How are analytical tests today able to take a risk-based approach with E&L? What has changed in this area compared with
10 years ago?
Christiaens (Toxikon Europe): To take a "riskbased" approach, it is necessary to understand what the real risk is. Several years ago, risk-based approaches
were often taken solely based on a paper evaluation of the known composition of a raw material (e.g., anti-oxidants, slip
agents, nucleating agents, and other processing aids) or on the results of limited extraction studies. Today, the risk of
finding leachables in the drug product and the harm it can cause to the patient is much better understood. As a consequence,
more emphasis is placed on the risk evaluation of actual leachable data.
Feilden (Smithers Rapra): Taking a risk-based approach to E&L has been aided by the implementation of ICH Q8, Q9, and Q10. Aspects of quality by design
are also being introduced that could help reduce the overall testing burden, but these studies are very intensive at the start
of an E&L project.
It is now much easier to implement a risk-based approach to testing, but regulators are still very risk averse, so reducing
the amount of testing can be challenging. Often, the risk of not carrying out the testing outweighs any associated cost or
time savings that can be achieved.
Kesselring (EAG Life Sciences): The heightened sensitivity and widespread prevalence of mass spectroscopy as a detector for analytical techniques such as
gas chromatography, liquid chromatography, and inductively coupled plasma has had big impact on E&L evaluation. While this
improved technology, together with enhanced libraries (both commercially available and proprietary), allow for faster, and
more efficient and accurate assessment of E&L, they have also led to a significant increase in regulatory expectations.
Killian (EMD Millipore): As analytical instrumentation improves, so does the ability to detect compounds at lower concentrations. In some ways, this
has created new challenges with E&L studies, when it comes to identifying and quantifying small peaks observed in chromatographs.
In the past, these compounds would not have been detected by the instrumentation.
However, one currently accepted practice to address this issue is to develop an analytical evaluation threshold, which allows
the chemist to disregard small peaks and to instead focus on the larger peaks.
Rushing (ABC Laboratories): A risk assessment of the known compounds used in the manufacture of the container–closure system, such as processing aids
(e.g., slip agents and mold-release agents) or other additives to the product, may determine that there is no need to monitor
for these compounds during the E&L program. This approach can, in some cases, significantly simplify analytical tests. However,
these compounds may contain impurities or react unpredictably in the presence of the drug product formulation. As a result,
care should be taken when performing these assessments to ensure they are performed using the proper data and appropriate
During the past 10 years, we have seen significant advances in analytical technologies. Newer instrumentation can gather qualitative
structure information while simultaneously meeting the low sensitivity commonly required for E&Ls and reducing the length
of time required to perform toxicological assessments on observed leachables.
Are you seeing more trends in simulation studies to predict and prevent E&L with certain drug-packaging components, and
what are the benefits?
Christiaens (Toxikon Europe):
There is a growing consensus that simulation studies, as suggested by the Product Quality Research Institute–Parenteral
and Ophthalmic Drug Products work group, are a very relevant addition to the traditional E&L approach, typically as a step
in between extraction studies and formal leachable studies (using validated methods). Filling the containers with a relevant
simulant and studying the migration behavior of the pharmaceutical packaging under accelerated storage conditions will help
to understand which compounds (found in the initial extractable studies) are actually leaching out of the packaging components
into the drug product. In the ideal case, the drug product itself can be selected (e.g., in an accelerated leachable study
using screening analyses) because this approach should not only predict the real leachables profile, but also reveal potential
interactions between the leachables and the drug product.
Feilden (Smithers Rapra): Nothing can be done to prevent extractable testing at some point in the development process. However, simulation studies
are being more widely used to predict if there are going to be any leachable issues before the end of the shelf life or if
there are issues with the formulation. This is happening more with biological and parenteral formulations.
Killian (EMD Millipore):
Simulants (or model solvents) are very useful in E&L studies because they reduce the matrix interference with the analytical
assay and are less expensive and safer to use than actual product streams. Simulations are especially useful when evaluating
new packaging material. Several candidates can be evaluated side by side, and those with the most extractables can be eliminated
from consideration early in the process.
Rushing (ABC Laboratories):
The performance of leachable simulation studies to predict and potentially prevent leachables is increasing. The products
that would typically benefit from these studies are liquid-based formulations such as parenterals, oral solutions, and inhalation
These studies are typically set-up by using the actual drug product formulation (or a justified simulant) to mimic a worst-case
scenario interaction between the container–closure and the formulation. Accelerated conditions can be employed, but should
not be overly aggressive. An aggressive extraction approach typical of a controlled extraction study can lead to dozens, if
not hundreds, of observed compounds above the reporting threshold. From experience, we know that most of these compounds are
unlikely to extract under typical storage conditions. Traditionally, determining which compounds would actually leach required
performing stability studies on the actual drug product, but this approach can be time-consuming and costly, especially when
evaluating multiple container–closure configurations.
Simulation studies allow for better decision making process during the development program. As a result of the study design
of simulation studies, the compounds observed are more likely to be representative of the compounds that that can be expected
to leach. By using these data, we can make decisions on which packaging may result in overall leachable levels and which methodologies
will likely need to be employed to monitor for actual leachables in the drug product.