The Importance of Extractables and Leachables Testing
Throughout the drug development process, drug products need to be evaluated to ensure that potentially harmful impurities (known as extractables and leachables or E&L) 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 (Table 1).
Regulatory requirements for E&L testing can be confusing. Following the wrong extractables and leachables study protocol can result in costly delays, particularly for biopharmaceutical regulatory submissions, which require packaging safety and toxicology studies. Avomeen’s 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.
Table 1: E&L Packaging Concerns for Common Drug Product Classes
|Custom-designed E&L testing programs and protocols tailored to your needs while meeting regulatory standards||Consultative scientists well-versed in regulatory guidance deliver comprehensive E&L testing programs that meet regulatory standards||Proprietary, best-in-class polymer additive library containing hundreds of compounds to facilitate the identification of extractables|
Comprehensive E&L Program Support
Controlled Extraction Studies – 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. Avomeen’s 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.
Leachables Method Development & Validation – 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. Avomeen’s 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.
Extractable & Leachable Identification – Extractable studies identify volatiles, semi-volatiles, non-volatiles and inorganics present in the drug product, and also establish leachables threshold limits. These analytes include low molecular weight oligomers, additives, catalysts, mold release agents, dyes and colorants, plasticizers, antioxidants, and stabilizers. Leachables studies investigate the qualitative and quantitative leachables profiles over the proposed shelf life of the product, and also help to establish the correlation between extractables and leachables. Our industry-leading scientists generally develop techniques such as GC-FID and LC-DAD (at various wavelengths) for routine leachable monitoring.
Leachable Stability Studies – 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 and forced degradation studies as well. Avomeen’s 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.
Drug & Container-Closure Compatibility –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 (Table 1) 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.
Extractables & Leachables Risk Assessments – 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 Avomeen’s E&L studies can be used for toxicological evaluations and risk assessment.
Figure 1: Typical E&L Testing Program Design
Extensive Extractables and Leachables Testing Expertise
We work with our partners to tailor our extractables and leachables study protocols and programs to their specific requirements and needs, and have proven success supporting complex dosage forms. Our consultative scientists stay up-to-date with regulatory guidance, and have experience developing and executing E&L programs in compliance with a variety of regulatory guidance, including:
- USP <87> Biological Reactivity
- USP <661> Containers – Ophthalmics – Plastics
- USP <1031> Bio-Compatibility of Materials
- USP <1663> Extractables (Pharmaceutical Packaging/Delivery Systems)
- USP <1664> Drug Product Leachables (Pharmaceutical Packaging/Delivery Systems)
- USP <1660> Glass Qualification
- USP <661.1> Plastic Materials of Construction
- USP <661.2> Plastic Final Packaging Systems
PH. EUR. Guidance:
- Medicinal Products for Human Use Directive (2001/83/EC)
- 3.2 General Sections on Finished Containers
Sample Matrices Experience:
- Powders and granules
- Oral and topical liquids
- Creams, ointments and gels
- Oligonucleotides and biologics
- Combination products
Choosing the Right Extractables and Leachables Testing CDMO
Avomeen’s regulatory and industry experts ensure that every client receives the Avomeen standard of regulatory guidance that has helped countless organizations bring revolutionary drug products and therapeutics to market. Our consultative team is here to help you determine the required testing for your pharmaceutical product, appropriate for your current drug development stage, to help you achieve compliance with agency requirements. Get in touch with an expert to explore a partnership with Avomeen.