Considering Extractables And Leachables For Prefilled Syringes

Multiple materials are involved in the packaging of drug products in prefillable syringes. With regards to extractables and leachables, manufacturers need to consider the materials used for the barrel, plunger, tip cap or needle shield, the needle itself and any adhesives or lubricants, such as silicone oil. Because so many of these materials are in direct contact with the drug product, prefillable syringe systems may require a more involved extractables and leachables analysis.

Fran DeGrazio. Vice President, Marketing and Strategic Business Development at West Pharmaceutical Services, Inc.

Drug manufacturers should also consider how the product will be stored, which may have an impact on extractables during the shelf life of the drug. With a vial container closure system, the product sits upright when stored, so there is less direct contact compared with a prefillable syringe system, which may be stored horizontally. Manufacturers must consider the volume to surface area ratio between the drug product and the packaging material. This exaggerates any potential reaction or leachables that might occur either initially or over the drug product’s shelf life. In the case of prefilled syringes, greater contact is likely because of the greater surface area.

Manufacturers should always use the highest quality packaging materials for their drug product. Elastomers with barrier films and syringe barrels made of novel materials, such as Daikyo Crystal Zenith cyclic olefin polymers, can help to minimise leachables. Such polymers can be moulded into a variety of shapes and are capable of being used throughout the drug product’s lifecycle. For example, the Crystal Zenith polymer is available in large screw-top containers, vials and as an insert needle syringe system that contains no silicone oil, tungsten or adhesive. Use of this material can eliminate those leachables from the mix.

Testing requirements

Testing requirements for prefilled syringes are the same as for any parenteral product that comes into contact with packaging materials, as manufacturers need to understand the potential extractables that can arise from the packaging materials. Comprehensive extractable profiles can be generated based on studies employing multiple analytical techniques, such as gas chromatography/mass spectrometry, liquid chromatography/mass spectrometry and inductively coupled plasma/mass spectrometry, and using solvents of varying polarity; inclusive of a solvent with similar extracting propensity to that of the drug product. Once the component materials are characterised for extractables, drug product sponsors should develop and validate specific testing methods and test their drug product to identify any leachables present. Studies should demonstrate the absence/presence of leachables and be representative of the drug product’s shelf life.

Some packaging manufacturers offer support for extractables studies. For instance, we offer a comprehensive extractables profile on an elastomeric component, which allows the drug product sponsor to accelerate the leachables testing for qualifying a drug product’s container/closure system by skipping over the extractables analysis and moving directly to leachables studies.

Manufacturers can also reduce the testing burden by partnering with a packaging manufacturer that has laboratory capabilities. Several labs specialise in these types of analyses, which can be quite different to a drug assay that would typically be done by the pharmaceutical company. Pharmaceutical manufacturers should be aware that outsourcing these tests is considered a lab specialty. The selected laboratory should be able to provide support for the pharmaceutical company throughout stability testing and the lifecycle of the product.

Regulatory guidance

There are compendial requirements for elastomeric and plastic components in the US, European and Japanese pharmacopoeias. In addition, several general regulatory guidelines are in place that recommend strategies for conducting extractable studies on components, including the EMA Guideline on Plastic Immediate Packaging Materials; the FDA Guidance for Industry — Container Closure Systems for Packaging Human Drugs and Biologics; and the upcoming PQRI Thresholds and Best Practices for Extractables and Leachables in Parenteral and Ophthalmic Drug Products.

These guidelines, although helpful, are not an absolute prescription for testing. Packaging materials are different, as is every drug product, and individual drugs may react differently with the packaging materials. To ensure that proper testing is conducted and completed in a timely fashion, pharmaceutical companies should work with packaging suppliers early in the development process, particularly when it comes to laboratory analyses. Extractable and leachable studies cannot be completed quickly, so the manufacturer will need to build phase-appropriate studies and include evaluations into stability and quality assurance programmes.

To mitigate risk as early as possible, manufacturers should seek a packaging partner while a drug product is still in development. By relying on the packaging manufacturer’s experience and expertise, the pharmaceutical company will mitigate risk while moving its drug product to market quickly.

www.westpharma.com