In October 2020 the Safety Working Party, in response to a request from CMDh, concluded that chlorobutanol levels used in medicinal products can be considered safe for lifetime use, if they are at or below the derived PDE of 0.5 mg/day. For short-term use, higher exposures may be acceptable based on case-by-case evaluation. The full SWP position is available on the EMA website (see References section for link).
All MAHs are therefore required to review their product(s) and identify any product where this excipient is used. If any product is identified to contain any level of this excipient, a risk assessment should be conducted. This risk assessment should be provided either to the RMS and CMS for MRP/DCP products, or to the National Competent Authority (NCA) for national-only products. This risk assessment should be submitted by means of a type II variation type C.I.13 by 1st Sept 2021. The MAH is requested to clarify in the cover letter to this variation which of the following scenarios applies and where the product is currently marketed:
Where the SWP limit is exceeded. Please indicate in your response which of the following apply:
- The level of 0.5 mg/day is exceeded and the product is for long term use (Scenario a)
- The level of 2 mg/day is exceeded and the product is for short term use (Scenario b)
- The level of 0.5 mg/day is exceeded, the product is for short term use (Scenario c)
- Other (Scenario d):
The product is currently marketed in the following member states: _______________________
Where the PDE is exceeded, manufacture of the medicinal product without chlorobutanol is the preferred option due to the lack of safety information, the cardiovascular risk, potential reproductive toxicity and the availability of safer alternatives to this excipient. Therefore, reformulation of the medicinal product is expected or else the applicant should provide a full justification why chlorobutanol cannot be replaced by another excipient in the respective medicinal product and outline their risk mitigation strategy.
In the risk assessment, the justification for the acceptability of the level present in the product and risk mitigation strategy should be elaborated in detail to allow for further quality, preclinical and clinical assessment. Where reformulation is required a B.II.a.3.b.2 variation should be submitted by 1st Jun 2022.
The CMDh strongly encourages MAHs to use variation worksharing procedures for MRP/DCP and purely nationally authorised products if applicable.