While many factors contribute to the recent surge in glass delamination recalls, it is important to remember that no recalls, clinical, or laboratory studies to date have shown any evidence of harm to the patient from “glass flakes or lamellae”, and only a small fraction of drug products/container systems have a propensity for generating glass flakes. If one searches the literature, numerous examples of drug-product/glass-packaging interaction can be found in each of the past seven decades. The main reasons for increased glass delamination incidences in recent years are increasing inspection sensitivity for particles, high profile and costly recalls, and increased complexity of the formulations and, therefore, unknown criticality for corrosive attack of the containers. If glass delamination is observed, numerous types of alternate containers already exist in the market for packaging, and fast, reliable test methods are readily available for screening containers to evaluate the delamination risk for each drug-container combination.
A delamination screening package developed by SCHOTT is aligned with USP 1660 guidance (1) and can be used to evaluate a drug-product/container system. The containers to be tested can be drawn from real-time stability samples or generated under accelerated aging temperatures to determine the amount of chemical attack from drug products on containers and assess the risk of glass delamination occurrence through the shelf-life of the drug product. For most drug-product solutions, the rate of attack can be assumed reasonably through use of the Arrhenius rate law. A combination of tests investigating the drug solution itself and the morphology and composition of the near surface area of the container are required to determine the risk of glass delamination for a scientifically justifiable selection of an alternative container. Test methods consist of optical inspection for visible flakes and video-camera inspection for subvisible flakes (15–50 microns). If flakes are not observed, three other tests are then usually run in sequence.
First, the solution is removed from the container and examined by inductively coupled plasma optical-emission spectroscopy/mass spectrometry (ICP-OES/MS) for concentration of typical “glass” elements to determine the total amount of dissolution or leaching into solution at a given time point. This test also measures the ratio of glass elements to get evidence for the mechanism of attack.
The container is then assessed by a stereomicroscope method to look for light scattering and color bands in the container. Light-scattering regions indicate increased surface roughness, and color bands indicate an altered layer of material with a different index of refraction from the bulk glass of the container. Observation of either light scattering or color bands is followed up with cross-section scanning electron microscopy (SEM) to determine the extent of chemical attack on the surface and into the surface (i.e., depth-of-reaction zone). If a reaction zone is observed that grows with time, then there is an increasing risk of delamination with increasing storage time.
To get a better understanding of the delamination mechanism, secondary ion mass spectrometry (SIMS) depth profiling is conducted to determine the chemical composition of any reaction zones found. If flakes are observed in solution, then the flakes can be separated from solution by filtration and analyzed by SEM energy-dispersive spectroscopy (SEM-EDS) to determine their morphology and chemical composition. These results are compared to the findings from the SIMS- and SEM-analyses from the interior container wall. The testing methods above, with the exception of the stereomicroscope method, have been incorporated into the USP 1660 guidance chapter on testing of containers for chemical durability.
Crucial points to remember are:
Responding to predicted container delamination
If delamination or significant evidence for chemical attack of the container has been observed and the mechanism determined, several alternative solutions exist before considering the need to change the formulation. A first approach would be to use the same glass type (i.e., Type 1A, Type 1B, molded Type 1) but from a different container manufacturer to eliminate the contribution to glass delamination from the container manufacturing process. A second approach would be to switch to a different Type 1 glass, either with the same or different container manufacturer. A third approach would be to use a Type 1 glass with a coating, such as the SCHOTT Type 1 plus container with a plasma-impulse deposited silicon dioxide coating. A fourth approach would be to switch from glass to a high-performance plastic such as cyclic olefin copolymer (COC, SCHOTT TopPac) provided there are no concerns regarding increased moisture or oxygen permeability. If none of those approaches work, the last approach would be to modify the drug formulation.
1. USP General Chapter <1660>, “Evaluation of the Inner Surface Durability of Glass Containers,” (US Pharmacopeial Convention, Rockville, MD, 2012).
—Dr. Dan Haines is scientific advisor, SCHOTT Pharmaceutical Services, [email protected], tel: 570.457.7485 x653.