According to the California Highway Patrol, the plane crashed in the northbound lanes and came to rest on the southbound side.
Flame and smoke erupt from a twin-engine prop jet after it crashed on Interstate 405, just short of the runway at John Wayne Orange County Airport..
A man and a woman survived the crash and were removed from the plane's wreckage and were hospitalized with "non-life-threatening injuries", according to a report by CBS Los Angeles.
They were pulled out of the burning wreckage before being taken to a local hospital with injuries that are not believed to be life-threatening.
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The plane crashed in a ball of flames after clipping a vehicle short of Runway 20R, Ian Gregor of the Federal Aviation Administration said.
The FAA said the pilot declared an emergency shortly after the plane had departed from John Wayne Airport. No one on the ground was injured. Two people were injured in the small plane crash. After checking that he and his passenger were OK he said they "gave each other a hug that we were still alive". Video shows moment of impact when small plane crashes on 405 Freeway in Southern California.
The cause of the crash was being investigated.
The airport was closed to arrivals, but planes never stopped departing.