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6 BioPharm International ® Quality and Regulatory Sourcebook March eBook 2023 www.biopharminternational.com AnAly tics scribed by FDA in their guidance for industry (8). These include particle properties (such as average size and size distribution, shape, and morphology, as well as surface properties like charge in relation to the pro- pensity to aggregate), chemical attributes (composi- tion of the particle and assay and distribution of the active ingredient), and structural attributes of the particle that relate to function. Capturing the critical quality attributes and asso- ciated analytical methods in specifications for these materials provides a far greater challenge than for small molecule APIs. Application of enhanced method development for phase-appropriate analytical development of nanomaterials Although keeping processes unchanged to ensure re- producibility, from pre-clinical to late-phase trials, is favorable, it is even more rare for nanomaterials than for small molecule APIs. Besides the continuous im- provement and optimization of the synthesis process, thorough characterization of the nanoparticles and defining critical attributes and methods to determine them are a parallel process. 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 Procedure Development (9), a proposal is made to structure ana- lytical 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 ac- tivities are employed during analytical procedure de- velopment like: • drafting an analytical target profile (ATP) to help methodology selection • using multivariate design of experiments (DoE) to improve on the investigation of robustness • applying a risk-based approach to identify/address critical steps in the procedure early in development. The aim of enhanced method development is to provide a more robust analytical method, yet f lexi- ble 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. Phar- macoeconomics. 2021 Nov. 39(11) 1243-1269. 2. Dowden, H. and Munro, J. Trends in Clinical Success Rates and Therapeutic Focus. Nature Reviews Drug Dis- covery, 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 Nanomedicine to Impact Patients: An Analysis of US Federal Funding and Interventional Clinical Trials. Bio- conjugate Chemistry. 2020 31(3) 436–447. 8. FDA. Guidance for Industry, Drug Products, Includ- ing Biological Products, that Contain Nanomaterials. (CDER, April 2022). 9. ICH. Q14 Analytical Procedure Development, Step 2b version (2022). ■ Drug substance synthesis must be accompanied by product-specific analytical processes.