Multi-dose vial (revision 15)

A multi-dose vial, termed a multiple-dose container in compendial language, is a container of an injectable preparation intended to permit withdrawal of successive portions of its contents without change in the strength, quality or purity of the remainder. The definition is functional: it describes an intention and the conditions that make the intention safe, not a size or a shape. A 10 mL vial may be a single-dose or a multiple-dose container depending on its formulation and its labelling.^[1]

Two requirements follow from repeated entry. Because each penetration of the closure is an opportunity for microbial ingress, and because the contents are held at or near room temperature for a period afterwards, a multiple-dose preparation must contain an antimicrobial preservative whose effectiveness has been demonstrated by the challenge testing described in USP <51>. And because the preservative controls but does not eliminate risk, the period during which the container may be used after its first puncture is limited, conventionally to 28 days unless the manufacturer specifies otherwise.^[2][3]

The 28-day convention is frequently misread as a statement about chemical stability. It is not: it derives from the antimicrobial effectiveness of preserved formulations and from infection-control practice, and it is independent of whether the active substance remains within specification. A preparation may be chemically stable for a year and still be discarded at 28 days, and a preparation may lose potency well before 28 days despite its preservative performing perfectly.^[3][4]

Documented outbreaks of blood-borne and bacterial infection traced to multiple-dose vials have been reported repeatedly, almost always from practices that reuse a syringe or needle to re-enter a vial rather than from failure of the preservative itself. This distinction — between the container as a vector and the container as a reservoir — shapes the infection-control guidance and explains why that guidance concentrates on the syringe.^[5][4]

USP <659> distinguishes several container categories, and the distinctions govern labelling and use.

Single-dose container

A single-unit container for an article intended for parenteral administration only, used once and discarded. Ampoules and prefilled syringes are inherently single-dose; a vial is single-dose if so labelled.

Multiple-dose container

A multiple-unit container for an article intended for parenteral administration only, permitting withdrawal of successive portions without altering the remainder.

Pharmacy bulk package

A container of a sterile preparation for parenteral use containing many single doses, intended for further dilution or dispensing in a suitable environment, and not for direct administration. Its permitted period after entry is short — commonly stated on the label and typically measured in hours.^[1]

The requirement for a preservative in a multiple-dose container appears in the general requirements for injections, and the demonstration of effectiveness is by the antimicrobial effectiveness test in USP <51>. That test challenges the formulation with specified organisms — Staphylococcus aureus, Pseudomonas aeruginosa, Escherichia coli, Candida albicans and Aspergillus brasiliensis — and requires defined log reductions at defined intervals over 28 days. For injectable products the criteria are the most demanding of the product categories the chapter defines.^[2]

The 28-day duration of the test and the 28-day default period after puncture are related but not identical claims. The test demonstrates that the preservative system suppresses growth of a substantial deliberate inoculum over 28 days under laboratory conditions; the use period is a practice rule informed by that demonstration. Guidance is explicit that a manufacturer may specify a shorter period, and that a shorter period so specified governs.^[3][2]

Preservatives used in injectable products are a small set, constrained by systemic toxicity at the concentrations required, by compatibility with peptides and proteins, and by the pH range over which they remain active.

Concentrations are those conventionally used in marketed injectable products; the effective concentration is formulation-specific and must be demonstrated for the product rather than assumed from the class.^[2][6]

The phenolic preservatives illustrate that a preservative is not an inert additive. In insulin formulations, phenol and m-cresol bind at a specific site on the hexamer and shift the conformational equilibrium, and their presence is required for the physical stability of the formulation as well as for its preservation. Removing the preservative from such a product is therefore not merely a microbiological change.^[6]