In the last 5-10 years, we've seen a welcome increase in the level of sophistication applied to the analytical and toxicological assessment of extractables and leachables.
The toxicologists and analysts have each contributed to making the other's lives easier. The development of the TTC concept in the assessment of extractables and leachables has given the analysts a confident insight into the (generic) exposures of potential interest to the toxicologist. The analyst is thus able to focus on specific analytical goals. With an established Safety Concern Threshold (SCT) in mind, an appropriate Analytical Evaluation Threshold (AET) can be established. After extraction and analysis, the analysts know which substances to record in their report. At the same time, the analyst's focus on the toxicologically-relevant detection limits provides the toxicologist with the confidence that all of the substances of possible concern have been captured. Together, this mutually beneficial relationship drives towards a more confident bottom line on container closure safety.
There is still a refreshing amount of debate over some process specifics, and I hope to discuss these in more detail in Barcelona. Five of particular interest to me are (a) choice of SCT for organics, (b) adjustment of SCT based on treatment duration, (c) the validity of organic SCTs for inorganics, (d) how to assess "non-detects" and (e) how analysis of one container system can lead to assessment of different sets of substances.
The toxicologist's classic TTC, translating into an SCT, of 0.15 µg/day remains the departure point of choice in Europe for leachables. It represents an exposure that is highly unlikely to pose an excess cancer risk of more than one in one million persons exposed at this level every day for a lifetime. In the US and Canada, the current PQRI guidance matches this SCT for OINDPs (orally inhaled and nasal drug products) but favours 1.5 µg/day for PODPs (parenteral and ophthalmic drug products). However, it is quite common to see 1.5 µg/day specified as the "jump off" SCT in analytical reports, irrespective of administration route, even in Europe. Is this adequately protective?
The "standard" SCT (whether one opts for 0.15 or 1.5 µg/day) was derived for daily, lifetime exposure. But many pharmaceuticals are intended for short-term, sporadic, or even single dosing. The concept that higher doses of a mutagen can be tolerated over less-than-lifetime or intermittent exposure is well-accepted, but what adjustment factors can be confidently used for specific durations? ICH/EMA have provided such guidance for unavoidable mutagenic impurities, but how can we best use this to inform a leachables evaluation?
Analytical reports frequently set a SCT of 0.15 or 1.5 µg/day for inorganic leachables. However, the database underpinning the derivation of the TTC consists only of certain subsets of organic substances. So is there a better approach for setting AETs for inorganics?
The standard method to determine whether a container-closure system contributes any extractable/leachable is to compare sample and blank values, subtracting the latter from the former. But sometimes both values are reported as <LOD. Can both results be accepted to be zero? Or should a more health precautionary stance be taken, i.e. the <LOD blank value as zero and the <LOD sample blank value as = LOD?
Another interesting situation is when there is one analytical report on one container-closure system, yet the substances requiring assessment change depending upon the bottle contents. This arises when the dosing volumes of two formulations vary sufficiently. For example, if a dosage of a formulation is set at 25 ml/day, a 100-ml bottle lasting 4 days might have an AET of 6 µg/container (or typically 3 µg/container to account for analytical uncertainty), generating a list of extractables/leachables at >6 µg/container that require evaluation. But if the same bottle is used to store a formulation consumed at 100 ml/day, then the AET would be only 1.5 µg (or 0.75 µg to account for uncertainty). In the latter case, additional substances might qualify as being >AET and thus require evaluation.
The case studies I intend to discuss in Barcelona will cover these and other topics, and I'm looking forward to further discussion.
Pete Watts will be presenting "Case studies of pharmaceuticals E&Ls health risk assessments" on Wednesday 12 November, Conference Day 2.