Nitrosamines in Elastomers?

A USP Stimuli article on Elastomeric Components for Inhalation Packaging / Delivery Systems has been published in Pharmacopeial Forum (PF) 45(6). Comments can be send to the USP until January 31, 2020.

Currently, the official USP chapter <381> and the draft of <381> are specific for elastomers for packaging / delivery systems for injection. <381> does not cover elastomers in packaging / delivery systems used for other routes of administration. In addition, the functionality tests in <381> are not relevant to elastomers used in inhalation packaging / delivery systems. Therefore, the Stimuli article provides some background information and an approach to answering these deficiencies by proposing additional tests and acceptance criteria for elastomers used in inhalationpackaging / delivery systems in <381>.

According to the Stimuli article N-Nitrosamines are reaction products between specific organic precursor molecules, secondary amines (R2NH), and a “nitrosating agent”. In the compounding of rubber, secondary amines are likely formed from vulcanization accelerators such as thiurams and dithiocarbamates. Therefore, the stimuli article proposes to add tests and acceptance criteria for N-nitrosamines to the list of physicochemical tests in <381>. The proposed method for inclusion into the USP–NF is based on the ASTM F1313 method, which describes the determination of six volatile N-nitrosamines which are also listed in USP chapter <1664.1>:

  • N-Nitrosodibutylamine (NDBA)
  • N-Nitrosodiethylamine (NDEA)
  • N-Nitrosodimethylamine (NDMA)
  • N-Nitrosomorpholine (NMOR)
  • N-Nitrosopiperidine (NPIP)
  • N-Nitrosopyrrolidine (NPYR)

Proposed acceptance criteria

According to the stimuli article the FDA established an action level of 10 ppb for individual nitrosamines for rubber nipples. In addition, products comply with European Directive 93/11/EEC if the total quantity of released N-nitrosamines is less than 10 ppb. A presentation by the FDA to the Product Quality Research Institute (PQRI) Leachables and Extractables Workshop in 2005 stated the following:

  • Controls for nitrosamines in metered dose inhaler elastomeric components are tighter than for baby bottle rubber nipples,
  • Volatile nitrosamines are controlled both individually and in total,
  • Safety limits depend upon drug product characteristics (e.g., design, fill, total daily dose).

Based on the available FDA statements, an initial proposal for acceptance criteria for elastomers in inhalation packaging/delivery systems is provided in the stimuli article:

  • NDBA: ≤ 1 ppb
  • NDEA: ≤ 1 ppb
  • NDMA: ≤ 1 ppb
  • NMOR: ≤ 5 ppb
  • NPIP: ≤ 1 ppb
  • NPYR: ≤ 1 ppb
  • Total N-nitrosamines: ≤ 10 ppb

Feedback on This Proposal

Readers are invited to provide comments on the suggested methods and acceptance criteria provided in the Stimuli article to determine N-nitrosamines. The comments received will be taken into account while preparing a new section on the control of elastomers in inhalation packaging/delivery systems to be added to a future revision of <381>.

After your registration to Pharmacopeial Forum online you will have access to the full stimuli article Elastomeric Components for Inhalation Packaging / Delivery Systems.

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