(Source: RAPS 2015-06-24）
New guidance just issued by the US Food and Drug Administration (FDA) calls on pharmaceutical and biopharmaceutical companies to more closely control the amount of excess product contained in vials of injectable drugs and biologics.
Background
Liquid products must often be administered through an intermediary device, such as a syringe. Unlike a solid pharmaceutical tablet, which contains the full dose of the product in solid form, a vial of liquid product usually contains more than the recommended dose.
That occurs because 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 writes in its latest guidance document, “Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products”.
Even more concerning to regulators, the pooling of doses or repeated use of a single vial can increase the exposure of patients to adverse events, most notable those caused by microbial contamination.
Guidance on Fill Size
As a result, FDA has now finalized new recommendations intended to cut down on the over-filling of vials “without appropriate justification” in the hopes of cutting down on medication errors, adverse events and misuse of liquid drug products.
The key words there: appropriate justification. As FDA explains in its guidance, its not proposing a rigid framework with which to regulate products with a broad brush.
“Dosing flexibility is necessary with injectable drug products,” FDA concedes in the guidance. But at the same time, it adds, “applicants should determine the appropriate vial fill sizes during product development, considering how the vials are likely to be used.” Accordingly, single-dose vials should contain enough product for (only) a single patient, with only a minimal amount left over so as to discourage pooling of excess product.
FDAs guidance contains three guiding principles:
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.
Consumers and/or health care providers should not be routinely required to use more than one vial to administer a typical single dose of the drug product.
Multiple-dose vials should contain no more than 30 mL of drug product except under specific circumstances.
Overfill
So what happens if a company does need to overfill a vial? FDA says companies should adhere to the US Pharmacopoeias (USP) General Chapter <1151>, which advises companies to design a product “to meet the label claim and acceptable overfill, and [to] allow for correct dosing.”
Deviations will need to be justified through the use of “extractable content testing data.” Such data should be included in the products application for approval and be representative of the commercial process, FDA said.
More Information on RAPSe
More Information on Allowable Excess Volume and Labeled Vial Fill Size in Injectable Drug and Biological Products