Under trial prisoners, Shaikh Mohammad Mumtaz alias Firoon alias Sher Khan and Mohammad Ahmed Khan alias Muna escaped from the judicial complex, which is adjacent to the prison.
However, authorities are yet to confirm the exact time of their escape.
"What is mysterious, is that the prison officials informed the police department about the escape after much delay," SSP Rana Umar Khatab said.
"We still don't know about the timing of the escape. But already 12 police officials, including the central prison's Superintendent Ghulam Murtaza Shaikh, Deputy Superintendent Faheem Memon and Assistant Superintendent Abdul Rehman Shaikh, have been arrested and FIRs registered against them," he said.
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"Their arrest helped us destroy the Naeem Bukhari group LJ cell in Karachi," he said, adding "we just hope they don't regroup now".
According to a senior official of the Sindh police's counter-terrorism cell, Mumtaz and Ahmad Khan had "confessed" to dozens of target killings and terrorist acts.
Mumtaz of Orangi town is said to be involved in the targeted killing of 57 people, including members of the Shia community and police. He was charged in 32 cases.
Ahmed Khan of Korangi was involved in seven targeted killings.
In October 2014, a timely operation by the Rangers had led to the discovery of a 45-metre tunnel that was being built just a few meters from the Central Jail, apparently to aid the escape of 100 "dangerous militants".