BCG manufacturing and the bladder cancer BCG shortage
BCG, the century-old tuberculosis vaccine, is the best treatment for early bladder cancer, but it is a live bacterium that grows slowly and only one company makes it for the United States. Since 2019 urologists have been splitting doses and rationing courses.
Overview
Intravesical BCG is a freeze-dried culture of live, attenuated Mycobacterium bovis. Each manufacturer grows its own sub-strain (TICE in the United States, Connaught, Danish 1331, Tokyo 172, Moscow and RIVM elsewhere) on solid or liquid media for weeks, harvests, lyophilises and fills it under biologics GMP (21 CFR 600 series, regulated by CBER). Because the product is a living organism, potency is measured in colony-forming units, batches vary, contamination is ruinous and output cannot be raised quickly.
The shortage began when Sanofi Pasteur's Connaught-strain product (ImmuCyst) ran into manufacturing problems at its Toronto plant from 2012 and the company withdrew from the market in 2016 and 2017, leaving Merck's TICE BCG as the sole US supplier. Merck raised production but demand exceeded it, and BCG has been listed as in shortage by the FDA and ASHP since 2019. Professional societies responded with a joint statement recommending a one-third dose per instillation, shortening maintenance and reserving BCG for high-risk non-muscle-invasive disease, and trials of alternatives (gemcitabine and docetaxel instillation, and newer strains such as the Tokyo-172 based programme) accelerated. Merck announced a new BCG plant in Durham, North Carolina, in 2020 to add capacity later in the decade.
- Hypoxic, necrotic core that drugs reach poorly
- Attenuated Salmonella given intravenously
- Payload made in situ: methioninase (SGN1), IL-2 (Saltikva)
- VNP20009 in the 2000s: tolerable but ineffective; attenuation cuts potency
How it works
A slow-growing live bacterial culture, lyophilised and released on colony counts, so capacity is fixed by fermentation time and the number of licensed plants.
- Cheapest effective immunotherapy for bladder cancer
- Decades of safety data
- Off-patent
- One licensed US supplier
- Months from seed lot to vial
- Live product with batch variability and contamination risk
Latest papers
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