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"Managing Risks Associated with Extractables and Leachables"
Vincent Jeanguyot, Project Manager , Intertek Expert Services, Intertek Chemicals & Pharmaceuticals is armed with experience of over two decades in the fi eld of additives for polymers and coatings. During his recent visit to India, he talked to Pharma Bio World at length about the toxicological implications of extractables and leachables, stress on their assessment in drug approval process and the latest analytical techniques and state of the art technologies industry is using to for estimating their levels.

What are the major existing & potential sources of extractables & leachables?
There are many sources for extractables and leachables, and of course it depends on the type of container closure systems (OINDPs, MDIs, DPI etc), however the main ones are by far the plastic and elastomeric components from the container closure systems (actuators, dip tubes, body, stems, seals, etc), as well as the adhesives and inks which originate from the labels or secondary packaging. Of course, there are other sources like the metal components from the devices.
All in all, every chemical which is used during the manufacturing of the materials from the container system - from the polymer stabilisers or accelerators which are necessary to keep the manufacturing of the polymeric materials under control to the chemicals used for surface treatment, curing or simply processing purpose - can potentially be regarded as a source of extractables. Furthermore, one should keep in mind that leachables and secondary leachables can also relate to process materials used over the drug manufacturing process (such as filters) or to a reaction between the extractables of the container closure system and the drug product itself, which makes the investigation so complicated.

What are the various toxicological risks associated with E&L and their implications on drug formulations?
The various thresholds which are considered for the evaluation of the daily dose of extractables rely not only on the toxicological relevance of the found extractables but also on the route of administration of the drug products. Therefore, the toxicological relevance of the found extractables is as such not sufficient to draw conclusions and must be linked to the daily dose. Depending on the final route of administration of the pharmaceutical formulation, different thresholds can be considered: for instance, for OINDPs the threshold is logically much lower for leachables which show carcinogenic and non-carcinogenic toxic effects (typically 0.15µg/ day) than for leachables without structure-activity relationship concerns (typically 5µg/day). For parenterals, other thresholds may be considered depending on whether the leachables is classified as sensitiser or irritant, or depending on the genotoxicity of the leachable. For drug products which are applied orally, thresholds which derive from the specific migration limits given in the food regulation can even be considered.
The toxicological risks associated with E&L can be clearly identified thanks to extractables studies and toxicological assessments. Much more important: these risks can be managed. This is crucial not only for ethical reasons, but also because this can ensure a successful product launch or avoid endangering existing business.

Please comment on how the perception of industry has changed over the years towards E&L and evolution of conventional ways of assessment to adopting latest state of the art extraction technologies?
Obviously, the perception of the industry towards E&L has been - and is still - largely influenced by the guidance from authorities, mainly the FDA and the EMA. In this regard, the recommendations from the PQRI Working Group to the FDA for OINDPs in 2006 have been a major boost for the E&L matter. Before this submission and the proposals for safety concern thresholds, the industry was aware of the need to manage the E&L though the absence of data-based recommendations or policy acted as a brake on the development of procedures to approach E&L.
Nowadays, the FDA, the EMA and the PQRI continue to guide the industry and new thresholds are being established, however the pharmaceutical companies play also a leading role in trying to select ahead materials of better quality for their container closure systems. Various projects involving pharmaceutical companies as well as material suppliers and scientists are being conducted in order to target low extractables materials and characterise them, resources get mutualised in order to lower the costs while ensuring the harmonisation of the testing protocols. In this respect, all the industry stakeholders play a role in the establishment of procedures, not only with regard to the extraction methodologies but also with regard to analytics as a whole.

May we have your comment on the role of E&L assessments in drug approval process?
The role of E&L assessments tends to become more and more important. Not only because of the guidance or recommendations from the FDA or the EMA, but also because the drug manufacturers have understood and accepted the fact that the packaging and the various materials from their container closure systems could also impact their business by affecting the quality of the API. Depending on the outcome of an extractable study, various follow-up studies such as interaction studies and of course leachable studies may indeed be conducted within the frame of the approval process. This is clearly a reason why the designs of extractables studies and the associated protocols are crucial to guarantee a successful evaluation.

Tell us about the global standards for E&L and how do they vary from country to country? How do you compare these with the standards in context with the Indian market?
All in all, as I have previously mentioned, two main authorities guide the industry, namely the FDA and the EMA. The decision trees on the presentation of the documentation of plastic packaging materials are slightly different, and some requirements with respect to E&L testing protocols vary from the FDA to the EMA (for instance, the EMA does not necessarily require extraction tests with a placebo or the drug formulation as extraction medium, while the FDA tends to require leachables check experiments eg on samples from stability tests), however, despite these differences, the approach remains very similar and relies on a worst case investigation. The Indian market which is almost solely a market of generics should not be regarded as a significantly different market in this context, as the approval process relies on a similar decision tree.

Tell us about the safest & cost effective methods & latest state –of- the- art technologies available for detecting E&L levels?
All in all, the choice of the technologies for E&L studies is more guided by the scientific and technical requirements than by any other factor, even though other parameters and especially the cost factor play a role of course. Therefore, as the analytical evaluation thresholds are extremely low in the low ppb range, the preferred techniques involve mass detectors, which allow a very sensitive and specific detection of E&L. Nowadays, E&L studies can rarely be successfully conducted without hyphenated techniques such as GC/MS, GC/MS/MS, LC/MS, LC/MS/MS because these technologies allow the identification of semi-volatile extractables as well as heavier molecules, but they also allow a quantification down to the ppb level.
Other techniques such as ICP/MS can be used for metal analysis, while thermodesorption-GC/MS can be used for screening purpose. All these techniques tend to replace the first generation chromatographic systems such as LC/UV and GC/FID which are less specific and much less sensitive, furthermore the most recent analytical systems can be very cost effective if they are equipped with autosamplers that can be used for sample work-up and more generally for sample preparation prior to analysis.

What are the various competencies needed by analytical testing labs for rapid extraction of E&l with good insight of the origin of extractables?
I would say that the choice of an extraction technique should not be guided solely by the rapidity of the extraction. Otherwise, microwave assisted extraction would certainly be the preferred technique.
Actually every extraction technique has pros and cons. MAE is fast but the high energy of the microwaves tend to degrade thermolabile compounds while Soxhlet extraction is suited to the extraction of practically all extractables but it is slow. All in all, various techniques can be used from sonication to ASE, reflux, sohxlet or MAE, however the analysts must keep in mind that if the extraction must indeed be performed in worst case conditions, E&L studies rely on 'controlled' extraction experiments and therefore, it is crucial that the analyst understands the advantages and the drawbacks of each extraction technique to make sure that he can adapt the design of the study accordingly and avoid both overestimation and underestimation of the extractables profiles.
The origin of extractables can be determined either experimentally, for instance by running exhaustive extraction experiments on the individual materials of the container systems or by analysing these materials by thermodesorption GC/ MS, however a good understanding of the polymer chemistry including processing is generally required to identify the source of the found extractables.

How does one determine the limitations of E&L experimental designs & select the best method for extraction?
As I have mentioned before, quite often E&L studies lead to wrong assessments because of inappropriate experimental designs. The success of an E&L study depends on both the extraction solvents and on the extraction technique. If one of these two ‘parameters’ is not properly adjusted, there is a high risk to fail due to an overestimation or underestimation of the daily dose of extractables.
The PQRI recommends the use of multiple extraction techniques while various projects are on-going in order to assess the effectiveness of several extraction techniques - including very sophisticated ones such as SFE – within the frame of E&L studies. However, I would like to emphasise that there is absolutely no correlation between the success of an E&L experimental design and the degree of sophistication of the extraction equipment.
Because E&L experimental designs rely on controlled extraction experiments, the most powerful extraction technique in terms of extraction yield is not necessarily the technique which must be chosen and this is what makes the job of the analyst so challenging.