Rubber caps, an essential component to ensure the integrity of parenteral drugs

When we talk about primary packaging for parenteral drugs, we mean an integrated packaging system usually consisting of: a bottle containing the medicine in liquid or powder form, a rubber stopper adhering to the neck of the bottle and a simple or ‘tear-off’ aluminium closure that wraps and secures it in turn.

Rubber stoppers for pharmaceutical use, correctly called 'rubber stoppers', are clearly different from common rubber products for industrial and domestic use. The are used not just to seal the container, but also to perfectly isolate the medicine, ensuring sterility and preventing any form of contamination. Optimal performance requires top-quality formulations that ensure maximum rubber-drug compatibility.

Types of rubber stoppers for pharmaceutical use

Rubber stoppers for drugs are available in different sizes, types, shapes and configurations. With some slight variations, they are generally cylindrical and tapered in shape. Rubber stoppers are made to perfectly match the mouth of the most commonly used bottles and vials, with a diameter ranging from 13 to 32 mm.

As far as formulation of the rubber used is concerned, there are two different compounds that are widely used for pharmaceutical applications. Both ensure low gas permeability, good elasticity and strength during the curing process, thus avoiding the creation of elements that could be extracted from the drug formulation and alter it. The two compounds available are:

• Bromobutyl rubber: composed of a butyl elastomer base and a halogen bromine element, it is characterised by lower hygroscopicity, i.e. it has a lower tendency to absorb moisture. This is why it is recommended for pharmaceutical products that need to be freeze-dried.
• Chlorobutyl rubber: composed of a butyl elastomer base and a chloro-halogen element; it has a higher heat resistance.

Each can be suitably treated to improve its elasticity, which is essential to ensure the rubber stopper's performance over time. This treatment is called vulcanisation and can be performed using two different methods:

• Sulphur-based: widely used in the past and still in demand today for old pharmaceutical formulations still on the market.
• Non-sulphur-based: provides a lower level of extractables and is more suitable for complex pharmaceutical formulations.

The production of rubber stoppers for pharmaceutical use

Rubber stoppers are produced in a highly controlled environment, according to a strict quality management system, starting with the selection of ingredients, through to the formulation of compounds and the constant monitoring of international pharmacopoeia requirements. They are made following a very precise process comprising the following steps:

• Mixing: all the necessary ingredients, raw materials and additives, are mixed until a homogeneous mixture is obtained.
• Printing and vulcanisation: the rubber is then printed on rubber sheets that undergo a process of "vulcanization," which changes their molecular structure to increase their elasticity, strength, and viscosity.
• Trimming: the sheets are finally die-cut in order to obtain the rubber closures.
• Washing: The rubber is then washed and, in some cases, silicified. This usually takes place within a 'controlled contamination' environment, known as a clean room, where there is active air filtration and constant control of key environmental parameters. Accurate inspections are also carried out on 100% of the parts in the clean room, using high-resolution vision systems.
• Packaging: products are packed in individual bags ready for sterilisation, or are sterilised and shipped directly to the customer.

Scientific testing and quality of rubber stoppers for pharmaceutical use

As with all primary packaging systems for pharmaceutical use, manufacturers of rubber stoppers must adhere to strict regulations, dictated by international bodies such as the FDA and Pharmacopeia. Regulatory obligations include numerous and repeated checks that must be carried out on products, such as:

• physical-chemical tests
• functionality tests
• analysis of extractables

In particular, the last test ensures full compatibility between the rubber stopper and the drug formulation.

In addition to these routine tests, 100 % of the rubber stoppers are inspected by advanced vision systems during the production cycle, which scan the entire product surface. This is used to check for visual defects and to check accuracy of size.

As a further guarantee of the absolute quality and safety of the product, part of the production phase - usually the one between washing and packaging - is carried out in environments designed to prevent biocontamination, where particle levels, temperature and air humidity levels are kept under control. Indeed, anyone entering the clean rooms must follow precise hygiene and dressing protocols to ensure that the monitored parameters are properly maintained. In addition, to ensure total asepticity, the washing machines automatically transfer the load to a more controlled environment, where the production cycle is completed.

Once packed in sealed bags, the rubber stoppers can be delivered directly to the customer, who will then sterilise them and use them in their own capping systems. In this case we speak of RTS products, i.e. 'ready to sterilise', whereas rubber stoppers that are supplied already sterilised by the manufacturer are called RTU -'ready to use '.

Sterilisation is usually performed in one of two ways: through steam, or through gamma radiation. The second method is preferred in the pharmaceutical field due to the very high penetration power that radiation achieves, thus allowing greater flexibility with respect to the shape, size or complexity of the objects to be sterilised.