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In September , Dr. Bettine Boltres, West&#;s contact for scientific affairs and technical solutions for glass, shared with us the most frequently asked questions that she encounters on glass-related topics. We are pleased to share Part 2 of the series where Dr. Boltres will share the remainder of the 10 most common questions she gets asked concerning glass vials.
You can read Part 1 of the series here.
6. What&#;s the difference between glass sterilization and depyrogenation?
As a follow-up question to question no. 5 from Part I of this Blog series, we want to look at the difference between sterilization and depyrogenation.
According to EMA sterilization is a &#;a suitably designed, validated and controlled process that inactivates or removes viable microorganisms in a product until sterility is obtained. Sterility is the absence of viable microorganisms, as defined by a sterility assurance level equal to or less than 10&#;6.&#; Depyrogenation is a &#;process used to destroy or remove pyrogens (e.g. endotoxins).&#;
Pyrogens are substances that induce a fever reaction (from the old Greek words for &#;inducing fire&#;) in the body. These can be produced by the body itself, e.g., in inflammations (endogenous pyrogens) or they can be introduced through external sources (extraneous pyrogens), e.g., from bacteria, viruses, fungi, etc. In the pharmaceutical industry bacteria-derived pyrogens pose the biggest challenge. One specific class of pyrogens are the endotoxins, mainly the lipopolysaccharides (LPS) from the outer cell membrane of bacteria, which may be released after the death and lysis of the cells. These endotoxins are highly heat stable and quite &#;sticky.&#; The USP and Ph. Eur. recommend a depyrogenation of at least 250°C for at least 30 min. This already indicates that autoclaving is not regarded as an efficient depyrogenation method.
On the other hand, also according to the CDC Glossary, sterilization is a process to &#;render a product free of all forms of viable microorganisms.&#; This can be achieved by methods such as those described in Question No. 5 of part I of this blog series.
As for glass containers, both the depyrogenation and sterilization steps have already been integrated into the production process. Directly after forming, the containers are proceeding through a so-called annealing oven, where they are subjected to dry heat of around 550 - 650°C. At this temperature the pyrogens are inactivated. Coming out of the annealing oven, the glass containers are practically free of endotoxin pyrogens and sterile. In an ideal world, they could now be introduced directly into the aseptic filling process. However, in the real world, there are still handling and transportation steps in between this and the final filling so that the sterilization steps need to be repeated.
To summarize, sterilization is a process that ensures that no viable microorganisms are left, while depyrogenation inactivates specific kinds of very stable substances, such as endotoxins. Having gone through a dry heat depyrogenation process such as the depyrogenation tunnel, leaves the products sterile, but a sterilization process such as autoclaving, does not result in depyrogenation.
7. What is the function of the blowback feature:
You might still sometimes see this issue: You fill your vials with a large amount of drug solution and down the filling line just before you close them with a crimp cap, the stoppers pop out of the vials. This scenario is not seen that often anymore, but many years ago this was a more common scenario. In a bulk filling line, the vials came out directly from the depyrogenation tunnel, still quite hot, and were directly filled with liquid solution that in turn warmed up and expanded in space. At the same time, the stoppers were placed onto the vial. This stoppering led to a compression of the air inside the vial, just the opposite of what the liquid and the air inside the vial desired to do. In addition, many years ago it was a common habit to over-siliconize the stoppers and sometimes even siliconize the vials on the inside, which made them very slippery. This combination of events leads to the pop out just before the vials could be closed with the seal. In a joint approach of some European glass vial manufacturers and the pharmaceutical industry, it was decided to add an &#;overhang&#; at the internal crown finish of the vial to keep the stopper in place. This was called the European (EU) blowback feature. Rubber manufacturers then adjusted some of their designs to match this feature and created EU blowback-matching vial stopper designs.
Additionally, a US blowback design, which offers an indentation slightly below the internal crown finish, also became available on the market, including matching rubber stoppers. However, the US blowback glass vial design is not preferred as the vials are harder to manufacture. Also, the EU blowback design is better at accommodating a larger variety of stoppers.
There can be situations where the vial stopper and the vial do not fit together at all. So, there needs to be a certain awareness for this topic. On the other hand, modern stoppers often do not need an excessive amount of silicone oil anymore, e.g., West NovaPure® stoppers have a FluroTec&#; film on the surface which eliminates the need for additional silicone oil for functionality. This reduces the risk for pop out. Also, biologics are often filled with a lower filling volume leading to a lower amount of liquid that can expand. Another recent development is that vials are increasingly used in a ready-to-use format where they do not directly come from the depyrogenation tunnel anymore.
West has done a comprehensive study with multiple combinations of vial neck designs and stopper designs with and without blowback features and found all of them to fit together properly (TR /199 Container Closure Integrity of Rubber-Glass Vial Systems). After many years of experience from the market, we know that it is generally possible to mix and match vials with blowback features and stoppers without blowback feature.
Additionally, a new rubber formulation, /40, was developed which is glass vial blowback design-agnostic (TR /211 Evaluation of Container Closure Integrity for /40 Lyophilization Stoppers).
Sketches from ISO :
8. Can I store my glass vial/rubber stopper/aluminum crimp seal combination at -80°C?
Based on the recent developments and the accompanying temperature sensitivities in the biologics product arena, there is an increasing need for storing these biologics at lower temperatures, such as -20°C, -60°C, -80°C or even lower. This was not considered when developing the vials, stoppers and seals many decades ago. So, the industry set out to investigate this topic. There are mainly two points that need to be considered: Is there an increased occurrence in glass breakage, and does this combination keep container closure integrity (CCI)?
The first question can be answered by looking at the first part of this blog series, the question about how strong glass is. The low temperature does not really impact the glass strength. As mentioned, it is rather a question of glass handling than the glass material. However, to be on the safe side, Valor® Glass vials can be used, which are chemically strengthened and thus have a significantly increased strength.
The second question is a bit more complicated. The key point here is the difference in physical expansion when these three completely different materials are exposed to colder temperatures. The extent of expansion is described by the so-called coefficient of thermal expansion (CTE) which is lower for materials that have a lower physical expansion or shrinkage and higher for materials that show a greater change in volume upon changing temperature. Of these three materials, glass has the lowest CTE meaning that it really does not change dimensions when frozen at -80°C. Rubber, on the other hand, has a higher CTE.
In lower temperatures, the rubber stopper shrinks more than the glass, creating a risk for a gap in the sealing area. This gap is then a potential place for ingress. Once the temperature rises, the rubber material expands, resealing the area again. As CCI measurements are typically performed before and after cold storage, this potential ingress is not caught. To be fair, at -80°C bacterial ingress is quite unlikely, but CO2 ingress might occur e.g., when shipping on dry ice.
So, what can be done now? First, you need to ensure that all primary packaging components fit together. If you want to get a step-by-step approach on how to choose the right combination of vial, stopper and seal, we invite you to watch West&#;s webinar on demand Selecting Container Closure Components with Confidence: A Data-Driven Approach to Container Closure Integrity. Then you need to take a close look at your inline capping process. The capping parameters need to be set in a very precise way to ensure that the crimp caps are tightly closing the vial. The whole capping parameter set up is quite complex and deserves a blog on its own. As one indicator for proper capping, you can use residual seal force (RSF) testing.
To support our customers, we have already characterized several of our combinations at low temperatures. Here are a few examples included below. Please Contact Us for more information on these technical reports.
9. Which is the best secondary packaging for my vials?
Just to clarify this one thing up front: By secondary packaging we mean the tubs, nests, trays and bags. The choice for the right outer packaging depends on many different factors, mainly connected to your filling line. If you already have a secondary packaging, you have to consider its design when choosing a new filling line. Likewise, if you already have a filling line, you should keep its container loading mechanism in mind when choosing your secondary packaging. Let&#;s go through some of the options briefly:
Is it a bulk filling line? In this case, you will wash and depyrogenate the vials yourself. You will probably go for bulk vials which means that they come fresh from the converting process, not washed, not depyrogenated, not sterilized. These bulk vials are typically delivered in AkyLux® trays and are not nested. Also, there is usually no polymer divider in between the vials to prevent glass-to-glass contact. There are two options of how the vials are placed in the trays: They can be neck up or neck down. This depends on the preferences of the operator feeding the vials into your filling line and the set-up of your filling line.
Do you need to fill large quantities of vials and you don&#;t have a washer and a depyrogenation tunnel? Then you could decide on ready-to-use vials in nested trays. Here, the vials come washed and sterilized and are sitting in nests which are placed in solid trays to prevent glass-to-glass contact. Per the setup of your line, also in this tray the vials can be placed neck up or neck down.
Is it a RTU smaller-batch filling line? For this option, you could also use the nested trays with pre-sterilized vials. Another option is pre-sterilized vials in nest and tub configuration. They come with a liner on top and a sealed lid which functions as a microbial barrier but is permeable to Ethylene oxide (EtO) which is typically used as the sterilizing gas. Depending on the setup of your line, there can be specific design features that you need to pay attention to, such as the bag folding pattern of the outer bag.
Do you have a robotic cell filling line? For this special setup, you can only use glass containers nested in tubs in combination with the according nested elastomeric closures. As also there are different nest and tub configurations out there, so you have to make sure that the seating pattern of both matches.
Click here to learn more about different vial secondary packaging for your project based on your filling set up.
10. Is my protein adsorbing to the inner glass surface?
This is a very general question and really needs many hours of detailed discussions to be answered. There is no easy yes or no answer. Some of the many factors influencing this are glass surface structure, glass surface charge, liquid medium properties, protein tertiary structure, protein charge and several more.
In general, the glass surface has a rather negative charge characterized by the silanol groups that are predominant at the surface.
Proteins can have a very complex structure with different charges throughout the entire molecule depending on the amino acids that are present. They have amine groups which can be positively charged and carboxyl groups which can be negatively charged. Their overall charge strongly depends on the pH of the solution they are in and the amount of amino and carboxy groups they carry. Scenarios can go from an overall positive charge to neutral to overall negative.
Typically, the mechanism through which proteins would adsorb to the glass surface are hydrogen bonds between the hydrogen atoms of both sites or ionic bonds between the positively charged amine and the negatively charged silanol groups.
That was the chemical adsorption. But there is also the possibility of physical adsorption which plays a minor role compared to the chemical adsorption. The glass surface is not entirely smooth, i.e., it has small pockets here and there where proteins can potentially &#;get stuck&#; and stay. And even here you have electrostatic forces supporting this process.
Hence, there cannot be a general yes or no answer. This needs to be tested under realistic conditions for all parameters. And in case it turns out that in one specific case, glass is not an ideal solution, there is the option of using high-quality polymer, e.g., polymer (COP)
West Pharmaceutical Services, Inc. is the exclusive distributor of Corning® Valor® Glass vials. If you would like to discuss vial solutions for your molecule please Contact Us so that we connect you to an account manager in your region or learn more about West glass vials by visiting our Valor web page.
References:
6. Question:
EMA/CHMP/CVMP/QWP//: Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container; European Medicines Agency,
USP <> Depyrogenation; United States Pharmacopeia ()
Ph. Eur. 5.1.12. Depyrogenation of items used in the production of parenteral preparations; European Pharmacopoeia ()
USP <85> Bacterial Endotoxin Testing; United States Pharmacopeia ()
Centers for Disease Control and Prevention:
https://www.cdc.gov/infectioncontrol/guidelines/disinfection/glossary.html#:~:text=Validated%20
process%20used%20to%20render,expressed%20in%20terms%20of%20probability
7. Question:
TR /199 Container Closure Integrity of Rubber-Glass Vial Systems
TR /211 Evaluation of Container Closure Integrity for /40 Lyophilization Stoppers
8. Question:
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..
Boltres, B. (). When Glass Meets Pharma. ECV Insights. ISBN: 978-3--432-2
CTEs: Meike Rinnbauer, Technische Elastomerwerkstoffe, Verlag Moderne Industrie,
TR /259 Container Closure Integrity of Corning® Valor® Glass vials and with NovaPure® Closures and Flip-Off® Seals at -80°C
10. Question:
Boltres, B. (). When Glass Meets Pharma. ECV Insights. ISBN: 978-3--432-2
NovaPure®, FluroTec&#;, Ready Pack&#;, and Flip-Off® are trademarks or registered trademarks of West Pharmaceutical Services, Inc. in the United States and other jurisdictions.
Crystal Zenith® and D Sigma® are registered trademarks of Daikyo Seiko, Ltd.
Corning® and Valor® are registered trademarks of Corning Incorporated.
AkyLux® is a registered trademark of Corplex France Kaysersberg.
Crystal Zenith, D Sigma, and FluroTec technologies are licensed from Daikyo Seiko, Ltd.
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.
If you want to learn more, please visit our website glass bottles for pharmaceutical use.
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
-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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