West Ham United cruised past Andorran side FC Lusitans 4-0 on aggregate in the previous round and head into their latest clash on the back of a 3-3 draw with Peterborough United in a pre-season friendly last weekend.
Elliot Lee netted the only goal of the game in Andorra and the 20-year-old could be handed another run out while teenage forward Martin Samuelsen could also make another appearance.
Birkirkara head into the game having secured a 3-1 win at Ulisses in the second leg of their first-round tie. With former Italy and Juventus striker Fabrizio Miccoli in their ranks, the Maltese side travel to east London in buoyant mood.
What the new manager said
"If we qualify of course, it's good for the club," said Slaven Bilic in his pre-match press conference.
"It is good for the spectators and individually the players. To play against clubs that play different styles, it boosts your confidence and your quality as a man and a player.
"But it takes from you too. Last year I was at Besiktas and the Europa League cost us because it was something like playing 20 games Saturday, Thursday. At the beginning it's great for you if you're winning."
Team news
Big names like Adrian, James Tomkins, Mark Noble and skipper Kevin Nolan are all expected to be named in a strong-looking side, whilst only Pedro Obiang of the new signings is in contention with new star man Dimitri Payet banned.
The absence of Diafra Sakho will mean that Modibo Maïga should lead the line after spending last season on loan with FC Metz in France. Youngsters like Reece Burke, Elliot Lee and Reece Oxford could all earn valuable pre-season minutes on the pitch.
The winner will move one step closer to the group stages of the Europa League and join some of Europe's biggest names.