In the course of risk analyses on the manufacturing route of your product including the complete supply chain and the used production equipment, we identify potential entry points of individual elemental impurities. Together with the results of screening for elemental impurities in product batches, this helps assess to what extent there needs to be a routine control strategy for a specific element in accordance with ICH Guideline Q3D.
If the risk analysis identifies it as necessary to have a testing concept for the routine control strategy of individual elements, we develop and validate an affordable method that is suitable for routine use for release analysis.
We use high-resolution LC-MS measurements to elucidate the chemical structure of degradation and synthesis by-products as well as unknown components. This enables us to make initial statements about the structure of the elemental impurities. For complete structural elucidation, our LC-SPE trapping system provides the option of obtaining small quantities directly for subsequent NMR measurements. These measurements are coordinated in collaboration with our cooperation partners.
Identified substances can then be synthesised in collaboration with cooperation partners or isolated using (semi-)preparative techniques, and then qualified by HWI as a reference standard.
Extractables and leachables
Finished medicinal products may contain materials that originate from the packaging or were carried in during the production process. These impurities can be toxicologically relevant and pose a health risk to the patient. It is therefore crucial to determine the compatibility of these materials.
Our team of experts designs and carries out the necessary regulatory analyses of plastic packaging materials for extractables and leachables in medicinal products.
For new marketing-authorisation applications or amendment procedures, we assess this data and provide it to you as a report.
- Extraction studies: exploratory investigations of primary packaging and/or devices to identify extraction profiles of potential extraction products, including the full identification and toxicological qualification of relevant extraction products
- Confirmatory migration studies of medicinal products as part of stability studies
- Regulatory support, including the creation of specifications and submission of justifications, expert reports and consultation
- Matrix-specific method development and validation to perform leachables studies
Genotoxic impurities can arise as by-products during the synthesis of active substances or certain excipients. Formation in the finished medicinal product is also possible. There are strict limits for genotoxic impurities in active ingredients, excipients and medicinal products with very low limits in the lower ppm or ppb range. We develop and validate customised LC-MS and GC-MS test methods with corresponding detection and quantification limits. The determination of alkyl mesylates in mesylate salts as an example of current issues is well established in our laboratories.
We test for residual solvents according to European Pharmacopoeia and ICH Guideline Q3C (R7). Optionally, residual solvent determination is possible using our own in-house validated microprocess for substances and preparations only present in the lowest quantities.
Troubleshooting production issues
We offer an express service for troubleshooting undesired impurities in your production. This service includes clarifying the structure of soluble organic impurities using LC-HRMS and GC-MS screening methods. We identify inorganic impurities at our cooperation partners using SEM-EDX or ICP-MS. We also have access to imaging methods such as X-ray microtomography/nanotomography, micro CT and Raman microscopy/imaging.
In accordance with the requirements of the current EMA guideline and literature data and as far as supported by qualified toxicologists in our network, we determine PDE values, which we use as a basis to perform risk-based analytical testing as part of the purity validation. This includes method development or optimisation, method validation and the analysis of samples from the purity validation, the sampling of which (swaps/rinse) we are also happy to help with.