Parenteral drugs: FDA replaces guidance on aluminum content limits
To reduce the risk of aluminum toxicity in infants and adults with impaired renal function, the US Food and Drug Administration (FDA) has issued revised draft guidance to help manufacturers minimize aluminum exposure from small-volume parenteral (SVP) drugs packaged as single doses and in pharmacy bulk packages (PBPs). Additionally, the guidance offers recommendations for labeling these products.FDA states in the guidance that “aluminum toxicity from prolonged use of parenteral nutrition (PN) represents a major safety concern, particularly in patients with renal impairment or pediatric patients with immature renal function.”
The recommendations for total aluminum exposure (TAE) and aluminum concentration limits (ACL) in this guidance apply to SVPs that are the subject of new drug applications (NDAs), abbreviated new drug applications (ANDAs), and supplements to those applications.
The guidance has been updated from a previous draft guidance issued in December 2022. A new Section VI on regulatory considerations has been added to assist manufacturers in implementing the guidance, particularly regarding the steps they should take if a drug shortage occurs. The introduction has been revised to clarify the intended purpose of the guidance. Additionally, the steps for deriving the recommended ACL have been updated, along with the examples used to calculate the IAE and the ACL.
The agency reiterates that total aluminum exposure (TAE) from parenteral nutrition products should not exceed 4 to 5 micrograms/kilogram a day. The individual aluminum exposure (IAE) from each SVP should not go above .6 mcg/kg a day. These thresholds were also specified in the December 2022 guideline.
The new section on regulatory considerations specifies that sponsors of approved or marketed NDAs or ANDAs conduct a risk assessment of their products for controlling aluminum in their products according to the principles in this guidance. In addition, manufacturers should conduct confirmatory testing and submit any changes to the application within two years of publication of a final guidance. In addition, changes in specifications for approved applications must be submitted in a prior approval supplement.
Further, FDA states in the guidance that any drug product batch found to contain “unacceptable levels” of aluminum should not be released for distribution and may be considered adulterated and removed from the market.
Manufacturers should reach out to FDA’s drug shortage staff if any manufacturing changes or recalls related to aluminum contamination in SVPs are likely to cause drug shortages.
The deadline for submitting comments is 2 September.
Draft guidance
