Evaluating Parenteral Packaging for Glass Delamination

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 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.

Dan Haines

Root causes for glass delamination

To understand and test for glass delamination, one must first understand the primary root causes: the chemical composition of the glass, the container manufacturing process, the chemical interaction of the drug product with the interior surface of the container, and the effects of processing. For parenteral drug products, Type 1 glass (United States Pharmacopeia [USP]<660>; ASTM E438) (1) is used, but the compositional differences between glasses is significant, varying by up to 10 weight percent for single elements. These compositional differences result in significant physical differences, primarily melting/working temperature, as glasses that contain more silicon (e.g., Type 1A glasses) require more heat to shape the container.

The majority of parenteral products use either molded or tubular glass containers. Molded containers require a single high-heat cycle (melting, pouring, blowing/pressing) and use compositions that are usually low in silicon and high in alkali/alkaline earth elements, resulting in interior container surfaces that are quite uniform in surface chemical homogeneity. Tubular containers made from glass cane require two high-heat cycles; the tubing is made first, then segmented or "converted" in a second heating process to the final container design. Careful control of the converting process in the base/heel and shoulder/neck regions is crucial to obtaining interior container surfaces that maintain the bulk-glass resistance to chemical attack, due to the evaporation of some glass components (i.e., alkali borates) in the worked regions of the containers. Glass-cane compositions are typically Type 1A or Type 1B, having higher amounts of silicon and lower amounts of alkali/alkaline earth elements than molded containers. While both moulded and tubular glass compositions used for parenteral packaging have high chemical durability, tubular compositions are generally regarded to have higher chemical resistance than molded compositions. Notwithstanding the two high-heat cycles, proper control of the converting process results in tubular containers with the equivalent non-delamination of molded containers, as demonstrated in the work of Ennis, et al. (2).

The chemistry of the chemical attack of glass by water-based liquids is driven primarily by leaching and dissolution. The primary attack mechanism at acidic pH is the diffusion of water into the glass and exchange of hydrogen (i.e., hydronium) ions with the alkali (i.e., sodium or potassium) ions, which is called leaching. The primary attack mechanism at basic pH is the dissolution of the silicate backbone (i.e., silicon-oxygen bonds) by hydroxide ions. The influence of the drug-product formulation, such as buffer type and ionic strength, also contribute to rate of chemical attack but are beyond the scope of this article. Processing steps performed after the vial is manufactured that influence the interior surface layer also affect the chemical durability of the container. The most aggressive processing step is the post-filling sterilization of the drug product by terminal steam treatment. A list of the most relevant factors influencing glass delamination is shown in Figure 1. Most pharmaceutical companies today have done a risk assessment using risk factors such as these and use them as a guideline for selecting and testing new drug-product and container combinations.

Figure 1: Mechanisms for glass attack and factors to assess for contributing to glass delamination. (ALL FIGURES COURTESY OF THE AUTHOR.)

Predicting delamination

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 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. 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 indicators.

• 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, daniel.haines@us.schott.com, tel: 570.457.7485 x653.

References

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, MD, 2012).