Leachables in an intravenous buffer – a health risk assessment

Background

The client was carrying out stability studies on a container-closure system (CCS) intended for long-term storage of an intravenous buffer that is added to various drug substances (in vials) immediately prior to administration to patients. Leachables data were available for various time points including day 0 and about 1, 3 and 5 months.

Client

An international pharmaceutical company specialising in intravenous products intended for daily administration for up to 1 year.

Project goals

The primary goal was to assess whether the detected leachables might pose any significant threat to patient health.

A secondary goal was to deduce whether concentrations of leachables were increasing, decreasing or plateauing, or if additional leachables were identified, with longer storage times.

Approach

Bibra assessed potential health risk based on the maximum concentrations of any leachables detected at any time point. The REACH-approved in-house TRACE database served as an excellent mechanism for identifying critical reviews/Expert Opinions on the toxicology of the leachables, and these were used as a critical basis for the assessment, together with information included in several REACH dossiers. Supplementary detailed searches were conducted to ensure that no critical intravenous toxicity data were overlooked. The leachables time‑concentration patterns were interpreted.

Project outcome

The available toxicity data allowed bibra to confidently conclude that the chemically-identified leachables would not pose any significant risks to patient health at the estimated maximum exposures. One organic leachable was not identified and was therefore assessed by application of the Threshold of Toxicological Concern (TTC) concept which, in combination with ICH guidance on less-the-lifetime exposure to mutagens, demonstrated that the patients would not be at significant cancer risk, even if this unknown compound were to be a potent mutagen.

In general, only minor increases or decreases in leachable concentration were observed with time, although one new leachable was identified (at a very low concentration) only at the latest time point. Analysis at longer time points is planned.

Bibra project team

Pete Watts

Daniel Threlfall

 

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