Revised Ph. Eur. Chapter 3.2.9. Rubber Closures

Recommendation

15/16 November 2023

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Requirements, Challenges & Solutions

A general revision of Ph. Eur. Chapter 3.2.9 "Rubber Closures" has been proposed in Pharmeuropa 33.2. The deadline for comments is 30 June 2021. In particular the proposal includes changes to the following sections.

Definition and Scope

The use of natural rubber latex is not permitted but dry natural rubber may be used in the manufacture of rubber closures. Natural rubber latex is known to cause allergies, but dry natural rubber may be used since the allergens are removed during processing. Rubber closures are typically treated with silicone oil or other lubricants, including materials chemically or mechanically bonded to the closures. Closures made from silicone elastomer are not in the scope of this chapter. They are covered in Ph. Eur. 3.1.9 Silicone elastomer for closures and tubing.

Definitions and other quality requirements:

• Type I closures meet the strictest quality requirements and are preferred;
• Type II closures have mechanical properties suitable for special uses (e.g., for multidose containers) but do not meet the more stringent quality requirements described for Type I;
• The components of the pharmaceutical preparation in contact with the closure are not adsorbed and do not migrate into or through the closure;
• Extractables & Leachables: The closure does not release substances in quantities sufficient to affect the stability of the pharmaceutical preparation or to present a risk of toxicity;
• The closure is compatible with the pharmaceutical preparation (throughout its shelf life);
• The closure is washed and may be sterilized before use.

Composition Changes

Furthermore, it has been clarified that the manufacturer of the pharmaceutical preparation must obtain assurance from the supplier of the rubber closure that the composition of the closure does not vary and that it is identical to the one used during compatibility testing. If the supplier informs the manufacturer of the preparation that changes have been made to the composition, "it is recommended to carry out a risk assessment to determine whether it is necessary to repeat the compatibility testing, totally or partly, depending on the nature of the changes".

The FDA recently published a guidance on Packaging Changes: Glass Vials and Stoppers with detailed examples on how to handle and classify stopper changes (e.g. changes to the composition, changes in stopper sterilization method (e.g., from moist heat to irradiation), etc.).

Extractable Elements, Functionality & Fragmentation Testing

• The extractable heavy metals test has been deleted to align with ICH Q3D and Ph. Eur. policy on elemental impurities.
• The Introduction to functional tests has been expanded to clarify cases in which the tests for penetrability, fragmentation and self-sealing may have to be adapted or can be omitted.
• The specific fragmentation testing procedure for closures used for dry preparations has been removed.

For more information please see the proposal for Ph. Eur. chapter 3.2.9. Rubber Closures for Containers for Aqueous Parenteral Preparations, for Powders and for Freeze-Dried Powders in Pharmeuropa.