Pharmaceutically clean elastomeric components

The need for inert, effective closure components has led to a renaissance in novel rubber formulations, as well as new techniques for “ready-to-sterilise” and “ready-to-use” elastomeric components.

Today, elastomeric materials must comply with all test requirements as specified by European (EP), Japanese (JP), and US (USP) Pharmacopoeias. The applicable sections are:

• EP V, 2002, Section 3.2.9,
• USP 28, Section <87>, <88>, <381>, and
• JP 14, Section 59

In addition to the chemical and physical requirements of EP 3.2.9 and USP <381>, polymeric closures must meet standards for biological reactivity (in vitro cytotoxicity, subcutaneous and systemic toxicity) requirements as listed in USP sections <87> and <88>.

A definition of “clean” elastomeric closures includes the absence of undesirable chemical agents (whether they arise from the closure materials themselves or through their fabrication or processing), plus the absence of biological agents, particles, and foreign matter. Visible and subvisible particle contamination, bioburden, process residuals and endotoxin levels are best managed through consistent, efficient, fully validated washing and sterilisation.

Ready-to-sterilise (RTS) is a term describing elastomeric closure components that have been subjected to a validated process that cleans and prepares the components for final sterilisation before assembly of the finished, filled vial.

The RTS operation consists of:

• Final water for injection (WFI) rinse;
• Packaging in cleanroom conditions into bulk packaging materials, typically in a sterilisable bag, and
• Documentation that specifies the attainment of specific levels of bioburden, endotoxin and particle burden.

Regulatory agencies have promulgated strict requirements for qualifying and validating processes, test methods, systems, and components: for example, the US Food and Drug Administration’s CPMP/CVMP Note for Guidance on Quality of Water for Pharmaceutical Use (May 2002). This guidance, which specifies purified water for initial wash of elastomeric closures, forces manufacturers of primary packaging materials for parenteral products to develop more efficient, consistent, fully-validated and cGMP-compliant processes for preparing RTS containers and closures.

Ready-to-sterilise processing

Compliant processing for RTS components must be based on a well-documented and validated process that assures clean surfaces with defined levels of endotoxin, bioburden and particles, as well as controlled levels of silicone oil. A typical RTS process for elastomeric closures might consist of the following steps:

• Loading closures in a Class 100,000 environment into a pharmaceutical-quality pass-through washer;
• Washing with USP Purified Water and detergent;
• Rinse with USP Purified Water;
• Final rinse of wash load with WFI and siliconisation using a silicone oil emulsion;
• Drying and unloading into a Class 100 cleanroom, and
• Final packing of closures in sterilisable bags or heat-sealed polyethylene bags.

As each wash load is tested for particles, bioburden, endotoxins and silicone oil level, test results are summarised on a certificate of analysis. Typical specifications might look like this:

• Bioburden ? 5 CFU per 100cm3;
• Bacterial endotoxins ? 0.10 EU per mL of 10 pooled samples;
• Particles ? 3.4 PCI, tested as packed, and
• Silicone levels — certified per washer load when silicone is specified.

Today, companies also have the option of ready-to-use (RTU) components. The RTU processes is developed to meet FDA validation requirements relating to equipment, processes, product, docu-mentation and testing methods, according to CFR 211.94 Drug product containers and closures.

The process is a documented, validated process for preparing pharmaceutical components to comply with international standards and current regulatory requirements. RTU helps ensure consistency of component preparation for every batch to run and perform the same.

RTU products are delivered in packaging designed for each customer’s specific use, including rapid-transfer port bags for ease of introducing components into barrier systems. The bags are packed in plastic cartons and placed on plastic shipping pallets to minimise particle contamination and facilitate handling within the customer’s clean environment.

Validation programme

Prerequisites for producing pharmaceutically clean elastomeric closures include precise, reproducible wash cycles based on a constant wash load size, a functional quality assurance system, and a thorough validation programme that covers the process, equipment, test methods and systems.

Installation qualification, operational qualification, and performance qualification of process equipment should include washing machines, packaging lines, conveyor belts and heat sealer for primary packaging materials, and testing methods and devices. However, the main part of the validation programme is the wash process validation, which can be divided into two phases, namely bacterial endotoxin reduction study and cycle programme validation.

Bacterial endotoxin reduction studies (BER) and the cycle programme validation are based upon a product family matrix.

Two criteria are used to classify elastomeric components into product families: elastomer formulation (composition) and component configuration. The configurations are related to component use, such as closures, syringe plungers and needle covers.

Within the configuration family, size (13mm, 20mm etc.) and shape can be considered as the main criteria. Shape is defined by three characteristic features: cup within the component, flat surface forming a solid plug, or cavity in the part.

The standard industry protocol for bacterial endotoxin reduction studies includes inoculating components in the area most difficult for the process water to reach to demonstrate a minimum 3-log endotoxin reduction. For elastomeric components the most difficult areas for process water to reach would be the bottom of a cup or the inside of a cavity. A flat surface would be the least difficult configuration for achieving acceptable endotoxin reduction since all surfaces of the component are easily accessible to the wash water, pressure and velocity.

Within the cycle programme validation, components are processed using the applicable washing cycle/programmes to validate that the washed product complies with the predefined specification for bioburden, endotoxins and particle burden. During production, each wash load of processed components is tested to verify that it meets the specification.

Silicone is applied by adding silicone oil with a viscosity of usually 350 or 1000 centistoke and WFI to the component washer during the final rinse cycle. The amount of silicone added is validated for each individual item and silicone level. Specifications for silicone oil are based on data generated during the component washing process.

A statistically valid number of product loads (wash cycles) are tested for surface silicone oil. Three additional wash loads are then processed using these results as specifications. The test results for these three wash loads must fall within the parameters and specifications established for the individual item.

Leading component manufacturers have focused considerable effort on developing clean, safe, effective rubber formulations and coatings that enhance the compatibility of elastomeric closures with modern drug products. As part of these efforts, the RTS process provides additional assurance for safety and cleanliness for elastomeric packaging components.

When RTS components are packed in sterilisable bags, manufacturers can introduce them directly into their cleanrooms. As a result, the RTS process contributes significantly to streamlined manufacturing operations related to closure preparation. Choosing RTU sterile components allows manufacturers to move packaging components from the warehouse directly to the sterile fill area, eliminating work-in-process staging issues for sterile components.