Let's start by looking at what is required when using analytical and stability studies on extractables and leachables to assess their impact on product quality and safety.
I suggest the three core elements are:
- good information from the analysts
- access to comprehensive and reliable toxicity information
- high quality toxicity expertise
A toxicologist can only work with the analytical information provided, and bibra is fortunate in that clients' reports are generated by high-quality analytical companies, giving us a great start. A second key requirement is comprehensive access to reliable toxicity information on a large number of substances (potential leachables). Over several decades, we've built up searching skills and invested about £8 million in constructing a unique in-house toxicity databank and database. This database (TRACE) is a REACH approved source. The databank contains close to half a million of the best primary toxicology papers and Expert Group assessments. The TRACE database is crucial because Expert Group assessments are not well indexed in other information sources. The third key component is toxicological expertise. The desk-based toxicologists at bibra have worked together for many years (several for 26-36 years) and have built up a great deal of experience in coping with all sorts of data sets, many of them incomplete.
Let me explain how we, at bibra, carry out a health risk assessment, based on a leachables analytical study. First it's important to combine a consistent and transparent approach with flexibility. Starting with an assessment of the analytical report(s) and dialogue with the client, we create an exposure scenario for the product, and estimate possible consumer exposures (on a "reasonable worst case basis") to the leachables. Health risk characterisations and assessments are then carried out. Ideally, these are based on substance-specific data, but other options (see below) are available and may be needed. Any uncertainties should be addressed and discussed. REACH guidance documents represent the most modern expertise on risk characterisation and assessment, and are the products of the joint intellect and effort of regulators, industry, NGOs and academics. While derived for the Industrial Chemicals sector, this comprehensive guidance can be usefully applied by health risk assessors in all sectors.
If substance-specific hazard data are inadequate, alternative methodologies are needed, and we are fortunate that the last decade or so has seen a considerable improvement in the availability of alternatives to substance-specific toxicity data. For example, OECD and ECHA have produced excellent guidance documents on read-across, allowing the risk assessor to determine whether they have a robust case for using toxicity data on similar compounds in their health risk assessment. (Q)SAR software models (e.g. DEREK, OECD Toolbox, Toxtree) can be extremely helpful in identifying structural alerts and weighing up whether an untested substance is likely to possess a particular toxicological characteristic. The improvements in publicly available toxicity data sources have been a big help too. Without doubt though, our most valuable source is TRACE.
If toxicity data are lacking on a leachable and any read-across analogues, other risk assessment methodologies may be applicable - for example, the TTC (Threshold of Toxicological Concern) concept, which was originally developed by FDA to help them assess low level packaging migrants in food. Over the years, the TTC concept has been adopted for assessment of other substances, such as added food flavourings and pharmaceutical impurities. More recently, papers have been published supporting the use of TTC in assessing plant protection product residues, impurities in consumer products, and extractables and leachables.
Often, we are also involved at earlier stages e.g. comparing the extractables profiles of alternative device components, or prioritising health-critical extractables for subsequent leachables study.
I think it's also important to remember, from a toxicologist's perspective, what are the greatest challenges facing E&L analysis. I see three.
- First, the analysts' ability to detect substances at ever lower levels means that the regulator and health risk assessor have increasing number of chemicals to evaluate. While we risk assessors enjoy that work enormously, the increasing number of unidentified E&Ls can be challenging. The TTC approach can really pay dividends in assessment of these "unknowns", but its correct application requires an experienced toxicologist.
- The second is judging the value of the results of Extractables versus Leachables studies. The primary intent of the former is characterisation of the packaging materials and processing equipment, and the latter is the most appropriate basis for the health risk assessment. However, small amounts of leachables may be "masked/swamped" by high-concentration formulation components, and the leachables study must be actually capable of detecting any health-critical extractables. Additionally, chemical interactions between leachables and formulation components might give rise to novel compounds, not seen in the extractables studies.
- The third challenge is to keep up with the published literature and with any new risk assessment methodologies that can usefully be applied.
In my talk on 8 May, I'll be referring to case studies involving electronic nicotine delivery systems/devices (ENDS/ENDD), also known as e-cigarettes, an area of notable growth over the last few years. Our clients in the e-cigarette industry recognise that assessing the possible health impact of leachables is critical, and use such assessments, both to select suppliers of the device components and to demonstrate consumer safety. There's a significant marketing opportunity for manufacturers of components (canisters, wicks, elements, gaskets, filters, etc) with reassuring leaching profiles, especially given the current uncertainty over future regulation. FDA, the European Commission and certain EU member States are keen to regulate them as medicinal products (some countries already do so). Our clients are naturally determined to develop products that safe as well as technologically efficient. With safety in mind, the health risk assessment of the nicotine and excipients is also key