The 10 most frequently asked questions on glass: Part 2

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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.

• Corning Valor® Glass vials with West NovaPure® /50 and /50 stoppers (TR /259 Container Closure Integrity of Corning® Valor® Glass vials and with NovaPure® Closures and Flip-Off® Seals at -80°C),
• Daikyo Crystal Zenith® (CZ) with West NovaPure® /50 and Daikyo D Sigma® stoppers (TR /242: Container Closure Integrity Testing on NovaPure®, and
• Daikyo Closure Configurations for Ready Pack&#; Containment Solution with Daikyo CZ 2 mL Vials).

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.

When looking for a partner to meet your OEM needs, it is crucial to choose a company you can trust with confidence. Since , Progressive Automations has been offering industry leading flexibility, quality, support, and field experience to become the trusted partner for various OEMs worldwide. We will be covering the top 10 questions we get from our OEM customers which you will find useful in your search for a parts supplier of electric linear actuators.

Learn more about our specialized services for OEMs, and why we're a worldwide trusted partner!

1. I have irregular requirements for actuators, but a plannable yearly quantity. I would like to avoid long lead times and get a discount based on my EAU. How do you support this requirement?

Progressive Automations offers zero-lead time blanket orders that give you flexibility on timeline, quantity and actuator model, while ensuring the unit price is based on the total EAU. A blanket order is an agreement to purchase a certain quantity of units over a certain timeframe and requires credit approval. Please reach out to us if you would like to learn more.

2.    What are the extents of your customization capabilities?

Our customization capabilities are limitless. The datasheets we have show the standard specifications and commonly requested customizations; however, this does not limit us from custom manufacturing to your needs. A notable example of our customization capabilities can be seen below:

PA-14 datasheet-listed capabilities

and specifications 

The company is the world’s best vial stoppers supplier. We are your one-stop shop for all needs. Our staff are highly-specialized and will help you find the product you need.

Basic screws and washers for external and

internal components

Custom option available for limit switch feedback

with regular wiring internally

Plastic top cap with no seals added

Basic lead screw internal component

Cable strain relief installed inside of gearbox cover

Standard cable orientation and standard hole

for cable on gearbox cover

Custom option available for brushless motor with

regular wiring

PA-14 customizations we have

previously done

Added thread lockers on external and internal screws 

Added extra protection using heat-shrink covered

wires for limit switch feedback

Metal top cap with rubber oil seal and epoxy added

Added rubber stopper on end of lead screw

Cable strain relief installed on the gearbox cover

Repositioned cable orientation and removed

standard hole for cable on gearbox cover

Added strain relief plug on brushless motor housing

and added heat shrink wrap to fit tightly through plug

3.    Are you able to support our OEM replacement business?

Yes, we can supply your components completely white-labelled, exclusive to your company so you may have complete ownership over your products.

Browse our entire range of customizable electric linear actuators!

4.    If we want to offer a certain warranty to our customers, can you match it with a warranty extension?

On top of our standard 18-month warranty, we will flexibly extend warranty terms so you can reap the benefits of selling extended coverage as part of your product. &#; Please reach out to your dedicated Success Manager for more information.

5.    Is there any way I can avoid lead times?  

Once the production standard has been established for a standard or custom order, we have zero lead times for blanket orders which we manufacture in advance.

6. Do you offer credit/net terms?

Yes, we do offer credit terms. After submitting your credit terms application form, our accounting department will review your application and contact you back with an update.

https://www.progressiveautomations.com/pages/credit-terms

7.   Is there a free sampling program for your existing customers?

Yes, our existing customers can test out actuators even before they are released. Get ahead of your competition by having better-performing products before them! &#; Please reach out to your dedicated Success Manager for more information.

We also have a free actuator guide written by engineers, for engineers to help you on how to select, test and implement linear motion for any application.

8.    Can you develop an actuator from scratch for us?

Yes, we have the facilities, manufacturing equipment and engineering expertise to develop an actuator from scratch for you. There are restrictions on what makes economical sense, so reach out to us if you want to learn more and partner with us to create your ideal solution.

9.    How do you ensure that your supply chain is consistent, efficient, and will not fail even in the face of global uncertainties that we have faced?

This question can be split into two sections:

How are you managing your own supply chain to prevent delays and interruptions?

By being a multinational company with multiple warehouse locations and having thousands of different shipping partners, redundancy ensures we have all the back up plans needed to face any global uncertainty. If one of our warehouse locations or shipping partners can no longer operate, our team gets informed immediately and will switch to our alternative options. This prevents any delays or interruptions as we want to ensure the best service for all our valued partners and customers. We have maintained 97% on-time shipments since March , even when faced with unsurmountable uncertainty.

How are you managing resources to ensure enough manpower to accommodate OEMs&#; demands when the economy recovers?

Progressive Automations works with a vast selection of manufacturing partners that we monitor with active management. All our manufacturing partners are bench marked based on their time deliveries and quality control. Based on this score, we load balance by assigning the suitable volume for our different factories to ensure excellent service, lowest lead time and highest quality.

10. How do we ensure that our proprietary data is protected? Plans, prototypes, etc.

At Progressive Automations, security of all proprietary data is of the up most importance and we are more than happy to sign Non-Disclosure Agreements. We ensure all proprietary data is kept protected in access-controlled shared drives with export controls on a need-to-know basis.

Chat with our sales team to learn if our electric actuators are the right fit for you!

In summary

As one of the top suppliers of electric linear actuators, Progressive Automations offers industry leading flexibility, quality, support, and field experience that any OEM can reliably count on. If you have any other questions on what we can offer for your OEM needs, please do not hesitate in reaching out to us! We are experts in what we do and want to ensure you find the best solutions and supplier.

 1-800-676-

Want more information on vial stoppers supplier? Feel free to contact us.