5 Things to Consider when Choosing a Stopper for Drug Development

At Adelphi we advocate for Drug Development to be carried out in the Final Drug Packaging from day one.

Too often we see development projects fall at the last hurdle due to unforeseen issues relating to drug packaging. If you are carrying out your development work in a container which isn’t suitable for market from a regulatory standpoint, how do you know when you move it into that market-friendly container that it’s going to perform the same? If you have carried out all your stability tests in plastic, how do you know it won’t interact with glass? If you have been using a vial with a plastic screw cap to develop a parenteral formulation, how do you know you’ll have the same results with the Type I glass vial and Rubber Stopper you’ll need to take it to market. Not to mention the additional costs incurred and the time lost due to validating different packaging.

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It is important to remember that primary packaging is in direct contact with your formulation throughout its shelf life. It is part of the final drug offering. Don’t leave it too late to consider its crucial role in your project.

Here we have compiled 5 questions you should be asking before settling on a rubber stopper for your development project.

1. Does it provide good CCI with your chosen vial?

CCI stands for Container Closure Integrity. Ensuring good CCI means the prevention of any air or liquid ingress or egress in order to maintain the sterility of the vial contents. Good CCI is essential for preserving the efficacy of a drug and preventing contamination.

A typical container-closure system for an injectable product consists of a vial and a stopper held securely in place by an aluminium crimp seal or a push-fit vial cap. It is important to ensure that the stopper and vial are compatible and provide good container closure integrity. Talk to your primary packaging partner and ask if they can provide assurance on compatibility. Remember that the container and closure need to work as a team: you shouldn’t consider one without the other.

If you have already chosen vials and stoppers and are unsure as to their compatibility, our primary packaging partners SCHOTT Pharma and West can provide CCI Testing Services.

2. Does it meet Regulatory Requirements?

Rubber closures for pharmaceutical use must meet the relevant requirements of the market where you intend to offer your product. The three main global pharmacopoeias are the European (EP), Japanese (JP) and United States (UP) pharmacopoeias.

Ask your healthcare packaging supplier for an example quality certificate before purchasing stoppers. This should include a statement from the manufacturer stating that the rubber formulation complies with chemical requirements detailed in section 3.2.9 of the European Pharmacopoeia, chapter 7.03 of the Japanese Pharmacopoeia, and the physicochemical tests described in USP General Chapter 381.

3. Is it readily available?

A detail which is often overlooked yet is absolutely crucial is availability. The pharmaceutical primary packaging industry is constantly evolving to meet regulatory updates, as well as challenges brought on by the complex needs of emerging biotech and gene therapies. If you have picked up a random bag of stoppers from your stores and assumed they will be fine, you may later find they were made from a rubber formulation which is no longer recommended, or is even discontinued. It is always advisable to check with your packaging partner that the stoppers you have are recommended for new projects and will be readily available for the foreseeable future.

4. Does your formulation need to be freeze dried in order to remain stable?

Whilst it may be too early to know the answer to this question, it is worth considering whether it’s a possibility. If so, you should know that a specially vented lyo stopper would be required in order to lyophilize within a vial. More important to know is that should your drug product require lyophilisation, it is highly advisable to use a stopper with a hydrophobic and ‘slippery’ barrier film to both sides. This film, or coating, prevents the pre-lyo liquid clinging to the stopper, aids machinability and prevents the stopper sticking to the compression plate in the lyo chamber.

The good news is it is possible to get both injection/serum stoppers and lyo stoppers with such a coating, for example West’s FluroTec™ NovaPure® Stoppers.

5. Will your formulation interact with the rubber of the stopper?

As we mentioned earlier, primary drug packaging, remains in direct contact with your drug formulation, so it is critical to the success of your project that you ensure there are no negative interactions between your formulation and the rubber of the stopper.

Annex 9 of the WHO Guidelines on packaging for pharmaceutical products states: “The kind of packaging and the materials used must be chosen in such a way that: —the packaging itself does not have an adverse effect on the product (e.g. through chemical reactions, leaching of packaging materials or absorption); —the product does not have an adverse effect on the packaging, changing its properties or affecting its protective function.”

If you find you are having a problem with interaction or you would like to minimise the risk from the outset, we would recommend the use of a rubber stopper featuring a barrier film on the product-contact area. Products such as the West FluroTec® stopper provide an inert barrier between the drug and the rubber of the stopper, mitigating the risk of a reaction.

In Conclusion

We hope the above has provided some clarity on what you should be looking out for when specifying a stopper for your project, and that it also explains why this should be an early consideration in your development journey.

Now, there’s no need for you to be an expert in primary packaging yourself, you just need to know the people who are, and are willing to help!

Our final piece of advice? Find yourself a partner in the pharmaceutical packaging world. A primary packaging company you can turn to with any questions or concerns you might have. Who will provide free advice, documentation, samples, and when you’re ready: the required items from stock.

At Adelphi we can assist with all these points, and we have a large stockholding of primary packaging for parenteral products, meaning we can supply you with small quantities while you’re in the development stage of your project, and can continue to supply as your demand grows.

When it comes to ensuring the safety and integrity of pharmaceuticals, every detail matters. One such critical component is the pharmaceutical rubber stopper. This small but vital part ensures that medications remain sterile, secure, and effective from manufacturing to administration. However, choosing the right stopper requires understanding its materials and applications. In this guide, we'll delve into everything you need to know to make an informed decision.

Understanding the Role of Pharmaceutical Rubber Stoppers

The pharmaceutical rubber stopper is an essential element in drug packaging. It serves as a seal for vials and bottles, protecting the contents from contamination, moisture, and air. Additionally, these stoppers facilitate proper drug delivery by allowing needles to pierce through without compromising sterility.

Given their critical role, choosing the right pharmaceutical rubber stopper is not merely a matter of convenience but a pivotal aspect of drug safety and efficacy. This makes it crucial to understand the types of materials used in manufacturing these stoppers and their specific applications in various pharmaceutical contexts.

Common Materials Used in Pharmaceutical Rubber Stoppers

Various materials are used to manufacture pharmaceutical rubber stoppers, each with unique properties suited to different applications. Here are some of the most common materials:

a. Butyl Rubber

Butyl rubber is widely used due to its excellent barrier properties against gases and moisture. It offers a robust seal, preventing contaminants from interacting with the drug. Butyl rubber is especially beneficial for products that require a high degree of sterility and long shelf life.

b. Silicone Rubber

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Silicone rubber is known for its flexibility and temperature resistance, making it suitable for a variety of pharmaceutical applications. Its inert nature ensures minimal interaction with the drug, preserving the medication's integrity. Silicone rubber stoppers are often used in high-temperature environments or when autoclaving is required.

c. Natural Rubber

Natural rubber stoppers provide excellent elasticity and resealability. They are often used when repeated sampling is necessary. However, they may not offer the same level of chemical resistance as synthetic options, making them less suitable for certain formulations.

d. EPDM (Ethylene Propylene Diene Monomer) Rubber

EPDM rubber is chosen for its resistance to a wide range of chemicals and its excellent durability. It's often used in situations where the stopper will be exposed to aggressive compounds or where long-term stability is crucial.

Applications of Pharmaceutical Rubber Stoppers

Pharmaceutical rubber stoppers are integral in various facets of the pharmaceutical industry. Here are some key applications:

a. Injectable Vials

Rubber stoppers used in injectable vials must maintain sterility and ensure that the medication is free from contaminants. Butyl and silicone rubbers are typically preferred due to their excellent sealing properties and inert nature.

b. Lyophilized Products

For freeze-dried (lyophilized) products, the stopper must withstand the freeze-drying process without losing its integrity. Silicone and butyl rubbers are commonly used here for their durable and chemical-resistant properties.

c. Diagnostic Devices

Pharmaceutical rubber stoppers are also used in diagnostic devices, where maintaining a sterile environment is crucial. The choice of material often depends on the device's specific requirements and the nature of the sample it contains.

d. Reconstitution Devices

Devices that require the reconstitution of drugs often utilize rubber stoppers that can be punctured multiple times without losing their effectiveness. Natural rubber, known for its resealability, is frequently used in these applications.

Key Considerations When Choosing Pharmaceutical Rubber Stoppers

When selecting a pharmaceutical rubber stopper, several factors need to be considered to ensure optimal performance and safety:

a. Drug Compatibility

Ensure that the stopper material is compatible with the drug formulation to prevent reactions that could compromise the medication's efficacy or safety.

b. Regulatory Compliance

Compliance with regulatory standards is essential. Choose stoppers that meet the necessary FDA or other regulatory body requirements to ensure they are safe for use.

c. Manufacturing Process

Consider the stopper's manufacturing process, including any lubricants or coating used, as these can affect the stopper's performance and the drug's stability.

d. Application Environment

The conditions under which the drug will be stored and used are crucial. Select materials that can withstand the specific environmental conditions, such as temperature extremes or exposure to aggressive chemicals.

In conclusion, the pharmaceutical rubber stopper plays a pivotal role in the safety and efficacy of drugs. By understanding the materials used and their applications, you can make informed choices that ensure the highest standards of drug safety and effectiveness are maintained. Making the right choice in pharmaceutical rubber stoppers is not just about compliance but about safeguarding health and wellness.