2021 FDA Science Forum
The Usefulness of Broad Ion Beam Milling System in Studying Drug Product Formulation-Container Interactions
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Contributing OfficeCenter for Drug Evaluation and Research
Abstract
Background
Focused ion beam (FIB) is one of the advanced techniques commonly used to prepare high-quality cross-sectional samples of glass vials. However, sample preparation with FIB is usually expensive, time consuming and labor intensive. As an alternative, broad ion beam (BIB) milling system was employed to prepare high-quality cross-sections to investigate pharmaceutical vials. BIB may be used for a larger cross-section with lower level of damage to the samples compared to FIB technique. In this study, BIB has been utilized to investigate particulate generation in parenteral drug products due to drug formulation-container interactions.
Purpose
The purpose of this study is to investigate the usefulness of BIB milling technique to study the interactions between the container and drug solution in generic and brand products.
Methods
The study design included sample lots of complex injectables of various generic and brand drug products. The drug product samples were filtered and analyzed under stereomicroscope. Emptied vials were prepared using BIB to expose the features on the inner surface of container-formulation interface and further characterized with field emission scanning electron microscope (FE-SEM).
Results
Both ANDA and RLD products showed thin flaky particulates collected on membrane filters under optical microscope with size from subvisible to visible range. However, the thin flaking off layer on the inner surface of glass vials were easily damaged using either random break method or rotary cutting saw, which made the detection of the source of particulates very difficult. BIB used in this study demonstrate the capability to create a relatively large cross-section with good flatness and little damage to the surface. The prepared samples revealed the layer created by the interaction between formulation and glass container under FE-SEM.
Conclusion
The combination of BIB and FE-SEM allowed preparation of high-quality cross-sectional samples for exploring the source of particulates while analyzing its composition simultaneously. The implementation of BIB proved to be valuable especially for samples when visual inspection is not feasible. In summary, the development and application of a platform as a characterization technique as described here can provide information to support a science-based evaluation of complex injectables.
