Leachables drug product

Container Extractables and Leachables and Drug Product StabiUty... 

The subject of extractables and leachables in drug products is an area of active discussion in the pharmaceutical industry. Further the regulatory agencies have issued guidances on this subject in recent years. The FDA guidance on container closure systems defines extractables and leachables as follows [124] Extractables are compounds that can be extracted from elastomeric or plastic components of the container closure system when in the presence of a solvent. Leachables are compounds that leach into the formulation from elastomeric or plastic components of... 

U.S. Food and Drug Administration (FDA), Extra 6 Safety thresholds and best practices for extractables and leachables in orally inhaled and nasal drug products, PQRI Leachables and Extratables Working Group, available http //www.pqri.org/pdfs/ LE Recommendations to FDA 09-26-06.pdf. 

As a result, materials for medical devices and drug products must be tested for leachable components. Once a known toxic compound is discovered, it must be identified for the assessment of toxicity, followed by the monitoring of levels using validated methods as required by the FDA. This identification procedure could be a time-consuming process with traditional methods that are based on fractionation and individual component analysis. 

The higher viscosity of semisolid dosage forms and transdermal systems may cause the rate of migration of leachable substances into these dosage forms to be slower than for aqueous solutions. Due to extended contact, the amount of leach-ables in these drug products may depend more on a leachable material s affinity for the liquid/semisolid phase than on the rate of migration. 

Leachability study (migration of chemicals into drug product) using LC/MS, GC/MS, ICP/AA, pH, appearance of drug and container, thermal analysis (DSC,TGA), and infrared (IR)... 

Leachables in orally inhaled and nasal drug products (OINDP) are compounds which are present in the drug product due to leaching from container closure system components. Extractables are compounds that can be extracted from OINDP device components, or surfaces of the OINDP container closure system when in presence of an appropriate solvent(s) and/or condition(s). Leachables are often a subset of, or are derived directly or indirectly from, extractables. Extractables may, therefore, be considered as potential leachables in OINDPs. Some leachables may affect product quality and/or present potential safety risks, therefore regulatory guidance has provided some recommendations regarding the analysis and toxicological safety assessment (i.e., qualification) of such compounds. 

Complete information is important in order to assist in the initial selection of container closure components, design laboratory extraction studies for components, and to establish a linkage, or correlation, between potential leachables (i.e., extractables) and observed leachables in a particular drug product. Such a correlation is required by regulatory guidances for certain dosage forms. ... 

After an application for a new drug product is approved, quality control tests must be established to demonstrate that the container closure system and all of its components possess the characteristics established in the original suitability studies. The appropriate packaging system should be included in all applicable stability protocols and observed for instability and drug product leachables. 

Similar information is required for the metal canister and actuator/mouthpiece. The guidance further requires that the drug product be evaluated for leachables with appropriately validated test methods, and that appropriate acceptance criteria for the levels of leached compounds in the formulation should be established. 

Each chemical entity identified as a drug product leachable under appropriate stability storage conditions was also identified as an extractable from one or more container closure system component (i.e., qualitative correlation). 

The observed level of a given leachable at the end of drug product s shelf life was less than or equal to the potential level of the qualitatively correlated extractable as measured in appropriate container closure components (i.e., quantitative correlation). 

Qualitative and quantitative leachables/extract-ables correlations exist for multiple container closure system component batches/lots, and multiple drug product batches/lots. 

Removal of extractables from an elastomer or plastic matrix can be accomplished by a variety of techniques, including solvent extraction (e.g., reflux and Soxhlet), supercritical fluid extraction, thermal evolution, etc. Jenke has thoroughly discussed and classified extraction strategies for container closure system components associated with a drug product leachables assessment. His discussion is based on two so-called directives paraphrased as follows ... 

In other words, extraction procedures used in control extraction studies and for routine extraction tests of container closure system components must produce extractables profiles that can be qualitatively and quantitatively correlated with drug product leachables profiles to the proposed end of a drug product s shelf life. As stated in the regulatory guidance ... 

It is important, however, to remember that no analytical method, technique, or combination of methods and techniques can provide complete assurance that every individual extractable/leachable associated with a drug product and its container closure system has been detected and identified. To quote Jenke ... 

GC/MS can also be used to quantitate extractables and leachables with extremely high selectivity, specificity, and sensitivity. For example, Norwood et al. used GC/MS with selected ion monitoring to quantitate polycyclic aromatic hydrocarbons (PAHs) as leachables in suspension MDI drug products. The analytical method employed a cold filtration technique to remove suspended drug substance and excipients, followed by GC/MS analysis. Stable isotope labeled... 

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