Background An explosion in a Chinese factory in 2016 caused a global shortage of essential broad-spectrum antibiotic piperacillin-tazobactam. Hitherto, no detailed, policy-relevant analysis has been conducted on this major shortage event. Thus, we aimed to (1) investigate causes; (2) describe supply chain challenges; and (3) uncover policy gaps to support possible mitigation actions. Methods Applying an analytical framework for security of medical supply chains, we investigated the changing roles of Pfizer-led and Chinese API suppliers. We identified demand surge, capacity reduction and co-ordination failures. Triangulating between scientific literature, corporate, and regulatory documents, we analysed the impact of Western and Chinese policy contexts on supply chain resilience. Results We uncovered ‘red flags’: geographically dispersed manufacturing failures due to complexity of sterile production; undetected supply chain concentration and interlinkages; and Chinese policy-led API supplier consolidation. We found these warning signals were ignored in the absence of a co-ordinated policy framework to identify and mitigate emerging global supply risks. Firstly, policy makers lacked visibility on growing ‘volume dependency’ in the chain. Secondly, national policy makers lacked a global view of supply risk. Thirdly, we show antibiotic API manufacturing economics were impacted by a number of non-pharmaceutical policy decisions (e.g. state aid, environmental standards, procurement rules) which contributed to supply chain vulnerability. Conclusions Our findings suggest possible policy gaps in governance of supply chain resilience. Firstly, disclosure of API suppliers including degree of dependency may better pre-empt bottlenecks, facilitating priority setting for public investments in re-shoring where global API supply currently relies on few, or single plants; secondly, a whole-of-government approach may counter the potential impact of non-pharmaceutical policies on supply chain resilience. Our findings confirm suggestions from previous studies that international data sharing would be beneficial considering the global shortage effects which can emerge from a single point of failure.