Specific Populations (8.4)]. 
454   
455  2.  Warnings and Precautions Section 
456   
457  The WARNINGS AND PRECAUTIONS section for SVP drug products used in TPN must 
458  contain the following statement that should be included within a subsection entitled Aluminum 
459  Toxicity or with a similar heading:20  
460   
461  WARNING: This product contains aluminum that may be toxic. Aluminum may reach 
462  toxic levels with prolonged parenteral administration if kidney function is impaired. 
463  Premature neonates are particularly at risk because their kidneys are immature, and they 
464  require large amounts of calcium and phosphate solutions, which contain aluminum. 
465   
466  Research indicates that patients with impaired kidney function, including premature 
467  neonates, who receive parenteral levels of aluminum at greater than 4 to 5 g/kg/day 
468  accumulate aluminum at levels associated with central nervous system and bone toxicity. 
469  Tissue loading may occur at even lower rates of administration. 
470   
471  In addition to the risk of aluminum toxicity in premature neonates (preterm newborns),21 there is 
472  also a risk of aluminum toxicity from the use of SVP drug products in PN beyond the neonatal 
 
19 See the draft guidance for industry Indications and Usage Section of Labeling for Human Prescription Drug and 
Biological Products  Content and Format (July 2018). When final, this guidance will represent the FDAs current 
thinking on this topic. For the most recent version of a guidance, check the FDA guidance web page at 
https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
20 21 CFR 201.323(e). In this statement the term g is a symbol for microgram. The Institute for Safe Medication 
Practices (ISMP) stated that the term g has been frequently misinterpreted and involved in medication errors, and 
therefore ISMP recommends that the term mcg be used instead of g.  See ISMPs List of Error-Prone 
Abbreviations available at https://www.ismp.org/recommendations/error-prone-abbreviations-list. FDA does not 
intend to object to the use of the term mcg instead of g in this context. 
 
21 See section IV of the ICH guidance for industry E11 (R1) Addendum: Clinical Investigation of Medicinal 
Products in the Pediatric Population (April 2018). (The neonatal period for preterm newborn infants is defined as 
beginning at birth and ending at the expected date of delivery plus 27 days.) 
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473  period in preterm infants.22 Therefore, FDA recommends that the Aluminum Toxicity subsection 
474  also describe the risks of aluminum toxicity in preterm infants. Furthermore, because tissue 
475  loading may occur with lower daily amounts of aluminum in addition to lower rates of 
476  administration, FDA recommends that this subsection also describe this risk from lower daily 
477  amounts of aluminum in SVP drug products used in TPN.  For example, the following additional 
478  language can be added to this subsection: 
479   
480  For similar reasons, preterm infants who receive greater than 4 to 5 mcg/kg/day of 
481  parenteral aluminum can accumulate aluminum at levels associated with aluminum 
482  toxicity (central nervous system and bone toxicity). Tissue loading may also occur in 
483  patients with renal impairment, including premature (preterm) neonates and preterm 
484  infants, from lower daily amounts of aluminum. 
485   
486  The WARNINGS AND PRECAUTIONS section must describe the limitations in use imposed 
487  by clinically significant adverse reactions23 and should include steps to take to decrease the 
488  likelihood, shorten the duration, or minimize the severity of an adverse reaction.24 For SVP drug 
489  products used in the preparation of TPN solutions with a total admixed aluminum content of no 
490  more than 5 mcg/kg/day, the following is an example of how to include such information in the 
491  Aluminum Toxicity subsection:  
492   
493  Exposure to aluminum from DRUG-X at the recommended dosage is not more than Y25 
494  mcg/kg/day [see Dosage and Administration (2.x) and Description (11)].  
495   
496  When prescribing DRUG-X for use in parenteral nutrition solutions containing other 
497  small volume parenteral products and/or pharmacy bulk packages, limit the total daily 
498  patient exposure to aluminum in the admixture to no more than 5 mcg/kg/day [see Use in 
499  Specific Populations (8.4)].  
500   
501  If the total aluminum exposure is no more than 5 mcg/kg/day in a subpopulation (e.g., 
502  subpopulation-A) but exceeds 5 mcg/kg/day in another subpopulation (e.g., subpopulation-B), 
503  the drug product may be approved in subpopulation-A but in subpopulation-B, use is not 
504  recommended because of the risks of aluminum toxicity. The following is an example of how to 
505  include information in the Aluminum Toxicity subsection when SVP or PBP drug products are 
506  approved for use in the preparation of PN solutions in one subpopulation (e.g., patients 1 year of 
507  age and older) when the total aluminum exposure does not exceed 5 mcg/kg/day, but use is not 
508  recommended in another subpopulation (e.g., patients younger than 1 year of age) because of the 
 
22 See the ICH guidance for industry E11 (R1) Addendum: Clinical Investigation of Medicinal Products in the 
Pediatric Population. Infants and toddler period is defined as 28 days to 23 months old. 
 
23 21 CFR 201.57(c)(6)(i). 
 
24 See the guidance for industry Warnings and Precautions, Contraindications, and Boxed Warning Sections of 
Labeling for Human Prescription Drug and Biological Products  Content and Format (October 2011). 
 
25 Y equals IAE  and is determined from calculations described above in this guidance (see section IV.A., 
SVP
Determination of IAE  of Drug Products with Known or Labeled Aluminum Concentration).  
SVP
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509  risk of aluminum toxicity (the total aluminum exposure exceeds 5 mcg/kg/day in the 
510  subpopulation): 
511   
512  When prescribing DRUG-X for use in parenteral nutrition solutions (containing other 
513  small volume parenteral products and/or pharmacy bulk packages) in adults and pediatric 
514  patients 1 year of age and older, limit the total daily patient exposure to aluminum in the 
515  admixture at no more than 5 mcg/kg/day. The use of DRUG-X for parenteral nutrition is 
516  not recommended in pediatric patients less than 1 year of age due to the risks of 
517  aluminum toxicity [see Use in Specific Populations (8.4)]. 
518   
519  3.  Pediatric Use Subsection in the Use in Specific Populations Section  
520   
521  If a drug product is approved for use in pediatric patients (either all pediatric patients or in a 
522  specific pediatric age group or groups), the Pediatric Use subsection in the USE IN SPECIFIC 
523  POPULATIONS section must include information about specific risks or safety concerns 
524  (hazards) associated with the use of the drug product in pediatric patients or a specific pediatric 
525  age group (e.g., infants).26 In this situation, the following is an example of aluminum toxicity 
526  information in this subsection:  
527   
528  DRUG-X contains aluminum that may be associated with central nervous system and 
529  bone toxicity. Because of immature renal function, preterm infants receiving prolonged 
530  parenteral nutrition treatment with DRUG-X may be at higher risk of aluminum toxicity 
531  [see Warnings and Precautions (5.x)].  
532   
533  If the use of the drug product for an indication not approved in pediatric patients is associated 
534  with a risk or safety concern (hazard) in pediatric patients, the risk or safety concern must be 
535  described in the Pediatric Use subsection.27 In this situation, the following is an example of 
536  aluminum toxicity information in this subsection when the use of the drug product in pediatric 
537  patients is based on age:28   
538   
539  DRUG-X contains aluminum that may be associated with central nervous system and 
540  bone toxicity.  The safety and effectiveness of DRUG-X (for Indication-Y) have not been 
541  established in pediatric patients younger than Z years old and the use of DRUG-X for 
542  parenteral nutrition is not recommended in this age group due to the risks of aluminum 
543  toxicity [see Warnings and Precautions (5.x)]. 
544   
545  4.  Description Section 
546   
547  For SVP drug products and PBPs used in the preparation of PN solutions, the DESCRIPTION 
548  section should contain a statement regarding the amount of aluminum in the drug product. The 
549  following is an example of this statement:  
 
26 21 CFR 201.57(c)(9)(iv)(B), (C), and (D). 
 
27 21 CFR 201.57(c)(9)(iv)(E) or (F). 
 
28 The use of the drug product in pediatric patients because of aluminum toxicity may alternatively be based on 
weight.  
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550   
551  DRUG-X contains no more than Y mcg/L of aluminum [see Warnings and Precautions 
552  (5.x)]. 
553   
554  If the SVP drug product is a lyophilized powder (for injection dosage form), this section should 
555  state the following:  
556   
557  After reconstitution, the aluminum concentration will be no more than X mcg/L.  
558   
559  However, if the maximum level of aluminum in one of the lyophilized powder products is 25 
560  mcg/L or less, instead of stating the exact amount of aluminum, this section can state the 
561  following:  
562   
563  After reconstitution, the aluminum concentration will be no more than 25 mcg/L. 
564   
565  B.  Container Label and Carton Labeling 
566   
567  The maximum level of aluminum present at expiry must be stated on the immediate container 
568  label and carton labeling29 of all SVP drug products used in the preparation of TPN solutions as 
569  follows:30 
570   
571  Contains no more than X g/L of aluminum.   
572   
573  However, if the maximum level of aluminum in one of these drug products is 25 mcg/L or less, 
574  instead of stating the exact amount of aluminum, the immediate container label and carton 
575  labeling may state the following:31 
576   
577  Contains no more than 25 g/L of aluminum.   
578   
579  If the SVP drug product is a lyophilized powder (for injection dosage form), the immediate 
580  container label and carton labeling must state the following:32  
581   
582  When reconstituted in accordance with the package insert instructions, the concentration 
583  of aluminum will be no more than X g/L.  
584   
 
29 According to section 201(k) of the FD&C Act (21 U.S.C. 321(k)), a requirement made by or under authority of 
this chapter that any word, statement, or other information appear on the label shall not be considered to be complied 
with unless such word, statement, or other information also appears on the outside container or wrapper, if any there 
be, of the retail package of such article, or is easily legible through the outside container or wrapper. 
 
30 21 CFR 201.323(c). In this statement, FDA does not intend to object to the use of the term mcg instead of g in 
this context. See footnote #20.  
 
31 21 CFR 201.323(d). In this statement FDA does not intend to object to the use of the term mcg instead of g in 
this context. See footnote #20. 
 
32 21 CFR 201.323(c). In this statement FDA does not intend to object to the use of the term mcg instead of g in 
this context. See footnote #20. 
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585  However, if the maximum level of aluminum in one of these lyophilized powder products is 25 
586  mcg/L or less, instead of stating the exact amount of aluminum, the immediate container label 
587  and carton labeling can state the following:33  
588   
589  When reconstituted in accordance with the package insert instructions, the concentration 
590  of aluminum will be no more than 25 g/L. 
591   
592  This maximum level of aluminum must be stated as the highest of one of the following: 
593   
594  1)  The highest level for the batches produced during the last 3 years, 
595   
596  2)  The highest level for the latest five batches, or 
597   
598  3)  The maximum historical level, but only until completion of production of the first five 
599  batches after July 26, 2004.34 
 
33 21 CFR 201.323(d). In this statement FDA does not intend to object to the use of the term mcg instead of g in 
this context.  See footnote #20. 
 
34 21 CFR 201.323(c). 
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600  GLOSSARY 
601   
602  Total aluminum exposure (TAE) (microgram/kilogram/day (mcg/kg/day)): The daily patient 
603  exposure to aluminum, from all components used in total parenteral nutrition (TPN) (SVP and 
604  LVP drug products) therapy, not to exceed 5 mcg/kg/day (see Figure 1). 
605   
606  Individual aluminum exposure (IAE) (mcg/kg/day): The maximum daily patient exposure to 
607  aluminum from an individual component of TPN (SVP and LVP drug products) therapy; the 
608  value not to exceed is variable among individual drug products and is dependent on the 
609  component and composition of the TPN admixture prescribed or intended for clinical use. 
610   
611  Aluminum content (mcg): The amount of aluminum present in a single dose of the individual 
612  drug product. It is derived from the aluminum concentration in the drug product.  
613   
614  Aluminum concentration (mcg/Liter (L)): The amount of aluminum per liter of the individual 
615  drug product determined from batch analyses.  
616   
617  Aluminum concentration limit (ACL) (mcg/L): The highest aluminum concentration 
618  established in each individual drug product that will ensure compliance with its individual IAE. 
619  It is the basis for the establishment of the acceptance criteria for elemental impurity aluminum in 
620  drug product specifications. The acceptance criteria should not exceed the recommended 
621  aluminum concentration limit for each drug product. 
622   
623  Drug product concentration (conc.) (milligram/milliliter (mg/mL)): The amount of the drug 
624  expressed in milligram per milliliter of the individual drug product defined in application.1  
625   
626  Maximum daily dosage (max. daily dosage) (mg or mL/kg/day): The prescribed maximum 
627  daily dosage of the specific drug2 expressed per kilogram of the patient body weight.  
628   
629  Specification for drug product: A specification is defined as a list of tests, references to 
630  analytical procedures, and appropriate acceptance criteria, which are numerical limits, ranges, or 
631  other criteria for the tests described for the drug product.3 
 
1 Note that the concentration of the drug (i.e., small volume parenteral (SVP) concentration (mg/mL) in formulas) 
and the prescribed maximum daily dosage of the drug product (i.e., SVP max. dosage (mg/kg/day) in formulas) 
should be expressed consistently in the same form, e.g., the active moiety, salt, or inorganic counter ion. 
 
2 Ibid. 
 
3 See the International Council for Harmonisation guidance for industry Q6A Specifications: Test Procedures and 
Acceptance Criteria for New Drug Substances and New Drug Products: Chemical Substances (December 2000). 
We update guidances periodically.  To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
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632  ABBREVIATIONS AND ACRONYMS 
633   
634  AA    amino acid 
635  ACL    aluminum concentration limit 
636  Al    aluminum 
637  ANDA   abbreviated new drug application 
638  API    active pharmaceutical ingredient 
639  CFR    Code of Federal Regulations 
640  FDA    Food and Drug Administration 
641  FD&C Act  Federal Food, Drug, and Cosmetic Act 
642  IAE    individual aluminum exposure 
643  IAE   individual aluminum exposure from large volume parenteral drug product 
LVP
644  IAE total aluminum exposure from large volume parenteral drug products 
LVPtotal 
645  IAE   individual aluminum exposure from small volume parenteral drug product 
SVP
646  IAE total aluminum exposure from small volume parenteral drug products 
SVPtotal 
647  ICH    International Council for Harmonisation  
648  ISMP    Institute for Safe Medication Practices 
649  kg    kilogram 
650  L    liter 
651  LVP    large volume parenteral 
652  mEq    milliequivalent 
653  mcg    microgram 
654  mL    milliliter 
655  NDA    new drug application 
656  NMT    no more than 
657  PBP    pharmacy bulk package 
658  PDE    permitted daily exposure 
659  PLR    physician labeling rule 
660  PN    parenteral nutrition 
661  PPN    peripheral parenteral nutrition 
662  QTPP    quality target product profile 
663  RLD    reference listed drug 
664  SVP    small volume parenteral 
665  TAE    total aluminum exposure 
666  TPN    total parenteral nutrition 
667  USP    United States Pharmacopeia 
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668  REFERENCES 
669   
670  LITERATURE 
671   
672  Arnold CJ, GG Miller, and GA Zello, 2003, Parenteral Nutrition-Associated Cholestasis in 
673  Neonates: The Role of Aluminum, Nutr Rev, 61(9):306310. 
674   
675  Bishop NJ, R Morley, JP Day, and A Lucas, 1997, Aluminum Neurotoxicity in Preterm Infants 
676  Receiving Intravenous-Feeding Solutions, N Engl J Med, 336(22):15571561. 
677   
678  Bohrer D, PC do Nascimento, R Binotto, and E Becker, 2003, Influence of the Glass Packing on 
679  the Contamination of Pharmaceutical Products by Aluminium. Part III: Interaction Container-
680  Chemicals During the Heating for Sterilisation, J Trace Elem Med Biol, 17(2):107115. 
681   
682  Bohrer D, PC do Nascimento, R Binotto, and R Carlesso, 2001, Influence of the Glass Packing 
683  on the Contamination of Pharmaceutical Products by Aluminium. Part II: Amino Acids for 
684  Parenteral Nutrition, J Trace Elem Med Biol, 15(2-3):103108. 
685   
686  Bohrer D, PC do Nascimento, R Binotto, E Becker, and S Pomblum, 2002, Contribution of the 
687  Raw Material to the Aluminum Contamination in Parenterals, JPEN J Parenter Enteral Nutr, 
688  26(6):382388. 
689   
690  Boyce BF, GS Fell, HY Elder, BJ Junor, HL Elliot, G Beastall, I Fogelman, and IT Boyle, 1982, 
691  Hypercalcaemic Osteomalacia Due to Aluminium Toxicity, Lancet, 2(8306):10091013, doi: 
692  10.1016/s0140-6736(82)90049-6. PMID: 6127501. 
693   
694  Fewtrell MS, NJ Bishop, CJ Edmonds, EB Isaacs, and A Lucas, 2009, Aluminum Exposure 
695  From Parenteral Nutrition in Preterm Infants: Bone Health at 15-Year Follow-up, Pediatrics, 
696  124(5):13721379. 
697   
698  Finberg L, HS Dweck, F Holmes, and N Kretchmer, 1986, American Academy of Pediatrics 
699  Committee on Nutrition: Aluminum Toxicity in Infants and Children, Pediatrics, 78(6):1150
700  1154. 
701   
702  Gilbert-Barness E, LA Barness, J Wolff, and C Harding, 1998, Aluminum Toxicity, Arch Pediatr 
703  Adolesc Med, 152(5):511512. 
704   
705  Klein GL, AM Leichtner, and MB Heyman, 1998, Aluminum in Large and Small Volume 
706  Parenterals Used in Total Parenteral Nutrition: Response to the Food and Drug Administration 
707  Notice of Proposed Rule By the North American Society for Pediatric Gastroenterology and 
708  Nutrition, J Pediatr Gastroenterol Nutr, 27(4):457460. 
709   
710  Klish WJ, SS Baker, CA Flores, MK Georgieff, AM Lake, RL Leibel, JN Udall Jr., M Cheney, 
711  PN Daniels, SS Harris, VS Hubbard, E Levin, A Prendergast, AE Smith, E Yetley, R Yip, S 
712  Zlotkin, RM Lauer, and EF Bell, 1996, Aluminum Toxicity in Infants and Children, American 
713  Academy of Pediatrics, Committee on Nutrition, Pediatrics, 97(3):413416. 
  21  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
714   
715  Larchet M, P Chaumont, M Galliot, R Bourdon, O Goulet, and C Ricour, 1990, Aluminium 
716  Loading in Children Receiving Long-Term Parenteral Nutrition, Clin Nutr, 9(2):7983. 
717   
718  Poole RL, KP Pieroni, S Gaskari, TK Dixon, KT Park, and JA Kerner Jr., 2011, Aluminum in 
719  Pediatric Parenteral Nutrition Products: Measured Versus Labeled Content, J Pediatr Pharmcol 
720  Ther, 16(2):9297. 
721   
722   
723  United States Pharmacopeia (USP) chapters 
724   
725  USP General Chapter <7> Labeling 
726   
727  USP General Chapter <659> Packaging and Storage Requirements 
728   
729  USP General Chapter <1660> Evaluation of the Inner Surface Durability of Glass Containers 
730   
731   
732  Guidances for Industry1 
733   
734  Draft guidance for industry Indications and Usage Section of Labeling for Human Prescription 
735  Drug and Biological Products  Content and Format (July 2018)2 
736   
737  Guidance for industry Controlled Correspondence Related to Generic Drug Development 
738  (December 2020) 
739   
740  Guidance for industry Formal Meetings Between FDA and ANDA Applicants of Complex 
741  Products Under GDUFA (November 2020) 
742   
743  Guidance for industry Warnings and Precautions, Contraindications, and Boxed Warning 
744  Sections of Labeling for Human Prescription Drug and Biological Products  Content and 
745  Format (October 2011) 
746   
747  ICH (International Council for Harmonisation) guidance for industry E11 (R1) Addendum: 
748  Clinical Investigation of Medicinal Products in the Pediatric Population (April 2018) 
749   
750  ICH guidance for industry Q2(R1) Validation of Analytical Procedures: Text and Methodology 
751  (November 2005) 
752   
753  ICH guidance for industry Q3D(R1) Elemental Impurities (March 2020) 
 
1 We update guidances periodically. To make sure you have the most recent version of a guidance, check the FDA 
guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-documents. 
 
2 When final, this guidance will represent the FDAs current thinking on this topic. For the most recent version of a 
guidance, check the FDA guidance web page at https://www.fda.gov/regulatory-information/search-fda-guidance-
documents. 
  22  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
754   
755  ICH guidance for industry Q6A Specifications: Test Procedures and Acceptance Criteria for 
756  New Drug Substances and New Drug Products: Chemical Substances (December 2000) 
  23