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Throughout the drug development process, drug products need to be evaluated to ensure that potentially harmful impurities haven’t migrated into the pharmaceutical product from container-closure systems, manufacturing components, process equipment, packaging, or delivery devices. Regulatory agencies require extractables and leachables testing to ensure drug efficacy and patient safety aren’t compromised by organic and inorganic compounds that may be inadvertently released into the product with some drug product classes having higher risk concerns than others.
Regulatory requirements for E&L testing can be confusing. Following the wrong extractables and leachables study protocol can result in costly delays eventually leading to requiring packaging safety and toxicology studies. Invitron regulatory experts have an in-depth understanding of various regulatory expectations in accordance with route of administration, formulation, container-closure system, dosage requirement, and drug delivery device requirements.
An extractable study identifies organic and inorganic chemical entities that may be extracted from packaging material under extreme conditions, such as harsh solvents, high heat, or pressure. Controlled extraction studies are qualitative and quantitative investigations of critical components of the container-closure system. These studies are essential to evaluating the safety of materials, informing material selection, meeting regulatory expectations, and controlling leachables in finished drug products. Controlled extraction studies can also be performed specifically to inform raw material selection and control. Invitron scientists are experienced in exhaustive extraction studies utilizing both PQRI & USP protocols, including USP <1663> Assessment of Extractables Associated with Pharmaceutical Packaging/Delivery Systems. Upon completion of the extractables screen, if any analytes remain above the safety concern threshold, it is necessary to perform a leachables analysis to deduce the levels of analytes from the worst case scenario.
A leachable study examines chemical components that can migrate from a packaging material to the product it contains under normal conditions and environmental factors over the course of that product’s lifetime. Leachables typically correlate to extractables, and after extractables have been characterized, compounds of concern are identified. Analytical methods are then developed and validated for those identified compounds of concern to quantitate leachables at low levels below the established safety thresholds for compounds of interest. Our scientists are adept at developing methods that are selective for leachables in the presence of both the active pharmaceutical ingredient (API) and excipients of the product. Our methods are appropriate for storage and stability programs, and are validated under ICH Q2 guidelines for specificity, accuracy, linearity, range, precision, reproducibility, and robustness for each container-closure component.
A leachable stability study typically uses samples from the ICH stability batch manufacture to access drug products for detection of leachable materials and their molecular decomposition. As leachable stability studies are conducted, our analytical team monitors samples stored in the final container-closure for leachable profiles from early time points through near end-of-shelf life, while being able to access samples in accelerated stability studies as well. Our experienced team of scientists carry out leachables studies per appropriate regulatory guidance, including USP <1664> Assessment of Drug Product Leachables Associated with Pharmaceutical Packaging/Delivery Systems. Samples in the final container-closure system are tested by developed analytical methods, and all leachant peaks are compared to the profiles obtained on a virgin sample that has not been in contact with the container-closure system.
Per 21CFR 211.94, drug and device containers should not be reactive, additive, or absorptive since these effects can to alter the safety, identity strength, quality or purity of the drug beyond the official or established requirements. Safety is assessed when comparing leachants to an established total daily intake. Complicating the picture, different dosage forms hold different levels of risk in this regard, so expertise across container and dosage types is essential. Our team has decades of experience assisting clients in evaluating drug and container-closure compatibility using “worst case” conditions, and the extractables screening data we provide is critical to intelligent planning for materials selection.
Risk assessments are a critical component of any E&L testing program, as FDA directs drug developers to use a risk-based approach. Risk assessments evaluate the differences in pharmaceutical packaging systems based on a number of factors, including maximum daily dose, dosage form, route of administration, toxicity classification, patient population, dose regimen (e.g. acute, chronic), and container-closure materials of construction. The data generated from Invitron’s E&L studies can be used for toxicological evaluations and risk assessment.