Distinguishing Extractables from Leachables
Extractables are compounds that can be extracted from packaging or container-closure materials under deliberately aggressive laboratory conditions, typically using solvents specifically chosen to maximize extraction efficiency, well beyond what the actual drug product itself would ever realistically cause under normal, labeled storage conditions over its actual shelf life.
Leachables are the subset of those, or related, compounds that actually migrate into the drug product itself under real, labeled storage conditions over the product's genuine shelf life, and this distinction matters because an extractables study is fundamentally a screening and risk-identification exercise designed to cast a wide net, while a leachables study confirms what genuinely ends up in the actual product patients ultimately receive, a materially narrower and more clinically relevant question than the broader extractables screening addresses.
Structuring a Complete Program
A typical program starts with an extractables study performed on the packaging or container-closure components themselves using a range of solvents chosen to represent the drug product's own relevant properties, including aqueous, organic, and varying pH conditions appropriate to the specific product, generating a broad candidate list of compounds that could potentially migrate into the product under some plausible circumstance.
This extractables data then informs a targeted leachables study, conducted with the actual drug product in the actual intended packaging, over real-time and often also accelerated stability conditions, analyzing specifically for the compounds already flagged as plausible extractables from the earlier screening study, rather than an open-ended, unfocused analytical search that would be both impractically resource-intensive and less scientifically grounded than a properly targeted approach informed by the preceding extractables work.
Analytical Strategy Combining Targeted and Non-Targeted Methods
Analytical strategy typically combines targeted methods, looking specifically for known or suspected compounds identified from the extractables data or from material composition information supplied by the packaging component manufacturer, with non-targeted screening techniques, broad-spectrum chromatographic and spectrometric methods capable of detecting genuinely unexpected compounds not anticipated by the targeted approach, to meaningfully reduce the risk of missing a genuinely unanticipated leachable that neither the extractables data nor supplier information had flagged in advance.
Relying solely on a targeted approach risks missing compounds that were not anticipated from the extractables data or supplier information, which is precisely the scenario non-targeted screening exists to guard against, and a program using targeted methods alone, however thorough within their own defined scope, cannot provide the same level of assurance against a genuinely unanticipated leachable compound that a properly designed combined approach can provide.
Risk-Based Scoping of Program Depth
The depth and rigor of an extractables and leachables program should scale with the specific product's actual risk profile, considering factors such as route of administration, where parenteral and inhalation products generally warrant more rigorous evaluation than oral solid dosage forms given their more direct systemic exposure route bypassing the body's normal absorption and first-pass metabolism barriers, dosage form, where liquid and semi-solid products generally present higher extraction risk than solid oral dosage forms due to more intimate, prolonged contact between the product and packaging surfaces, and the specific packaging material's own known extraction profile based on prior experience or published literature.
A program should be scoped to the genuine risk the specific product and packaging combination actually presents, not applied with uniform intensity regardless of that underlying risk, since an inhalation product using a packaging material with an extensive, well-characterized history of low extraction risk may not warrant the same depth of investigation as a novel packaging material being used for the first time with a high-risk parenteral product where prior extraction experience simply does not yet exist.
Toxicological Risk Assessment of Identified Leachables
Once specific leachable compounds are identified and quantified, a toxicological risk assessment determines whether the identified level poses a genuine safety concern, typically comparing the leachable's estimated daily patient exposure against an appropriate toxicological threshold derived either from compound-specific safety data where available or from a generic threshold of toxicological concern approach conceptually similar to that used for genotoxic impurity assessment under ICH M7.
This toxicological assessment step is what ultimately determines whether an identified leachable requires further action, such as packaging material reformulation or a change in supplier, or whether the identified level, despite being present, poses negligible genuine risk and can be documented and accepted without further packaging modification, meaning identification of a leachable alone does not automatically mean the packaging is unsuitable, only that a documented risk assessment is required to reach that conclusion either way.
Interaction with Stability Study Timing
Leachables studies, because they depend on real-time or accelerated stability conditions to genuinely characterize migration behavior over time, need to be planned and initiated early enough in the development program that results are available to support the intended regulatory filing timeline, since leachables studies typically cannot be meaningfully compressed or rushed without compromising the scientific validity of the migration data being generated.
Programs that treat extractables and leachables work as a late-stage activity, addressed only after the core formulation and packaging configuration are otherwise already finalized, frequently encounter timeline pressure if an identified leachable ultimately requires a packaging change, since that change would then require its own new leachables confirmation study performed under real time pressure rather than as part of an originally well-planned, appropriately sequenced development timeline.
Documentation for Regulatory Submission
Regulatory submissions should present the extractables and leachables program as a coherent, integrated body of evidence, clearly showing how extractables screening data informed the subsequent leachables study design, how identified leachables were toxicologically assessed, and the overall conclusion regarding packaging suitability, rather than presenting the extractables and leachables data as disconnected, separately generated datasets without a clear narrative connecting the screening work to the final risk conclusion regulatory reviewers need to evaluate.
Handling a Post-Approval Packaging Component Change
A proposed change to a packaging component supplier or material after regulatory approval should trigger a fresh extractables and leachables risk assessment specific to that change, since even a component described as equivalent by its supplier can carry a genuinely different extraction profile driven by formulation or manufacturing process differences the supplier's own equivalence claim may not fully capture.
The depth of confirmatory testing warranted for such a change should follow the same risk-based scoping logic applied to the original program, with a higher-risk product and a more significant component change both warranting more extensive confirmatory testing than a lower-risk product experiencing a comparatively minor component modification.
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