IN PARTNERSHIP
an extractables study from initial design through results and on to a leachables study, discussing some of the initial bases for the extractions used, the analytical techniques used and some of the terms found in the vernacular of extractables and leachables testing. The first step in any extractables study design is to assemble as much information as possible about the materials of construction, the dosages (if applicable), information about the drug excipients and – if there is a device – the device design. The study in question involved a medical device used to mix and administer drugs, which was not an implantable. The materials used in the fluid path of the assembled device were high-density polyethylene, polyisoprene rubber and stainless steel. A wide variety of mixtures of solvents are used as carriers for drugs used with the device, and the most severe dosage would be 36 devices used over a four-day period. All this information, and guidance documents from the US Food and Drug Administration (FDA) and ISO 10993-12 – and input from a toxicologist that one should assume 20μg/day of any compound would be considered safe – was used to propose the details of the extractables study.
A twofold leachable screening study The purpose of the study was twofold. The first was to develop methods in the drug product vehicles to demonstrate that the extractables could be detected. The second was to qualify methods for an accelerated leachables study. Extracts containing the extractables in higher concentration were purposely generated and used to spike into the drug vehicle matrices – three drugs were tested. Where there was compound identification, purchased standards were used to spike and confirm the compound IDs. Retention times and key mass fragments from the extractables were stored, enabling a search for the drug vehicle extracts for
“In the testing field, there are no hard-and-fast rules as to which extracting solvents to use. There are, however, ISO standards that help direct appropriate testing.”
60 | Outsourcing in Clinical Trials Handbook
extractables. Recoveries were calculated from the area ratios of the compounds in the extractables spike and those in the spiked drug vehicle. The study was able to demonstrate that the compounds, if present as a leachable, would be detected and were recovered acceptably (50% – 120%). This portion of the study was much more challenging and time-consuming than the extractables study.
A screening study was then done where drug product vehicle (DPV) was loaded into the device and held at 37°C for eight hours, cycling the vehicle about once per hour. The DPV was then extracted following the methods developed earlier in the screening process, and the extracts were searched by retention time and mass fragment – GCMS and HPLC-TOFMS – for potential leachables, a subset of extractables. Only a few of the extractable compounds were detected and only one that had not already been identified was detected. Based on this, a leachables study protocol was written and a leachables study conducted. The study was carried out on three drug products (DP) against control-testing – DP never contacting the device in duplicate – for eight hours at room temperature, with periodic cycling of the three DPs. Only five compounds were detected and only one of which had no ID. All five had been detected as extractables. A toxicological assessment was done per ISO 10993-17 and the device was found fit for its intended use and received FDA clearance – the total project spanned 10 months.
Regulatory questions Aspen did have to respond to a few questions – two of which, in the extractables phase, dealt with how it could be sure that compounds weren’t lost during solvent reduction. That was demonstrated by acceptable recoveries of spikes made prior to the volume reduction – solvent exchange and volume reduction for GCMS. Other questions requested additional justification for the extraction times and temperatures, all of which were answered to their satisfaction. Another concern was doing leachables on newly produced devices instead of at the end of the product’s lifetime. Since the drugs are not stored in the products, that became a question of the material’s durability during storage, and Aspen was able to cite available literature to justify its use.
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