The US Food and Drug Administration (FDA) today issued a new draft guidance document clarifying its standards for filling injectable drugs and biological products.

Background

Liquid products must often be administered through an intermediary, such as a syringe. Unlike a solid pharmaceutical tablet, which contains the full dose in solid form, a vial of liquid product usually contains more than the recommended dose since it may be difficult or impossible to remove 100% of the contents from the vial. For example, a vial which contains a recommended dose of 1 mL may have 1.1 mL of liquid product to ensure that a syringe can withdraw a 1 mL dose since some product will remain as residue on the wall of the vial.

The concern of regulators, however, is that some companies are placing either too much or too little product into their vials "without appropriate justification."

"Such excesses and deficiencies may result in medication errors and may lead to misuse of leftover drug product or pooling of vials to obtain a single dose," FDA wrote. Such pooling or use of leftover product can increase the risk of adverse events in patients, particularly as the practice raises the risk of microbial contamination.

New Guidance

To combat this problem, FDA is out with a new three-page guidance, Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products.

The guidance is meant to describe "when justification is needed for a proposed excess volume in these injectable drug products," FDA wrote. The guidance also describes the "importance of appropriate packaging sizes" for the products, and also recommends that fill sizes are "appropriate for the intended use and dosing" of the product.

FDA recommends following the US Pharmacopoeia's (USP) General Chapter <1151> Pharmaceutical Dosage Forms, which provides excess volume recommendations for injectable products. All deviations from this standard will need to be justified, and the guidance goes on to explain the justification process under USP General Chapter <1>, Packaging, Determination of Volume of Injection in Containers.

Overfills also come with specific labeling considerations. They should, for example, not be referred to as "overages," which are accidental overfills. In general, sponsors should also not declare the amount of overfill on the label of the container, FDA said.

In addition, sponsors should take care to determine the "appropriate" packaging sizes for their products based on likely use. FDA cited as an example single-use vials, which should be designed for a single patient as a single injection or infusion. If the amount of overfill is too high, FDA explained that the dose might be used multiple times.

"Single-dose vials should not contain a significant volume beyond what would be considered a usual or maximum dose for the expected use of the drug product," FDA wrote. "Significant" was defined as any amount permitting a second dose or that would "encourage pooling" for a second dose.

Problems can also exist at the opposite end of the spectrum when vials are intended for multiple uses. USP recommends that vials not be any larger than 30 mL (unless specified by monograph) due to the potential for contamination if the vial septum is punctured too many times.

Other Requirements

Sponsors are also advised to follow the requirements of 21 CFR 201.51(g), which states:

(g) The declaration of net quantity of contents shall express an accurate statement of the quantity of contents of the package. Reasonable variations caused by loss or gain of moisture during the course of good distribution practice or by unavoidable deviations in good manufacturing practice will be recognized. Variations from stated quantity of contents shall not be unreasonably large. In the case of a liquid drug in ampules or vials, intended for injection, the declaration shall be considered to express the minimum quantity and the variation above the stated measure shall comply with the excess volume prescribed by the National Formulary or the U.S. Pharmacopeia for filling of ampules. In the case of a solid drug in ampules or vials, the declaration shall be considered to express the accurate net weight. Variations shall comply with the limitations provided in the U.S. Pharmacopeia or the National Formulary.

Comments on the draft guidance should be submitted within 90 days of the guidance's publication in the Federal Register, now scheduled for 14 March 2014.

 

Guidance