Q. With your 36+ years' experience in reviewing and critically evaluating toxicological data and other scientific information what is your experience in general about the pharmaceutical industry's understanding and need for extractables and leachables today compared to a decade ago?
"The pharmaceutical industry was quick to recognise the importance of assessing the possible impact of leachables on product quality and/or patient safety, and is noted for its traditional willingness to embrace new concepts. Nowadays, the planning of E&L studies is a pivotal and routine component on the road to marketing pharmaceutical products. In contrast, the recognition that such studies are important has yet to be fully embraced by certain other sectors. Pharma are ahead of the curve in regard to expertise on this important topic."
Q. What are the primary considerations you use for analysing leachables -- analytical and stability studies -- and assessing their impact on product quality and safety?
"A very important point about health risk assessment of leachables is that the toxicologist can only work with the analytical information with which they are provided. So it's important to have confidence in the analytical organisations that carry out the E&L studies. Bibra is very fortunate in that many of our clients send us reports generated at any of four excellent analytical companies, which gives us a great start. A second key requirement is comprehensive access to reliable toxicity information on a large number of substances (potential leachables). We've had to build up searching skills over several decades now. In addition we have invested about £8 million over the past 50 years in constructing our own unique in house toxicity databank and database. This database (TRACE) is recognised as a REACH approved source. The databank contains close to half a million of the best primary toxicology papers and Expert Groups assessments (the latter 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 have been here for around 25-35 years) and have built up a great deal of experience in coping with all sorts of data sets, many of them incomplete."
Q. How is risk assessment, based on the leachables study results, carried out at Bibra?
"The key is to be flexible, around an SOP. The starting point is assessment of the analytical report(s). From this and dialogue with the client, we create an exposure scenario for the product, and estimate the possible exposures (on a "reasonable worst-case basis") to the extractables and/or leachables. Risk characterisations are then carried out for the identified chemicals, and health risk assessments generated. Ideally, these are based on substance-specific data, but other options (see below) are available and may need to be adopted."
Q. If substance-specific hazard data are inadequate, where would you recommend looking to for alternatives?
Actually 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 data on a similar compound in their health risk assessment. The (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."
Q. In addition to regulatory guidances, are there other sources of best practice guidance and information that you rely on?
"Bibra is rather unusual in that we assist clients across a wide range of sectors. It has been very clear that individual sectors go through periods where they focus on addressing particular challenges and invest in the generation of creative scientific solutions. Our awareness of these solutions - which often include innovative risk assessment methodologies - in one sector provides us with the opportunity to apply this knowledge to other sectors where, perhaps, there is a lower awareness of the opportunities offered by the fruits of another sector's hard work. An example might be the TTC (Threshold of Toxicological Concern) concept, originally developed by US FDA to help them assess low level packaging migrants in food. It took a few years, but the general TTC concept was later 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. In respect of guidance, the REACH documents on risk characterisation and assessment represent the most modern expertise in these areas and are the products of the joint intellect and effort of regulators, industry, NGOs and academics. While derived for the Industrial Chemicals sector, this REACH guidance provides comprehensive guidance that can be usefully applied to health risk assessors in all sectors."
Q. From a toxicologist's perspective, what are the greatest challenges facing E&L analysis?
"I would say there are three main challenges. The first stems from the analysts' ever-improving ability to detect substances at lower and lower levels. This must be seen as a positive advance, of course, but it increases the work burden on the health risk assessor who has to assess an ever-increasing number of chemicals. Of course, we risk assessors enjoy that work enormously, but the real challenge is that as the number of compounds detected goes up, so too does the number of unidentified E&Ls. The TTC approach can really pay dividends in assessment of these "unknowns", but it requires an experienced toxicologist. The second is judging the value of the results of Extractables versus Leachables studies. The real intention of the former is to characterise the packaging materials and processing equipment, with the latter being the most appropriate basis of the health risk assessment. However, small amounts of leachables may be "masked/swamped" by high-level components of a formulation, so it is important to take note of any extractables that might be health-critical and see if the leachables study was actually capable of detecting them. The third challenge is to keep up with the published literature and with any new risk assessment methodologies that can usefully be applied."
Q. Why is presenting at a forum like E&L Europe of interest to you?
"Presenting at the E&L conference is a great way to network with others working in the field. More important, though, is to actually attend the conference. This is an ideal way of identifying and meeting key personalities who are driving the science forward. It's also a great way to keep informed on the most up-to-date developments and to learn about the direction in which the science is heading, and to get a feel for the challenges and opportunities we might expect to see in the future."