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6 Pharmaceutical Technology ® Quality and Regulatory Sourcebook March eBook 2023 PharmTech.com AnAly tics lipid nanopar ticles, solid nanopar ticles, and core- shell like structures), and surface properties. Their unique properties are based on their physicochemi- cal properties, especially their average size and size polydispersit y. These properties can be optimized to enable t he entrapped or conjugated dr ug to be delivered to a specif ic target or to improve physi- cochemical stabilit y in the biologic f luids. In addition to the attributes mentioned for APIs, a range of specific attributes for nanomaterials is described by FDA in their guidance for industry (8). These include particle properties (such as average size and size distribution, shape, and morpholog y, as well as surface properties like charge in relation to the propensity to aggregate), chemical attributes (composition of the particle and assay and distribu- tion of the active ingredient), and structural attri- butes of the particle that relate to f unction. Capturing the critical qualit y attributes and as- sociated ana ly tica l met hods in specif ications for t hese mater ia ls prov ides a fa r g reater cha l lenge than for small molecule APIs. Application of enhanced method development for phase-appropriate analytical development of nanomaterials Although keeping processes unchanged to ensure reproduc ibi l it y, f rom pre-c l i n ica l to l ate-ph a se t r ia ls, is favorable, it is even more ra re for na no- mater ia ls t ha n for sma l l molecu le A PIs. Besides the continuous improvement and optimization of the synthesis process, thorough characterization of the nanoparticles and defining critical attributes and methods to determine them are a parallel pro- cess. A two-step approach in the phase-appropriate analytical development will not suffice and a more gradual approach towards late-stage methods needs to be employed. In the (draft) Q14 ICH guideline, Analytical Proce- dure Development (9), a proposal is made to structure analy tical development in an effective process. It advises moving away from the 'minimal approach', which may be considered the current standard, to what is called 'the enhanced approach'. In the latter, additional activities are employed during analytical procedure development like: • draf ting an analy tical target prof ile (ATP) to help methodology selection • using multivariate design of experiments (DoE) to improve on the investigation of robustness, • apply i ng a r i sk-ba sed approach to ident i f y/ address critical steps in the procedure early in development. The aim of enhanced method development is to provide a more robust analytical method, yet flexible in the lifecycle of the method. Additional activity at the start of analytical development should reduce overall cost. However, when taking the high attrition into account, this advantage may evaporate. Hence, the advanced approach described above makes sense particularly for complex systems like nanosystems. Key lessons The validity of early-phase evaluations for later-phase clinical studies depends on a comparability assess- ment by analytical testing of the used batches. The extent to which the analytical methodology needs to be developed depends on the development phase (phase-appropriate analytical development) and the key decision is between reliability and robustness of the analytical methods and the cost to achieve them (the analytical development dilemma). As the industry is trending toward more compli- cated systems like nanoformulations, current industry best practices in phase-appropriate analytical devel- opment need to be reconsidered for applicability for these systems. The 'enhanced approach' of analytical procedure development, as described in the draft Q14 guideline, provides inspiration to analytical develop- ment tailored for nanomaterials. References 1. Schlander, M.; Hernandez-Villafuerte, K.; Cheng, C.Y.; et al. How Much Does It Cost to Research and Develop a New Drug? A Systematic Review and Assessment. Pharmacoeconomics. 2021 Nov. 39(11) 1243-1269. 2. Dowden, H. and Munro, J. Trends in Clinical Success Rates and Therapeutic Focus. Nature Reviews Drug Discovery. 2019 18(7) 495–496. 3. Sun, D. et al. Why 90% of Clinical Drug Development Fails and How to Improve It? Acta Pharmaceutica Sinica B. 2022 12(7) 3049–3062. 4. Roberts, R.A. et al. Reducing Attrition in Drug Devel- opment: Smart Loading Preclinical Safety Assessment. Drug Discovery Today. 2014 19(3) 341–347. 5. CFR Title 21, 312 (Government Printing Office, Washington, DC) https://www.accessdata.fda.gov/ scripts/cdrh/cfdocs/cfcfr/cfrsearch.cfm?fr=312.23 (accessed Jan. 17, 2023). 6. Center for Drug Evaluation and Research. Investiga- tional New Drug (IND) Application. FDA.gov. https:// www.fda.gov/drugs/types-applications/investigation- al-new-drug-ind-application (accessed Jan. 17, 2023). 7. McGoron, A. J. Perspectives on the Future of Nano- medicine to Impact Patients: An Analysis of US Federal Funding and Interventional Clinical Trials. Bioconjugate Chemistry. 2020 31(3) 436–447. 8. FDA. Guidance for Industry, Drug Products, Including Biological Products, that Contain Nanomaterials. (CDER, April 2022). 9. ICH. Q14 Analytical Procedure Development, Step 2b version (2022). ■