Drug manufacturers spend significant amount of time and money in characterizing, identifying, minimizing the impurities in a drug product so that regulatory bodies make accurate decisions with respect to the product quality and safety. Migrants from process filters are a potential source of impurities within a drug product. Particular attention is paid to the filters that are placed in down-stream processes that are close to the point of final filling.
Extractables are defined as compounds that have the potential to be removed from any contact material by the use of exaggerated extraction conditions; such as worst-case sterilization conditions followed by extended durations of exposure to harsh solvents at elevated temperatures. Leachables are compounds that migrate out of a contact material into the actual pharmaceutical formulation during normal use conditions and these compounds are typically a subset of extractable and are generally found in the final drug product. Extractables and leachables can arise from any elastomeric or polymer material.
Evaluation of the filter for extractables and leachables should be facilitated by a collaborative effort between the drug product manufacturer and the filter manufacturer. While the drug product vendor has the regulatory and legal responsibility to demonstrate that such leaching does not affect the safety, efficacy, and compliance of the finished drug product, the filter manufacturer can facilitate that demonstration by providing the drug product vendor with appropriate and relevant information.
The vendor of the finished drug product is responsible for supplying regulators with a full and complete assessment of the potential impact of product contact material migrants that could potentially alter the drug product purity, safety, and efficacy. To facilitate (but not take the place of) the drug manufacturer’s assessment, suppliers of the filtration systems can provide the vendor with a full and complete extractables assessment for their materials and systems. The vendor and supplier share the responsibility for compiling or correlating the extractables and leachables data that are required to perform a thorough assessment of product impact.
The risk of leachable compounds is embedded into its toxicology via the direct toxic effects of the compounds or the potential indirect effect of the leachable compounds to the drug product formulation affecting its stability and efficacy. The evaluation of leachable compounds begins with a thorough identification of extractable compounds released from each filter in the manufacturing process production and packaging components under exaggerated conditions. The set of observed extractables helps to identify possible targets to be monitored in a subsequent leachables study.
The goal of an extractable testing process is to facilitate the extraction of as many compounds as possible under relatively extreme conditions, but not to breakdown the polymer into individual components so that the polymer loses its integrity. Extractable testing includes both analytical and biocompatibility evaluation. Solutes in actual drug product can cause interference with currently available analytical methods used to detect extractable substances. Therefore, it is difficult to distinguish between solutes in the product and potential non-volatile extractable from the filter device.
A comprehensive approach using selected model solvents is adopted to analyze the extractables released from the filter. Exhaustive extraction at worst case conditions using model solvent streams with a defined rational as a worst-case product model, followed by quantisation and identification is the basis of the analytical testing method. The complete filter device is subjected to a static soak with a minimum amount of solvent to concentrate extractable substances. Variables in the actual filtration process such as contact time of the product and filter, process temperature, sterilization conditions, the number of sterilization cycles, pretreatment of filter with flush solutions, all affect the level of extractables from a filter device.
Several quantitative methods such as Non-Volatile Residues, Total Organic Carbon and qualitative methods such as RP-HPLC, FT-IR, LC-MS, GC-MS, and NMR are some of the most common analytical techniques that can be used to analyze the extraction solution. The identification and quantification of extractables from the filter device must be correlated to the biocompatibility data which will be specific to a particular device and process conditions.
Based on this extractable profile a toxicity assessment can be made by the end-user for their leachable evaluation. This would be considered as a worst case because the concentration and number of extractable compounds are expected to be higher than what would be measured during a leachable study.
To aid in the toxicity assessment, is a risk assessment tool referred as The Threshold of Toxicological Concern (TTC)- which is a principle that refers to the establishment of a generic human exposure threshold value for (groups of) chemicals below which there would be no appreciable risk to human health. TTC defines a common exposure level for groups and classes of chemical compounds that will not pose a significant carcinogenicity or other toxic effects if exposed below the corresponding TTC limit. Beyond this pragmatic approach more traditional compound specific toxicological evaluations may need to be applied.
Qualification and the control of components that come into contact with the drug product formulation is an integral part of any drug approval and hence extractable and leachables should be investigated and resolved in an early process development stage when affects on product stability can be investigated. It is imperative that the drug manufacturers, vendors, toxicologists and regulatory bodies have timely communication to take informed decisions on risk and safety.
Determination of extractables and leachables for single- use systems and filters also must be addressed as part of process validation when single-use technology is used. The idea that compounds leach into pharmaceutical formulations or process fluids (e.g. buffer solutions and bulk storage) from processing and storage materials is not new or even unique to plastics.
All materials have extractables and potential leachables. When properly evaluated, these are easily addressed and rarely lead to disqualification of a single – use component. Ideally, processing methods and equipment are chosen early in the development life cycle of a pharmaceutical product. The choice should be made by a dedicated team of scientists, quality assurance and/or regulatory affairs (QA/RA) representatives, and validation specialists working in partnership with component and system suppliers.
Authors are working with Access Services Biopharm
Process Solutions, Merck Millipore