Pharmaceutical Rubber Stoppers: Production and Types

When discussing primary packaging for parenteral drugs, we are referring to a comprehensive packaging system typically comprising a bottle containing the medication in liquid or powder form, a rubber stopper affixed to the neck of the bottle, and a straightforward or 'tear-off' aluminum closure that encases and seals it.

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 designed for pharmaceutical use come in diverse sizes, types, shapes, and configurations. While there may be slight variations, they generally exhibit a cylindrical and tapered form. These stoppers are meticulously crafted to seamlessly fit the openings of commonly used bottles and vials, featuring diameters ranging from 13 to 32 mm.

Regarding the composition of the rubber, two distinct compounds are extensively employed for pharmaceutical purposes. Both compounds ensure minimal gas permeability, excellent elasticity, and strength throughout the curing process, thereby preventing the release of substances that could potentially alter the drug formulation. The two available compounds are:

1. Bromobutyl Rubber:

Comprising a butyl elastomer base and a halogen bromine element, bromobutyl rubber exhibits lower hygroscopicity, meaning it has a reduced tendency to absorb moisture. This makes it particularly suitable for pharmaceutical products requiring freeze-drying processes.

2. Chlorobutyl Rubber:

Chlorobutyl rubber, composed of a butyl elastomer base and a chloro-halogen element, boasts higher heat resistance compared to its bromobutyl counterpart.

Both types of rubber can undergo treatments to enhance their elasticity, a crucial factor in ensuring the long-term performance of the rubber stopper. This treatment, known as vulcanization, can be carried out using two distinct methods:

- Sulphur-based Vulcanization:

  Widely employed in the past and still relevant for older pharmaceutical formulations on the market.

- Non-sulphur-based Vulcanization:

  Offers a lower level of extractables and is more suitable for complex pharmaceutical formulations.

The production of rubber stoppers for pharmaceutical use

Production Process of Rubber Stoppers

Rubber stoppers undergo manufacturing in a meticulously controlled environment, adhering to a stringent quality management system that spans ingredient selection, compound formulation, and continuous adherence to international pharmacopoeia standards. The production process involves precise steps:

1. Mixing:

All necessary ingredients, raw materials, and additives are blended until a homogeneous mixture is achieved.

2. Printing and Vulcanization:

The rubber is then applied to sheets and undergoes vulcanization, a process altering its molecular structure to enhance elasticity, strength, and viscosity.

3. Trimming:

Sheets are die-cut to yield the final rubber closures.

4. Washing:

The rubber undergoes a washing process and, in some instances, is silicified. This occurs in a 'controlled contamination' environment, often referred to as a clean room. Here, active air filtration and constant monitoring of key environmental parameters take place. Rigorous inspections, utilizing high-resolution vision systems, are conducted on 100% of the components within the clean room.

5. Packaging:

The finalized products are either packed into individual bags, prepared for sterilization, or undergo sterilization directly before being shipped to the customer.

Scientific testing and quality of rubber stoppers for pharmaceutical use

Manufacturers of rubber stoppers, like all primary packaging systems in the pharmaceutical industry, must strictly adhere to regulations set by international bodies such as the FDA and Pharmacopeia. These regulatory obligations involve comprehensive and repeated checks on products, including:

- Physical-chemical tests

- Functionality tests

- Analysis of extractables

Of particular significance, the analysis of extractables ensures complete compatibility between the pharmaceutical rsrubber stopper and the drug formulation.

In addition to routine tests, advanced vision systems inspect 100% of rubber stoppers during the production cycle. These systems scan the entire product surface to identify visual defects and verify size accuracy.

To further guarantee absolute product quality and safety, a portion of the production phase—typically between washing and packaging—occurs in environments designed to prevent biocontamination. These controlled environments maintain specific particle levels, temperature, and air humidity. Access to clean rooms requires adherence to precise hygiene and dressing protocols to ensure the preservation of monitored parameters. Moreover, for total asepticity, washing machines automatically transfer loads to a more controlled environment, completing the production cycle.