Rationale to the revision of USP Chapter <381> Elastomeric Closures for Injections

A Stimuli Article on The Rationale and Proposed Changes to the Revision of  Elastomeric Closures for Injections <381> has been published in the Pharmacopeial Forum (PF) 43(5).

The USP says, "the intent of this Stimuli article is to provide the rationale for the proposed changes to USP Elastomeric Closures for Injections <381> and a summary of the proposed revisions. The current chapter was revised in 2009 to align with European Pharmacopoeia 3.2.9 Rubber Closures for Containers for Aqueous Parenteral Preparations, for Powders and for Freeze-Dried Powders."

The USP Packaging and Distribution Expert Committee (PD EC) has recently undertaken an in-depth review of the chapter which has resulted in the following significant revisions:

  • incorporate a new methodology for extractable elements,
  • create a separate chapter for functionality tests (Elastomeric Closure Functionality in Injectable Pharmaceutical Packaging/Delivery Systems <382>),
  • provide two new general information chapters (Elastomeric Evaluation of Elastomeric Components Used in Pharmaceutical Packaging/Delivery Systems <1381> and Assessment of Elastomeric Closure Functionality in Injectable Pharmaceutical Packaging/Delivery Systems <1382>) to assist the users of <381> and <382>.

These four new chapters have been published in the Pharmacopeial Forum (PF) 43(3) [May–June 2017]. Comments will be reviewed and incorporated into the chapters; the comment deadline for the proposed packaging chapters published in PF 43(3) had been extended to September 30, 2017. "If necessary, the revised chapters will be republished in PF for additional review", the USP notes.

The USP says "these chapters are intended for elastomer components used for injectable packaging/delivery systems. Future revisions may include elastomer components used for inhalation delivery devices and manufacturing systems" (see also draft for plastic materials used in manufacture <665>). According to the USP, "the various elastomer chapters are based on the concept that the most definitive way to establish the component suitability is to test the packaging system with the final drug product."

The proposed changes and rationale regarding the revision of <381>, especially in view of the proposed extractable elements test, are further described below:

  • Chapter <381> was re-titled to Elastomeric Components Used in Injectable Pharmaceutical Packaging/Delivery Systems,
  • Minimum requirements include assessment for physicochemical characteristics, biological reactivity, and extractable elements,
  • Extractable elements: Replacement of the current method for determining elemental impurities according to <231> (the chapter will be deleted from the USP on January 1st, 2018). Additionally, "the elements of interest in <381> were not specified or aligned with the risk-based principles in Elemental Impurities—Limits <232>, nor was modern methodology implemented to be consistent with Elemental Impurities—Procedures <233>". Extractable elements will therefore be analyzed by ICP/MS or optical emission spectrometry (OES). The extract solutions were optimized (i.e. acidic and including a complexing agent) to ensure recovery of the elements at 70° after 24 h. Since elements typically will have limited solubility, the extractions were intended to be aggressive to show elements that may exist in the elastomer formula, but not necessarily leach into actual drug products (i.e. further investigation according to <1664> is required). Additionally, the new extraction procedure has been verified using inductively coupled plasma mass spectrometry (ICP/MS).

According to the USP, "the data demonstrated that the extractions and recoveries can be verified by ICP/MS. Key points to consider by the USP methodology include:
• The volume of solvent may need to be increased and corrected for dilution, especially for larger components that are not completely submerged,
• Transition metals often result in isotopic interferences and ICP/MS adjustment may be necessary to ensure proper readings,
Alternative methods are possible if required sensitivity can be verified

The USP further says, "the goal is to implement a risk-based assessment to qualify elemental impurities in the final drug products." Thus, elements will be reported as found (= 0.05 µg/g is a reporting level not a limit). Furthermore, "the elements of interest were based on those to be considered in a risk assessment for parenteral administration. Zinc was previously specified in <381> and was also included due to concerns for affecting drug product quality. Other elements known to be intentionally added to the elastomer formulation would be included on a case-by-case basis."

"The elemental impurity limits in <232> were aligned with the International Conference on Harmonisation (ICH) Q3D Guideline for Elemental Impurities and consistent with the risk-based approach for justifying packaging as a contributor to drug impurities. The new <381> extraction methodology provides a means for understanding and eliminating safety and quality risks for potential extractable elements before qualifying a packaging system", the USP states.

After registration to the Pharmarcopoeial Forum you get access to the draft chapters and the complete stimuli article.

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