You can always 'clear' irb's registry of local variables by invoking an irb subshell. Think of how Bash shells work with respect to unexported environment variables. Since you metioned interactive mode, this solution ought to work for that.
As far as production code, I wouldn't want to undefine local variables as part of a solution - keyed hashes would probably be better for that type of scenario.
Here's what I mean:
$ irb
irb(main):001:0> a = "a"
=> "a"
irb(main):002:0> defined? a
=> "local-variable"
irb(main):003:0> irb # step into subshell with its own locals
irb#1(main):001:0> defined? a
=> nil
irb#1(main):002:0> a
NameError: undefined local variable or method `a' for main:Object
from /Users/dean/.irbrc:108:in `method_missing'
from (irb#1):2
irb#1(main):003:0> exit
=> #<IRB::Irb: @context=#<IRB::Context:0x1011b48b8>, @signal_status=:IN_EVAL, @scanner=#<RubyLex:0x1011b3df0>>
irb(main):004:0> a # now we're back and a exists again
=> "a"