An explosion at a chemical works on an industrial estate sent a fireball 40ft into the air, a witness told the BBC.
"There was a huge bang, the whole building rattled and we saw flames shoot 40ft as a cloud swept up," said Chris Ball, who works next to the site in Andoversford, Gloucestershire.
At its height 100 firefighters and 20 fire engines tackled the blaze at the Biolab plant near Cheltenham.
Police said there were at least three explosions after the fire broke out.
No evacuation plans
Biolab specialises in the treatment of swimming pool and spa water.
A Gloucestershire Police helicopter was called to help with the fire, and provided thermal imaging pictures to firefighters as well as enabling the police to broadcast loud-speaker messages to the public, passing on safety advice.
There have been no reported casualties, but residents in the immediate vicinity as well as in the Northleach, Bourton and Stow areas were asked to stay indoors and keep their doors and windows shut.
"The explosions made the building vibrate like a very heavy thunder storm," said Simon Pratt, who works for R & R Catering Hire, which backs onto Biolab.
"The building was totally ablaze and uncontrollable within just a few minutes," he added.
The A40 remains closed between Frogmill and Station Hill, and the A436 is closed between the Hampnett turning and the clockhouse cross roads.
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