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Overview of the Current Assessment Methods for Pharmaceutical Glass Containers

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Sunday 15 December 2013

GTS Technologist Margaret Flower, reviews the latest standards for hydrolytic resistance testing of pharmaceutical bottles, vials, ampoules, cartridges and syringes.GTS Technologist Margaret Flower, of independent research and development, consultancy and testing facility, Glass Technology Services Ltd (GTS), discusses recent revisions of standards for pharmaceutical glass containers.

Although plastic has seen increased use for primary and secondary packaging of many pharmaceutical preparations, glass remains essentially the material of choice for parenteral and other sensitive products.

Hydrolytic stability testing of these containers is clearly critical to maintaining this position and ensuring confident use of glass across the pharmaceutical, laboratory and medical sectors.

The suitability of containers for pharmaceutical products is based on their hydrolytic stability. This is expressed by their resistance to the release of soluble mineral substances into water under prescribed conditions of contact between the inner surface of the container, or glass grains, and water. The amount of extracted alkali is evaluated by titration.

According to their hydrolytic resistance, glass containers are classified as:

  • Type I: a neutral glass, with high hydrolytic resistance due to its chemical composition, considered suitable for most preparations, whether or not for parenteral administration.
  • Type II: usually a soda-lime-silica glass with a high hydrolytic resistance resulting from special treatment of the inner surface and generally suitable for most acidic and neutral preparations - or for aqueous preparations, including parenteral administration.
  • Type III: usually uncoated soda-lime-silica glass with a moderate hydrolytic resistance and generally suitable for non-aqueous preparations for parenteral administration and powders for parenteral use (excluding freeze-dried preparations) and preparations not for parenteral administration.

We obviously closely monitor any developments in the pharmacopoeia mongraphs that govern our testing processes across all glass types, to ensure we continue to provide full support throughout the industry supply chain.

Summary of Pharmacopoeia Changes

The United States (USP) and European (Ph. Eur.) Pharmacopoeias remain the most widely used in the global market and recent revisions to the USP have brought harmonization between the two -bringing welcome simplification and, in many cases, cost savings for customers that regularly request testing to both USP and Ph. Eur. The key changes have been:

  • Replacement of the powdered glass test by the Ph. Eur. glass grains test;
  • Deletion of the water attack at 121 degrees C test;
  • Incorporation of the Ph. Eur. surface glass test;
  • Inclusion of a new chapter, <1660>, to the USP for delamination propensity pre-screening.

In our view, although the glass grains test gives adequate information on the glass as a material, it does not provide sufficient information about what happens to the inner surface of the glass when in contact with water, therefore the surface glass test better replicates the behavior of the finished article in use.

The shape, size and contact surface area also influence the resulting amount of alkali extraction - so containers produced from the same glass and with identical capacities, but with a greater surface area to volume ratio, could give a higher value. The Ph. Eur. also includes a method for the hydrolytic resistance of glass types I and II to be determined by flame atomic absorption spectrometry (FAAS), where the amount of extracted alkali is evaluated by determining the individual values of the oxides of sodium, potassium and calcium in the solution.

Although FAAS allows the use of a much smaller sample of extract, which means it can be applied to small individual containers, you cannot rely on it in isolation. The results are not equivalent to those of titrimetry, which remains the reference method of both USP and Ph. Eur. standards.

Inductively Coupled Plasma (ICP) Spectrometry is seen as the future for trace elemental analysis. We use ICP, which is capable of identifying trace elements at parts per billionlevels, to test for the migration of heavy metals from packaging materials. It is one of the instrumental techniques enabling us to help glass manufacturers and processors to meet increasingly stringent legislative standards.

Delamination Propensity

USP is also now proposing a new general information chapter <1660 > on delamination, in response to recent product recalls. Aiming to provide information about factors that influence the durability of the inner surface of glass containers and predict the potential of a drug product to cause the formation of glass flakes and particles, the new chapter will likely result in further testing requirements for both the glass and pharmaceutical industries.

Although the surface glass test provides an indication of surface durability, it does not provide a direct correlation with the tendency to delaminate. The drug product itself has been found to be an important variable affecting surface durability and as the surface glass test uses water as the extracting medium, it does not take this into account. In addition, both production and processing methods are known to be an important factor for the delamination of type l glass articles.

Additional screening methods are being proposed to determine the suitability of vials for the intended product - including tests designed to accelerate delamination by exposure to aggressive conditions. Our technologists are monitoring developments closely and can offer these screening methods and analytical techniques to help our pharmaceutical clients meet these proposed standards.

Our teams are experienced in dealing with a number of problems which may present as a “delamination” issue when this is not necessarily the case.

Based on extensive experience of samples sent to us for delamination testing, often what looks like tiny glass fragments, flakes (lamellae) or deposits, are actually naturally occurring compounds that have precipitated out of- and dissolved back into- solution by the time the sample reaches our laboratory.

The true source of type I glass delamination is often the flame working of the glass, which causes boron to volatilise from the surface of the glass. This leaves behind a silica-rich surface layer, which has a different thermal expansion to the bulk glass, causing the surface to flake off when exposed to variances in temperature.

It may be possible, with further research, to determine if this problem could be rectified by further treatment after flame working to stabilise the skin before it fails.

In the case of type III glass, the term delamination is used to describe the effect of the constant attack on the glass surface from the liquids contained, which leaches the alkaline components of the glass - resulting in a more alkaline solution.

This in turn increases the rate of attack, leaving a skin of predominately silica on the glass surface, which eventually detaches and can be seen as very thin shimmering particles within the solution. This effect can occur with glasses which have good durability if exposed to high or cyclic temperatures.

Rather than assuming delamination, accurate independent testing can help to avoid costly litigation and product recalls, by ensuring the real root causes of any problem are revealed.

The glass supply chain is well aware that to ensure the efficacy of a product during its total shelf-life, pharmaceuticals must be regarded as a combination of the medicinal product itself and the packaging which contains it  – making the Finished Dosage Form (FDF) - and our industry leads the way in terms of product innovation and product performance in this sector.

This partial harmonisation of European and US Pharmacopoeias will be well received, both by glass manufacturers and by pharmaceutical and medical companies, who are increasingly using our services to achieve product certification.

One set of tests for hydrolytic stability makes the process much simpler and more cost-effective and for an industry which is heavily regulated and where development and innovation is constant - that has to be very welcome news.

However, potential requirements for comprehensive delamination pre-screening of a whole range of FDF products is likely to be less well-received, but could provide the data to help guide further research into its’ future prevention.

Glass Technology Services Ltd (GTS) has an established history offering ISO:17025 UKAS accredited testing services for pharmaceutical and medical companies and is registered under the US FDA GDUFA for FDF testing, as well as providing glass manufacturers and processors a comprehensive range of chemical, optical and mechanical testing and analytical services. In addition to United States and European Pharmacopoeia, GTS also tests for British, Russian and Japanese Pharmacopoeia standards.

Reproduction of this published material is provided courtesy of Glass International. Published in Glass International December 2013.


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