Biopharma Consulting

E-cigarettes

E-Cigarettes

From 20 November 2016 anyone selling E liquids and accompanying devices anywhere in the European Union will either have to comply with the revised TPD legislation – Directive 2014/40/EU) or EU Medicines legislation (Directive 2001/83/EC). Those companies marketing their products without Notification or obtaining Marketing Authorisation will be breaking the law.

Xiphora collaborates with Cambridge Regulatory Services (http://www.cambreg.co.uk/pharma-sectors/tpd-regulatory-compliance/) in relation to the e-cigarette notification scheme.

The common EU notification format is described in the following link: http://eur-lex.europa.eu/legal-content/EN/TXT/PDF/?uri=CELEX:32015D2183&from=EN.

The principal toxicological requirements relate to:

·         Toxicity of emissions

·         CMR (Carcinogenicity, Mutagenicity and Reproductive Toxicity) status of each ingredient

·         Cardiopulmonary toxicity

·         Addictive properties

·         Any other relevant toxicity information.

A traffic-light system has been devised for the evaluation of flavour components, an example of which is shown below.


 

Ethyl Butyrate


Comment: Approved EU food flavouring; non-mutagenic; readily hydrolysed in vivo to endogenous compounds. Considered safe for food use by JECFA, EFSA & FEMA.

Chemical Structure

CAS no

105-54-4; ethyl butanoate

FL no

09.039

Function

Flavouring

Max daily dose

<0.005 mg/canister; < 0.0025 mg per 5 mL

Cramer Structure Category

I (readily metabolised to innocuous components)

JECFA estimated exposure as 24000 and 16000 µg/day in EU and USA respectively.

Flavour assessment reference

JECFA: WHO Technical Report Series 868: Ethyl esters[1]

ADI 0-15 mg/kg/day[2]; FEMA positive evaluation[3]

Physicochem properties

Vapour pressure 0.13 mm Hg at 20 °C[4]

Bpt = 121 °C[5]

Mutagenicity

Negative in Ames’ assay[6]

Inhalation toxicity/Cardio-pulmonary

No data; simple carboxylic acid ester unlikely to be a lung irritant or toxin

Systemic toxicity

No toxicity data found; considered to be readily hydrolysed to endogenous compounds (ethanol + butyric acid) 

Reprotox

No data 

CMR

Considered to be non-CMR based on negative mutagenicity data and high ADI indicating lack of effect on reproductive organs.

Addictive

Likely to be devoid of addictive activity based on long history of safe use as a food flavouring and ready hydrolysis to endogenous compounds

 


 

Setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities

Guidance: http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2014/11/WC500177735.pdf

The guideline sets out methodology for determination of a PDE (Permitted Daily Exposure) value for use in relation to determination of acceptable levels of drug-substance carryover when shared manufacturing facilities are employed.

The PDE is also useful in the context of setting Operator Exposure Limits (OELs) and in relation to equipment cleaning criteria.

Working with four different clients to date, Xiphora has successfully determined PDE values on a large number (around 40) of existing drug substances (and on several experimental drugs/intermediates).

A redacted example of a typical report is shown below.