We recently sat down with Dr. Bettine Boltres, our contact for scientific affairs and technical solutions for glass. In her role she is supporting pharmaceutical companies to address glass-related topics from a scientific perspective and to gain a deeper understanding of the material that holds their valuable drug products. Having done this for many years, we wanted to know what the most frequently asked questions are that she encounters. Please read Part 1 of our two-part series around the 10 most commonly asked questions around glass vials:
1. What is Type I glass and why is there sometimes an &#;A&#; or &#;B&#; designation?
The required quality for glass containers for pharmaceutical applications is described in global pharmacopeia, e.g., USP Chapter <660> Containers &#; Glass or Ph. Eur. 3.2.1. Glass Containers for Pharmaceutical Use. Apart from pharmacopeia, the different glass types are also described in standards, such as ISO and ASTM.
USP and Ph. Eur. have classified Type I glass as Borosilicate (BS) glass and Type III glass as soda-lime (SL) glass, each one with a certain limit for hydrolytic resistance. Typical BS glasses on the market are FIOLAX®, Corning®51-D / 51-V and NSV® 51. As it is an accepted custom to treat SL glass with ammonium sulfate on the inside to increase its chemical stability, this inner surface-treated SL glass was added in pharmacopeia and classified as Type II glass. Although there are different sub types of BS glass on the market, these are not differentiated in pharmacopeia. However, ASTM E 438 does distinguish between Type I Class A which is a BS glass with a lower thermal expansion, such as DURAN® or PYREX® glass and Type I Class B, which is a BS glass with a higher thermal expansion (alumino-borosilicate glass as per ASTM), known as FIOLAX®, Corning®51-D / 51-V or NSV® 51 glass.
ISO simply lists different glass compositions without labelling them as Type I or II or A or B.
As new glass compositions come to the market, pharmacopeia and standards need to find a way to accommodate them.A recent example is the Aluminosilicate glass composition that is used in Corning® Valor® Vials which is in the process of being added to the USP <660> chapter this year.
Source Designations DescriptionUSP <660>, Ph. Eur. 3.2.1
Type IBorosilicate
USP <660>, Ph. Eur. 3.2.1
Type IIInner surface-treated soda-lime-silica
USP <660>, Ph. Eur. 3.2.1
Type IIISoda-lime-silica
ASTM E 438 - 92
Type I, Class ALow-expansion borosilicate glass
ASTM E 438 - 92
Type I, Class BAlumino
Link to Mingfeng
-borosilicate glass
ASTM E 438 - 92
Type IISoda-lime glass
2. What does the &#;R&#; in 2R mean?
Dimensional requirements for vials are laid out in ISO Injection containers and accessories. The first version of this standard was published as Injection containers for injectables and accessories in . ISO simultaneously worked on two versions, one for vials made of tubular glass (ISO -1: Part 1: Injection vials made of glass tubing) and for molded vials (ISO -4: Injection vials made of moulded glass). As these two production techniques produce quite different dimensional accuracy and tolerances, the requirements were set accordingly. To reflect the different production techniques also in the designation of the vials, an abbreviation for each technique was added. The German word for &#;tubular&#; &#;Röhre&#; was selected and lent the &#;R&#; to the injection vials made of tubular glass; the German word &#;Hüttenglas,&#; meaning &#;molded glass,&#; lent the &#;H&#; to the vials made of molded glass. So, the &#;R&#; behind a filling volume number (e.g., 2R) means that this tubular glass vial has the dimensions as given in ISO -1, while the &#;H&#; behind the number (e.g., 10H) means that this 10 mL vials was produced by molding and complies with the dimensional requirements from ISO -4.
However, as this background is not known to everyone, the &#;R&#; is sometimes also used for non-ISO vials, so we recommend to always double-check.
3. How strong is glass?
Unfortunately, this question cannot easily be answered. Because glass is a brittle material, its strength is not a material constant but very dependent on flaws occurring within the material or on its surface. In quite simple words: the more flaws, such as scratches and cracks, the glass has on its surface, the weaker it is. This reduces its theoretical strength which initially is in the GPa range to a practical strength of around 70 &#; 100 MPa. To quote Littleton, who was one of the pioneers in glass strength testing: &#;We do not measure the actual strength of the glass but the weakness of the surface.&#;
Also, for the sake of completeness, we want to mention that imperfections on an atomic level and stress from improper thermic treatment count as flaws.
A very comprehensive overview of how to avoid the introduction of surface flaws through handling is given in the PDA Technical Report 87 Current Best Practices for Pharmaceutical Glass Vial Handling and Processing. It is particularly useful in combination with PDA Technical Report 43 Identification and Classification of Nonconformities in Molded and Tubular Glass Containers for Pharmaceutical Manufacturing: Covering Ampules, Bottles, Cartridges, Syringes & Vials.
Improving glass handling is a very efficient way of keeping as much as possible of the initial strength of the glass. But there is also a way of increasing the strength of glass which is to subject it to an ion exchange process where the sodium ions in the surface regions are replaced by larger potassium ions that build up a compressive layer and can hereby increase the practical strength of the glass significantly. An example for this is the Valor® Glass that is being used with different medicinal products, such as vaccines, biologics and lyophilized products on the global market.
4. Is glass inert?
A common belief is that glass is inert. If we look at the scientific definition of &#;inert&#; we can find in the Cambridge Dictionary: &#;Inert&#;substances&#;do not&#;produce&#;a&#;chemical&#;reaction&#;when another&#;substance&#;is&#;added,&#; and in the Oxford Dictionary: &#;A material that is very stable and does not readily take part in chemical reactions with other substances&#;. Based on these definitions, there is almost no inert material, except for certain gases. Most solid materials do interact with their environment, even if only on a very small scale. For example, glass does interact with aqueous solutions. This can be on the outside with the humidity from the air where it builds up a &#;water skin&#; or on the inside with the aqueous drug solution. The extent to which the reaction takes place is dependent on many different factors, such as initial state of the glass surface, pH value of the drug solution, chemical properties of the involved substances in the solution, filling volume, converting process and several more. Examples for interactions are ion exchange between the glass and the solution, chemical reactions that cause substances to precipitate, chemical reactions that lead to a dissolution of the upper glass surface layers, chemical attack that leads to delamination of the upper surface layer, etc. As it is individual for each drug solution / vial combination, the potential interactions should be examined through extractables and leachables studies. Additionally, the surface condition can be visualized using spectroscopy techniques like scanning electron microscopy energy-dispersive X-ray spectroscopy (SEM-EDX), Time-of-Flight Secondary Ion Mass Spectrometry (TOF-SIMS) or X-ray photoelectron spectroscopy (XPS).
5. How can I sterilize my glass vials?
There are different sterilization techniques out there that all come with their own advantages and disadvantages. A widely used method on the market is terminal sterilization, which is a final autoclaving step after the vials have been filled with the drug solution. This is commonly done for water for injection or other aqueous diluents. Autoclaving involves heating up to 121°C and typically keeping it there for around 20-30 minutes. Based on the European Medicines Agency (EMA) Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container terminal sterilization is the preferred method.
Given the fact that many biologics are sensitive to heat, terminal sterilization is sometimes not an option, and an alternative treatment needs to be applied. As biologics are typically filled using aseptic filling processes, the empty vials must be sterile already before introducing them into the filling process. Nowadays, this is usually done by using Ethylene oxide (EtO). Hereby, the vials are placed in nests and tubs or nested trays and introduced into a chamber where they are fumigated with EtO at up to 70°C for around 6 hours. A disadvantage here is presented by the toxic EtO residuals that need to be fully removed and the environmental burdens the EtO residuals cause.
There are also other techniques that can be used but come with their own caveats. In the medical device world, it is very common to use gamma or e-beam sterilization. Such radiation approaches can technically also be used for glass containers. However, due to the trace amounts of certain metals in the glass composition, the color of the glass will turn brownish/yellowish depending on the exposure time and the concentration of the radiation. This effect is neither affecting the physical intactness of the vial nor its chemical stability, but as a cosmetic implication &#; even though it will disappear after a certain time - it is not well accepted. While not very common, it is possible to use a special cerium-doped borosilicate glass that will not discolor. Additionally, gamma radiation needs Co60 as a radiation source, which is currently under debate for capacity constraints.
Based on those disadvantages, other existing techniques for sterilization / decontamination are being evaluated for glass containers, such as N2O, VHP, VPA, etc. As they also all come with their own caveats, the future of sterilization remains to be seen.
Look out for Part 2 of this blog series where Dr. Boltres will share the remainder of the top questions she gets asked about glass.
References:
Trademarks mentioned:
Corning®, Valor®, and PYREX® are registered trademarks of Corning Incorporated.
All other trademarks appearing in this document are the properties of their respective owners.
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