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8 Pharmaceutical Technology QUALITY AND REGULATORY SOURCEBOOK EBOOK MARCH 2022 P h a r mTe c h . c o m FIGURE COURTESY OF THE AUTHOR. Quality: Validation wide range of possible sample concentrations. The validation of the linearity, accuracy, and precision of the assay portion of the method only captured a subset of product lengths. Subsequently, the validation studies did not demon- strate that the method was suitable for its intended use. This resulted in the need to amend the validation to in- clude concentrations that covered all possible product sizes. The good news is that the validation amendment studies were completed prior to submission; however, if submitted in a marketing application, there would be a significantly increased risk of a deficiency, resulting in a subsequent delay in product approval. Method validation timing One of the biggest areas of misperception with combi- nation products is when to initiate method validation and at what point it needs to be complete. To alleviate some of the confusion, it helps to look at the develop- ment milestones for both drugs/biologics and devices. Method validation timing for combination products should reflect the drug/biologic and device product/ process development milestones (see Figure 1). For devices, analytical method development is typi- cally completed during the design and development stage. Method validation is completed prior to verifica- tion and validation studies. For drug/biologic products, method development is completed by Phase II, and validation is completed prior to initiation of pivotal Phase III clinical trials. For combination products, method validation should be completed before verification and validation Discovery Design and Development Verification and Validation Product Launch Clinical Marketing Application Preclinical Phase III Clinical Phase II Clinical Preclinical Method Development Complete Method Validation Complete Medical Device Development Lifecycle Drug and Biologic Product Development Lifecycle Discovery Product Launch Key Method Milestones Post Validation Method Performance Monitoring Marketing Application Phase I Clinical Figure 1. Medical device and drug/biologic product milestones. Comparing indicators for both medical devices and drug/biologic products show when method validation is typically completed for each.