title: Evaluation of Container Closure System Integrity for Frozen Storage Drug Products.
abstract: Sometimes, drug product for parenteral administration is stored in a frozen state (e.g., -20 °C or -80 °C), particularly during early stages of development of some biotech molecules in order to provide sufficient stability. Shipment of frozen product could potentially be performed in the frozen state, yet possibly at different temperatures, for example, using dry ice (-80 °C). Container closure systems of drug products usually consist of a glass vial, rubber stopper, and an aluminum crimped cap. In the frozen state, the glass transition temperature (Tg) of commonly used rubber stoppers is between -55 and -65 °C. Below their Tg, rubber stoppers are known to lose their elastic properties and become brittle, and thus potentially fail to maintain container closure integrity in the frozen state. Leaks during frozen temperature storage and transportation are likely to be transient, yet, can possibly risk container closure integrity and lead to microbial contamination. After thawing, the rubber stopper is supposed to re-seal the container closure system. Given the transient nature of the possible impact on container closure integrity in the frozen state, typical container closure integrity testing methods (used at room temperature conditions) are unable to evaluate and thus confirm container closure integrity in the frozen state. Here we present the development of a novel method (thermal physical container closure integrity) for direct assessment of container closure integrity by a physical method (physical container closure integrity) at frozen conditions, using a modified He leakage test. In this study, different container closure systems were evaluated with regard to physical container closure integrity in the frozen state to assess the suitability of vial/stopper combinations and were compared to a gas headspace method. In summary, the thermal physical container closure integrity He leakage method was more sensitive in detecting physical container closure integrity impact than gas headspace and aided identification of an unsuitable container closure system.
  Sometimes, drug product for parenteral administration is stored in a frozen state (e.g., -20 °C or -80 °C), particularly during early stages of development of some biotech molecules in order to provide sufficient stability. Container closure systems for drug products usually consist of a glass vial, rubber stopper, and an aluminum crimped cap. In the frozen state, the glass transition temperature (Tg) of commonly used rubber stoppers is between -55 and -65 °C. Leaks during frozen temperature storage and transportation are likely to be transient, yet they can possibly risk container closure integrity and lead to microbial contamination and sterility breach. After thawing, the rubber stopper is expected to re-seal the container closure system. Given the transient nature of the possible impact on container closure integrity in the frozen state, typical container closure integrity testing methods (used at room temperature conditions) are unable to evaluate and thus confirm container closure integrity in the frozen state. Here we present the development of a novel method (thermal container closure integrity) for direct measurement of container closure integrity by a physical method (physical container closure integrity) at frozen conditions, using a modified He leakage test. In this study, we found that the thermal container closure integrity He leakage method was more sensitive in detecting physical container closure integrity impact than gas headspace and aided identification of an unsuitable container closure system.
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and alejandra.nieto-pena@roche.com.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Nieto
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and.
authors.forename: Holger
authors.initials: H
authors.lastname: Roehl
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and.
authors.forename: Helen
authors.initials: H
authors.lastname: Brown
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and.
authors.forename: Jonas
authors.initials: J
authors.lastname: Nikoloff
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and.
authors.forename: Michael
authors.initials: M
authors.lastname: Adler
authors.affiliation: Late-Stage Pharmaceutical and Process Development-Pharmaceutical Technical Development & Supplies Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland; and Lonza AG, Drug Product Services, Basel, Switzerland.
authors.forename: Hanns-Christian
authors.initials: HC
authors.lastname: Mahler
mesh_terms: D004340:Drug Contamination / Q000517:prevention & control; D004349:Drug Packaging / Q000379:methods / Q000592:standards*; D004356:Drug Storage / Q000379:methods / Q000592:standards; D005615:Freezing; D005898:Glass; D004364:Pharmaceutical Preparations / Q000592:standards*; D055114:X-Ray Microtomography / Q000379:methods / Q000592:standards*
chemical_list: D004364:Pharmaceutical Preparations
keywords: Container closure integrity; Container closure system; Frozen product; He leakage test; Headspace analysis; Vial