To give you a taste of what you can expect from these topics, read on for summaries of the key presentations at E&L USA this year.
Challenges for extractable and leachable testing and documentation for combination products
Combination products can be single entities, co-packed or co-labelled all containing a combination of a drug product and a device. Examples of the different combination drug products are prefilled syringes (single entities), infusion sets for haemophilia products (co-packed) and insulin infusion pump systems (co-labelled).
In general combination products should fulfil expectations for extractable and leachable documentation for both the drug product and the device. For co-labelled drug products like infusion pump systems the final FDA guideline from Dec. 2, 2014 “Infusion Pumps Total Life cycle” shows the increased expectations for co-development of extractable and leachable documentation between device and drug product manufacturer. It furthermore also specifies the importance of defining worst case conditions for in-use leachable testing of a combination drug product.
Carsten Worsoe at Novo Nordisk will describe expectations for extractable and leachable testing of single entities, co-packed and co-labelled combination products. In addition to this the presentation will show suggestions for defining worst case conditions for in-use leachable testing for combination products. Furthermore the use of the Analytical Evaluation Threshold suggestion by the PQRI POPD E&L group as a mean of defining a level where leachables possess a negligible safety risk will be used in case studies describing characterization of in-use leachables.
SCTs – a focus on TTC – a potted history and use in E&Ls health risk assessments
Ideally, a robust health risk assessment should be based on substance-specific toxicity data, but comprehensive testing of every chemical is not practical. For untested chemicals that also lack good “read-across” analogues, the Threshold of Toxicological Concern (TTC) and related guidance can be valuable to the risk assessor tasked with evaluating the health implications of exposure to untested compounds. Pete Watts of bibra will provide a brief history of how TTC values have been derived and accepted, and describe how they can be used to assess E&L data.
A Means of Establishing and Justifying Binary Ethanol/water Mixtures as Simulating Solvents in Extractables Studies
Ethanol/water mixtures are frequently used as simulating solvents in extractables studies. However, the basis for determining and justifying the right ethanol proportion in a simulating solvent for a particular drug product or solution has not been previously established.
A solvent strength model has been developed in this study, based on the correlation between the levels of a model compound (DEHP) extracted from a reference source material (plasticized PVC resin) and the proportion of ethanol in ethanol/water extractions solvents. This model was established by experimentally investigating DEHP leaching and takes the form:
% Ethanol in the simulating solvent = 28.841 x (Concentration DEHP)0.10
If the level of DEHP extracted from the standard source PVC resin is measured, then the level can be input into the above equation and the proper ethanol content of the appropriate simulating solvent can be determined.
The model has been applied to certain drug products and additives used in drug products and the proper ethanol/simulating solvents for these products have been established, as will be presented by Dennis Jenke, Baxter Healthcare Corporation, Baxter R&D. Additionally, the leaching behavior revealed in this study has been established to be consistent with previously published research and a mechanism for the observed behavior has been proposed.
Extractables Testing of Single Use Bags Utilizing a Portion of the BPOG Protocol
Four different bag types of 1 liter capacity were extracted using three of the BPOG recommended solvents (50% ethanol, 1% polysorbate 80, and WFI). Extractions were carried out per BPOG protocol for storage bags at 40 oC with sampling done at 1 day, 21 days, and in some cases 30 days, 50 days, and 70 days. Samples were analyzed utilizing the suggested BPOG methods (HS-GC/MS, GC/MS, HPLC-DAD-TOFMS, ICP/MS, anion IC, and TOC). Some of the interesting challenges encountered during the study will be shared along with general trends in data and comparison of findings across the extraction solvents and across time within a given solvent. Of particular interest are analytical problems encountered in the PS-80 extracts, which Roger Pearson at Aspen Research Corporation will present in detail at the conference.
In silico mutagenicity assessment methodologies relating to E&L strategies
Learn about an in silico mutagenicity assessment protocol for extractables and leachables based on the recently issued ICH M7 guidance for pharmaceutical impurities. This guidance permits the use of (Q)SAR models for prediction of bacterial mutagenicity to be used in place of an experimental assay. It is noteworthy that this guidance is the first time an in silico prediction is permitted to be used as a replacement for an in vitro or in vivo test. As part of the submission, the guidance recommends the use of two (Q)SAR prediction methodologies, one expert rule-based and one statistical-based, which can be supplemented by an expert opinion. It also outlines how available historical data can be used as part of this assessment.
Glenn Myatt, CSO at Leadscope will outline the components of the two recommended in silico methodologies and describe how the results from the two systems along with any available laboratory data are combined as part of a consensus call. The components of an expert review for both negative and positive calls will be reviewed, along with methodologies to ensure the results are well documented, consistently generated and traceable.
The E&L USA Poster Sessions will also touch upon some interesting points of research including: Planning for Compliance with Emerging Global Restricted and Regulated Substance Standards and the Migration of Ink Components.