Pre-testing for Glass Delamination in Pharmaceutical Vials

At a Glance

A leading manufacturer of branded injectable pharmaceutical products hired McCrone Associates, the microanalysis division of The McCrone Group, to investigate product-package compatibility for a drug candidate with a high pH level. Through a series of microanalytical tests, McCrone scientists determined the drug would corrode its glass vial packaging. This pre-testing of the packaging helped the company avoided wasting further resources on the drug candidate.

Situation

Packaging is a critical step in the drug development process and should be tested rigorously. Glass vials, which store injectables and liquid solutions, are often overlooked for packaging testing because they are assumed to be safe due to their longevity in the industry. Made of common borosilicate and soda lime glasses, vials are chosen for their strong barrier properties, cost effectiveness and perceived stability. Yet long history does not equate with safety. Glass vials can pose contamination risks, often invisible to the naked eye, and should be pre-tested to ensure product compatibility.

Issue

A leading manufacturer of branded injectable pharmaceutical products predicted one of its drug candidates would chemically react with its glass vial packaging, causing delamination. Delamination occurs when top layers of a glass surface separate and flake off, typically at a scale invisible to the naked eye. The flakes become suspended in the drug solution, posing a serious risk to the consumer and potentially damaging the manufacturer’s reputation if brought to market. The company, however, did not have the equipment or expertise to confirm their suspicion, so they consulted McCrone Associates to determine whether the drug would react with various vials from three different manufacturers.

Prior to sending samples to McCrone Associates, the drug company stored sets of vials at different temperatures for different time periods to determine under which conditions the vials were least likely to delaminate. Vials from companies A, B and C were stored at 55°C for two weeks, and additional sets of vials from each of the three companies were stored at 40°C, 30°C, 25°C, and 4°C for four weeks. A third set of vials from Company B was studied at these temperatures for eight weeks. Company B vials warranted additional study because they exhibited numerous striations along the inner vial wall, which was likely a byproduct of their manufacture, but a potential harmful variable (see Table 1).

Solution

McCrone Associates scientists first examined the empty vials using a stereomicroscope. They observed some pitting and striations on a few of the vials from each set but were unable to make definitive assessments of delamination. The vials were prepared for further analysis in McCrone’s ISO class 5 cleanroom by carefully breaking the vials into smaller pieces and mounting them on different substrates. Portions of vials from each temperature range were examined with a series of microanalytical techniques according to the different delamination symptoms they exhibited.

Company A’s vials showed an unusual pink and brown discoloration in all temperature ranges; therefore, a portion of the discolored residue from the vial walls from the 55°C set was isolated, along with the delamination flakes, for analysis and comparison using Fourier transform infrared microscopy (FTIR or micro-FTIR analysis). Both IR spectra showed a broad band at ~1100 cm-1, characteristic of silica and suggesting the discoloration was a property of the glass, and not a foreign contaminant.

Scientists also mounted samples from all vials on a carbon substrate for scanning electron microscopy (SEM)/energy dispersive x-ray spectrometer (EDS) analyses. Such analyses can confirm whether the contaminant is glass and can provide clues to the conditions under which delamination was most likely to occur.

For some of the Company C vials, images of glass pieces flaking off the interior walls were captured using SEM and confirmed to be glass delamination (Figure 1). Pitting was also found on the glass surface, and further examination at higher magnification demonstrated tapering and enlargement of the pits (Figures 2 and 3), indicating that as pitting increased, the pits’ borders overlapped and caused pieces of glass to flake or delaminate.

Figure 1: Glass pieces flaking off the interior walls of Company C vials captured by SEM/EDS analysis confirmed glass delamination was occurring.

Figures 2 and 3: Images of the glass surface of vials demonstrates tapering and enlargement of pits.

Finally, the vial fragments were analyzed using x-ray photoelectron spectroscopy (XPS, also known as electron spectroscopy for chemical analysis or ESCA). This technique was used to further examine residues on the glass surfaces and was essential in determining the chemical nature of glass delamination.

XPS analysis of the surface layers of all the vials showed changes in the relative amounts of glass component elements sodium (Na), calcium (Ca), magnesium (Mg) and silicon (Si) in the fragments. These changes are indicators of chemical attack of the glass by the drug product solution, which in turn produced preferential leaching of reactive components. Therefore, the XPS revealed that the chemical attack was the cause of pitting and, ultimately, the delamination of the vials.

Results

Using a combination of light microscopy, micro-FTIR, SEM/EDS, and XPS analyses, McCrone Associates scientists determined that the highly basic drug in this compatibility study produced glass delamination in all three vials, and that the delamination often occurred near the drug fill line. It was also determined that as the storage temperature and time increased for these vials, their vulnerability to delamination increased. The analyses results also revealed that pitting is often indicative of and a precursor to delamination. (For a summary of the study results, see Table 1).

The drug company discontinued the development of the product after reviewing the analytical results. “Patient safety comes first—and this particular drug reacted with packaging in volatile ways,” said the company’s lead product developer. “Even if we could solve the delamination problem with new kinds of vials or different packaging, there might still be a risk for extractables or leachables due to the drug’s high pH level and the way the drug reacts with its packaging. We saved money on additional testing and decided the drug was not worth the potential risk of letting it go to market.”

Table 1: Complete results of The McCrone Group’s delamination study with vials from manufacturers A, B and C.