‘Problem’ excipients: be cautious when making clinical decisions on formulation

We are writing in response to the article ‘How to identify and manage ‘problem’ excipients in medicines for children’, written by Sara Arthur and Anna Burgess and published in The Pharmaceutical Journal (2017;299(7903):42­–45). The article helpfully raises awareness of the potential toxicity issues associated with ‘problem’ excipient use in children’s medicines and directs readers to age-based safety limits recommended by the European Medicines Agency (EMA).

The article also appears to have generated some discussion on how to interpret the limits in the context of a clinical decision; some licensed medicines might have excipients that would appear to breach the safety limits if used in young children. This potentially leaves the pharmacist in a difficult situation when trying to advise prescribers or parents/carers, because the alternative may be to use a medicine or other product of potentially lower overall quality. A careful risk assessment is warranted.

To inform this risk assessment, the pharmacist should consider a range of treatment options and the information available. They should also consider the inherent need for any excipients, and how and why they have come to be used in a medicine. For example, propylene glycol has a range of uses in a variety of licensed products, including use as a co-solvent. In this example, propylene glycol might be used to facilitate the preparation of a solution rather than a suspension and hence ensure uniformity of dose. If such a medicine were re-formulated to exclude the propylene glycol, there is a risk that the alternative (presumably unlicensed) product might inadvertently be of a poorer overall quality and, for example, have a poorer uniformity of dose.

Moreover, the limits highlighted by Arthur and Burgess appear to change markedly at certain ages; for example; children aged under 6 years are restricted to 6mg/kg of ethanol, but children aged over 6 years have a much higher limit of 75mg/kg. In clinical practice, a pharmacist may be faced with a 5-year-old child with a dose of slightly over the 6mg/kg ethanol limit but well under the high limit for slightly older children. Before making a decision to exclude a medicine based on potential problems with an excipient, a broader product quality and risk assessment, which also evaluates the effectiveness of the formulation, is required.

As in all clinical decisions, the risks of the options are relative to each other and to the risk of not treating the patient at all.

More recently, updated guidance has become available in the form of the EMA’s new annex, which contains a list of all excipients known to have a recognised action or effect that must be displayed on the label of any medicine authorised in the European Union[1]

The annex was published in October 2017 after public consultation for each excipient. It has been adopted by the EMA’s Committee for Medicinal Products for Human Use, and endorsed by the European Commission’s Notice to Applicants Group. Manufacturers of medicines that already have a marketing authorisation are directed to the revised annex to implement wording to comply with this new document.

This new annex provides further information to the pharmacists, prescribers and patients/carers and, for some excipients, this includes a detailed analysis of thresholds for different populations accompanied by explanatory notes.

In summary, what appear to be ‘problem’ excipients may actually be doing a vital job, and the presence, absence and level of excipients in a formulation is an important consideration, but it must be viewed in a wider context. The new annex is a useful addition to the range of information sources to guide the clinical decisions associated with the choice of a formulation.


Andrew Lowey, lead clinician, Clinical Pharmacy and Technical Services, Leeds Teaching Hospitals NHS Trust; NHS Pharmaceutical Quality Assurance Committee — Working Group for Unlicensed Medicines; Editor, Handbook of Extemporaneous Preparation

Mark Jackson, director, North West Regional Quality Assurance Services, Specialist Pharmacy Services (North), Liverpool; NHS Pharmaceutical Quality Assurance Committee — Working Group for Unlicensed Medicines; Editor, Handbook of Extemporaneous Preparation


[1] European Medicines Agency. Annex to the European Commission guideline on ‘Excipients in the labelling and package leaflet of medicinal products for human use’ (SANTE-2017-11668). EMA/CHMP/302620/2017/EN. Available at: http://www.ema.europa.eu/ema/index.jsp?curl=pages/regulation/general/general_content_001683.jsp&mid=WC0b01ac05808c01f6 (accessed March 2018)

Last updated
The Pharmaceutical Journal, PJ, May 2018, Vol 300, No 7913;300(7913):DOI:10.1211/PJ.2018.20204508

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