For instance, there are usually many extractables from the same extraction, and some compounds may degrade before other compounds achieve the extraction plateau. This has resulted in regulators focusing on leachables that may migrate from packaging components and assessing the risk leachables might pose. However, with the advent of both new injectables systems and greater utilization of delivery devices, leachables may again be of concern. The associated risks need to be appropriately addressed through toxicological assessment and qualification. Common extractables include plasticizers, surfactants, processing aids, degradants, and container closure system materials. For example, extractables testing results for a gamma-irradiated component cannot be used to represent the results of the same component after autoclaving.
Stability sample leachable testing typically is performed with validated leachable methods. However, there is also a need for improved regulatory understanding and interaction with the provision of clear guidance on the expectations for submissions. The proposed study conditions along with the following instructions should be adhered to as closely as is practical. The potential draw-back of combining components is that it removes the possibility of tracking back the extractables from specific components. However, the study design should harmonize with regulatory expectations and be based on sound scientific principles that are appropriate for the type of dosage form s and route of administration. As the range of drug products expands, so too does the use of delivery devices.
These compounds then require further monitoring during the stability program of their amounts over the product shelf life. The solvents utilized include the drug product formulation or drug product placebo. The solutions from before and after the exposure are then analyzed to screen for leachables with the methodology discussed in this article. The collated data permits a toxicological assessment to be made with respect to any leachables found, ensuring patient safety. These may include application, the formulation, route of administration and length of use.
There is generally an overlap such that the leachables involved may be classified as a subset of the extractables. Leachables are chemical species that make their way into the product under normal product, application or storage conditions. Sources of leachables are potentially numerous and can include ink and adhesives from labels or secondary packaging material. The E-mail message field is required. While the International Conference on Harmonization has issued guidance on impurities resulting from the manufacture of drug substances and drug products, the topic of leachables falls outside of their scope.
The assessment results also will provide a list of likely leachable compounds that may require further evaluation, including their possible inclusion as targeted compounds for leachables method development and validation, which are utilized for monitoring leachables during stability programs over the shelf life of the drug products. The extractables study identifies species from manufacturing components where applicable and the packaging system that could migrate into the pharmaceutical product upon storage under normal conditions. However, more intricate units, e. To address safety concerns, approaches to toxicological safety evaluation of extractables and leachables have been developed and applied by pharmaceutical and biologics manufacturers. The evolution of container closures has resulted in the use of new packaging and delivery devices made from plastics, elastomers, multi-laminate foils, and adhesives. This provides the added benefit of reducing the concern for ink and labeling leachables but puts greater emphasis on evaluation of the plastic components and environmental leachables such as sanitizers. With that approach, control samples must be included; an evaluation of feasibility of the screening methods for the specific drug products is normally performed as well.
Further, extractables studies investigate packaging materials for their possible interactions, as well as examine how a seal behaves in contact with a medication. Recently there has also been added scrutiny from other countries e. A balanced consideration and approach should be applied, with the goal to achieve optimal extractables amount under practical lab conditions without causing degradation of the material. Certain types of these compounds are introduced from the polymer material synthetic process, such as residual monomers, oligomers, polymerization reaction initiators and their degradants, catalysts and polymerization media residuals, curing agents and their degradants for rubber materials, etc. Details of these approaches may differ depending on the nature of the final drug product.
Downstream processes closer to the final drug product formulation may have higher risk than upstream processes, and processes that involve high organic solvent content, high surfactant contents or extreme pH, etc. Extractables can be considered as potential leachables, although not all extractables leach into drug products or patients. Extractables studies may be performed as a risk mitigation activity to identify potential leachables for dosage forms with a high degree of concern associated with the route of administration. The aim is to gain greater regulatory acceptance of scientific risk-based approaches and control only those leachables which pose threats to human health. Traditionally, this was concerned only with those impurities arising from the manufacture and degradation of the pharmaceutical product. It is preferred that at least certain of the leachable methods are able to detect unspecified unknown leachable compounds so unspecified unknown leachables can be monitored during the leachable stability program.
Extractables and leachables assessment of all materials and especially fr. Extractables studies investigate these effects. However, there is little value in performing organic solvent extraction of metal springs, which would only yield inorganic impurities. Finally, some compounds may never achieve extraction plateau before the materials are degraded. If the component can be either gamma-irradiated or autoclaved, separate studies for each condition should be performed.
Secondary and tertiary packaging also needs to be considered at this stage. More recently, the European Medicines Agency has issued guidance on the use of plastics in primary packaging. Other potential sources of leachables are drug products, and intermediates manufacturing components, including such components as reservoirs, filters and filling tubes. Scientist I Bristol-Myers Squibb; and Robert Repetto, Senior Director External Affairs Pfizer. Nowadays extractables and leachables assessment of all materials - and especially elastomeric and plastic components - forms an integral part of the submission for approval of a new drug system or medical device. Material preparation: Controlled extraction studies are performed on individual components whenever possible to trace back the source of leachables, if leachables are detected in the drug product samples. For volatile extractables analysis, a sealed vessel extraction is preferred to prevent the loss of volatile extractables during the extraction process.