APR May/June 2023 - 16

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FORMULATION AND DEVELOPMENT
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Multidose Preservative-Free Container Closure Systems:
Developmental Considerations for
Sterile Small Molecule Drug Products
Erika Pfeiler, PhD1
1
and John Arigo, PhD2
Branch Chief, Division of Microbiology Assessment 2, Office of Pharmaceutical Manufacturing
Assessment, Office of Pharmaceutical Quality, Center for Drug Evaluation and Research,
Food and Drug Administration
2
Division Director, Division of Microbiology Assessment 1, Office of Pharmaceutical
Manufacturing Assessment, Office of Pharmaceutical Quality, Center for Drug Evaluation and
Research, Food and Drug Administration
Abstract
Novel container closure system (CCS) technology may allow multipledose
drug products to be marketed without added antimicrobial
preservatives to meet clinical and formulation needs. In order to ensure
patient safety, however, these CCS must be appropriately validated to
ensure that they operate as purported. This article outlines general
recommendations for validation studies for CCS intended for use with
small molecule drug products.
Packaging Concerns
Drug products can be packaged as multiple-dose (containing more
than one dose per container) in order to facilitate their use, either
by a healthcare provider or by the patient. However, ease-of-use
considerations must be balanced by the need for patient safety,
which may be jeopardized if the product becomes contaminated with
microorganisms during repeated manipulations. This may result in
an unacceptable exposure of the patient to harmful microorganisms
which puts the patient at risk for infection. Therefore, multipledose
drug products typically contain antimicrobial preservatives,
added as excipients, to inhibit the growth of microorganisms that
may be introduced during the course of repeated manipulations.1
This mitigates the risk that a patient may be exposed to harmful
microorganisms originating from the drug product and subsequent
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APR May/June 2023

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