The 10 most frequently asked questions on glass – Part I

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:

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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.

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:

1. Question:USP <660> Containers – Glass; United States Pharmacopeia ()
   Ph. Eur. 3.2.1. Glass Containers for Pharmaceutical Use; European Pharmacopoeia ()
   ISO : Guidelines on types of glass of normal bulk-production composition and their test methods; International Organization for Standardization ()
   ASTM E438 – 92 Standard Specification for Glasses in Laboratory Apparatus; ASTM International ()
   USP is announcing a proposal to modify the glass classifications in General Chapter and to create additional flexibility for packaging and storage requirements in specified monographs | USP-NF (uspnf.com)
2. Question:ISO -1: Injection containers and accessories - Part 1: Injection vials made of glass tubing; International Organization for Standardization ()
   ISO -4: Injection containers and accessories - Part 4: Injection vials made of moulded glass; International Organization for Standardization ()
3. Question:70-100MPa: Wagner, J, Müller-Simon, H, Lenhart, A. Practical strength of glass containers. Part 2. Influence of handling. Glastech. Ber. Glass Sci Technol. 67, , Vol. 7, pp. 196–201Littleton: Vogel, W. Glass Chemistry. 2. Aufl. Berlin: Springer, .
   PDA Technical Report 87 Current Best Practices for Pharmaceutical Glass Vial Handling and Processing; Parenteral Drug Association ()
   PDA Technical Report 43 Identification and Classification of Nonconformities in Molded and Tubular Glass Containers for Pharmaceutical Manufacturing: Covering Ampules, Bottles, Cartridges, Syringes & Vials; Parenteral Drug Association ()
   Schaut, R., A., et al. (). Enhancing Patient Safety through the Use of a Pharmaceutical Glass Designed To Prevent Cracked Containers. PDA J Pharm Sci Technol, 71(6), 511-528. doi:10./pdajpst..
4. Question:Cambridge Dictionary: Retrieved 3 Jul. https://dictionary.cambridge.org/dictionary/english/inert
   Oxford Dictionary: https://www.oxfordreference.com/display/10./oi/authority.;jsessionid=98DAC50CA7A9D9FF5BC11C6
   Oxford Dictionary: Retrieved 3 Jul. , from https://www.oxfordreference.com/view/10./oi/authority..
   Boltres B. (). When Glass Meets Pharma. ECV INSIGHTS!. ISBN: 978-3--432-2
5. Question:EMA/CHMP/CVMP/QWP//: Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container; European Medicines Agency,

Trademarks mentioned:

Glass is highly common in pharmaceutical packaging. The many glass types offer an abundance of benefits, which are essential for the longevity, concentration, and safety of what is stored inside. 

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They are ideal for packaging solutions as they are easy to sterilise, great for protecting the contents from ultraviolet rays, do not react with chemicals inside, and are often transparent so that you can easily see what’s inside. 

Although all types of glass can offer the above benefits, it is important to be aware that there are various types of glasses and all offer different properties, prices, use, manufacturing, and availability. Continue reading to learn more about the types of glasses, what they offer, how they are used, and more.

How Are Types of Glass Containers Made?

Glass vials, jars and bottles for pharmaceutical practices are created using various methods. The most common include:

• Blowing – compressing air into molten glass.
• Drawing – pulling molten glass through dies that shape the glass.
• Pressing – moulds the glass using mechanical force.
• Casting – uses the force of gravity to force and initiate the shape of the glass. 

All methods are tested before use to ensure that the glass container is safe and effective for pharmaceutical use. 

What Is Type I Glass?

Type I glass consists of various elements, all of which are great at resisting chemicals of strong acids and alkalis. 

It is made up of 80% silica, 10% boric oxide, and small quantities of both sodium oxide and aluminium oxide. All Type I glass containers are suitable for both parenteral preparations (such as vaccines, antibiotics and anaesthetics) and non-parenteral preparations (such as creams, lotions and wellbeing products). 

What Is Type II Glass?

Type II glass bottles are very similar to Type III glass, so much so that they are considered modified Type III glass bottles. 

Like Type I and Type III glass, Type II has a high hydrolytic resistance, which makes it highly resistant to hot water. This makes it suitable for resisting reactions and helps the contents remain in their original state. 

The difference between Type II and Type III glass bottles is that the inside of Type II bottles is treated with sulphur.  

The difference between Type II and Type I glass containers is that Type II glass has a lower melting point. Type I glass is great at protecting the contents from weathering. However, Type II glass is much easier to mould yet less likely to withstand hot environments. 

The easy-to-mould glass makes it suitable for storing neutral aqueous and acidic chemicals. 

What Is Type III Glass?

Type III glass is roughly comprised of just under 75% silica, 15% sodium oxide, and 10% calcium oxide, respectively. The remaining percentage consists of small amounts of magnesium, potassium, and aluminium oxides. These small quantities help the glass become more versatile. The aluminium oxide benefits the glass as it improves its chemical durability. Meanwhile, magnesium oxide helps the glass to mould more easily at lower temperatures. 

Type III glasses are much more versatile and can be used in parenteral and non-parenteral practices. They are also suitable for storing aqueous solutions.

The Key Differences Between Glass Types

Although the types of glass boast similarities, such as being made up of similar materials and being suitable for similar preparations, there are some key differences:

The Manufacturing Process of Glass Types

The manufacturing process of the glass types varies depending on the industry. The manufacturing processes of glass containers are listed above. 

The Cost of the Glass Types

Type III glass is the most affordable, and Type I glass is the most expensive. Type III glass is more readily available because Type I glass needs extra manufacturing to be more durable and resistant. Type II glass costs a little more than Type III glass because it requires a sulphur treatment (and sometimes dye) to help it resist UV rays. 

The Availability of Types of Glass

The most common glass is Type III, which accounts for 90% of glass production worldwide and is much more readily available. 

With a sulphur treatment on the inside, Type III glass transforms into Type II glass, which can also be readily available. 

Type I is less available due to its sophisticated manufacturing process, which makes it more durable. 

The Uses of the Types of Glass Bottles

Type III glass is the most common packaging solution for pharmaceutical glass bottle packaging and everyday household containers. It is often referred to as soda-lime-silica glass and makes up 90% of the world’s glass containers. 

Type II is less chemically stable and is, therefore, less common than Type III glass. It is ideal for chemicals that can react to light in pharmaceutical preparations as Type II glass is often dyed. The colour of the glass packaging can block UV rays and therefore protect the contents from the reaction. 

Type I glass is more common for pharmaceutical glass vials, as it provides greater heat and chemical resistance, which makes it more reliable and safer. Type I glass is often referred to as borosilicate glass and is used for heat products, such as light bulbs, fire glass, storing jet fuel, and acid. 

Overall, there are plenty of options to choose from for pharmaceutical packaging solutions. Type I glass is highly recommended for practices and preparations requiring more durable and resistant packaging. It can resist heat, thermal shock, and chemicals, making it much safer and ensures that the contents will not be affected. For those seeking more affordable and less durable packaging, Type III and Type II glass are ideal and practical.

Order Types of Glass Containers at Origin Today

You can find a whole selection of quality glass bottles, vials and jars available at Origin today. With glass dropper bottles, glass jars, and more options available, you can find the most suitable packaging for your organisation from our range. If you’d like to find out more about the types of glass, you can read our pharma packaging blogs for further insight.

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