The ISPE Drug Shortages Prevention Model serves as a guide to help prevent drug shortages by providing quality, regulatory, and technical recommendations for the pharmaceutical manufacturing industry. The ISPE Drug Shortages Task Team developed the model as a follow up to the ISPE Drug Shortages Prevention Plan that was released in 2014. The model provides expanded guidance that reflects the new insight and best practices that have emerged in the past several years. Experience with large-scale events such as Hurricane Maria and the COVID-19 pandemic, and more recent geopolitical events, have cast a wider lens on global supply chain and distribution vulnerabilities. In parallel, public and civic demand for change has been accelerating new regulatory requirements in some markets and increased pressure is being placed on manufacturers for supply chain resiliency globally.