A delamination screening package developed by SCHOTT is aligned with USP 1660 guidance (3) 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
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. An example of such an SEM-micrograph is depicted in Figure 2.
Figure 2: SEM cross-section showing reaction zone near heel of vial.
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. Figure 3 shows a typical container screening study protocol for development testing of a new drug product.
Figure 3: A container screening protocol example for accelerated testing at 60 °C.
Crucial points to remember are:
- Delamination is usually seen after months or years of stability storage; tests must be much faster.
- Optical inspection gives a yes/no answer and relies partly on chance; complementary analytical tools are needed to see early
- Delamination risk depends on the drug; tests need to use the drug or a placebo.
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, moulded 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.
Dan Haines is scientific advisor at SCHOTT Pharmaceutical Services, email@example.com
, tel: 570.457.7485 x653.
1. USP General Chapter <660>, "Containers—Glass" (US Pharmacopeial Convention, Rockville, MD, 2012).
2. R. D. Ennis, et al., Pharm. Dev. and Tech., 6 (3), 393-405 (2001).
3. USP General Chapter <1660>, "Evaluation of the Inner Surface Durability of Glass Containers" (US Pharmacopeial Convention, Rockville,