Parenteral drugs must meet strict release criteria to ensure patient safety upon administration. Sterility is a critical requirement, and is typically assessed using the compendial U.S. Pharmacopoeia (USP) <71> sterility test. However, with the growing demand to reduce batch release times, the test’s 14-day incubation period is becoming a concern, emphasizing the need for more rapid alternatives. Here, we compared the performance of the calScreener+ isothermal microcalorimetry (IMC) device (Symcel) to that of the compendial USP <71> sterility test, using a panel of sixteen microorganisms (six USP <71> reference strains and ten field isolates) in two inoculum sizes (100 and 5 CFU). The IMC-based method detected a higher number of positive samples compared to the compendial method (95.8% vs 87.5%; p < 0.05). Furthermore, IMC was consistently faster, reducing mean detection times from 43 hours to 19 hours at 100 CFU and from 46 hours to 28 hours at 5 CFU (p < 0.001). In conclusion, the calScreener+ IMC device shows promise as a rapid and sensitive alternative to the compendial sterility test, with the potential to speed up batch releases without compromising patient safety.