Botha, a pivotal figure in the Springboks' front-five, is struggling to overcome an Achilles problem and South Africa assistant coach Dick Muir confirmed it is unlikely that 74 times-capped Botha would make the starting XV.
"We are a little bit worried about Bakkies - he is our major concern," said Muir.
"It's his Achilles, and being a big man he obviously takes a lot of pressure in that area.
"He's so important for us for the remainder of the competition that we wouldn't take any chances with Bakkies.
"We will take it week by week - but I think he is going to be out this week unfortunately."
Danie Rossouw would be Botha's probable replacement, although there has also been a concern about lock Victor Matfield, whose hamstring niggle restricted his training during the early part of this week.
Springboks coach Peter de Villiers and his Wales counterpart Warren Gatland are due to name their starting line-ups for the Pool D encounter on Friday.
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