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In September 2023, 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 2018/199 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, 4040/40, was developed which is glass vial blowback design-agnostic (TR 2019/211 Evaluation of Container Closure Integrity for 4040/40 Lyophilization Stoppers).
Sketches from ISO 8362:2020
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/850374/2015: Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container; European Medicines Agency, 2019
USP <1228> Depyrogenation; United States Pharmacopeia (2017)
Ph. Eur. 5.1.12. Depyrogenation of items used in the production of parenteral preparations; European Pharmacopoeia (2021)
USP <85> Bacterial Endotoxin Testing; United States Pharmacopeia (2020)
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 2018/199 Container Closure Integrity of Rubber-Glass Vial Systems
TR 2019/211 Evaluation of Container Closure Integrity for 4040/40 Lyophilization Stoppers
8. Question:
Schaut, R., A., et al. (2017). 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:10.5731/pdajpst.2017.007807
Boltres, B. (2015). When Glass Meets Pharma. ECV Insights. ISBN: 978-3-87193-432-2
CTEs: Meike Rinnbauer, Technische Elastomerwerkstoffe, Verlag Moderne Industrie, 2006
TR 2023/259 Container Closure Integrity of Corning® Valor® Glass vials and with NovaPure® Closures and Flip-Off® Seals at -80°C
10. Question:
Boltres, B. (2015). When Glass Meets Pharma. ECV Insights. ISBN: 978-3-87193-432-2
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:
Liquid injectable drugs can be contained in a pre-filled syringe system, a cartridge-based system, or a vial-based system (with a rubber stopper and seal). For a vial-based system, the drugs first are aseptically filled into glass or polymer vials. During the subsequent Fill & Finish operations, the vials are closed temporarily by inserting a rubber stopper into the vial orifice. This is prior to crimping with an aluminum seal, which results in the final integral vial-based container closure system.
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Selecting a container closure system (CCS) is an important part of the pharmaceutical commercialization process. It is important to ensure that the components selected are compatible with the drug product to be packaged; however, it is equally important to ensure that the components are compatible with each other. Here we provide background on the importance of correct pairing between vials and stoppers and showcase <a href="/products/vial-containment-solutions/stoppers/4040-lyotec-lyophilization-elastomer-stoppers">lyophilization stoppers V-50-I (13mm) and S-87-I (20mm) in the 4040/40 Gray formulation</a> that can be paired with any vial blowback geometry.
January 27th of 2023 was a memorable day. That was when the United States Pharmacopoeia (USP) posted a Notice of Intent to Revise in their Revision Bulletins<sup>1</sup> that caused a wave of discussion. What was this notice and why was it so remarkable?
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