Are you perhaps cross-chaining? (I.E. running the chain on small-small, or big-big?) That's something that should be avoided on general principles, as it forces the chain to run on an extreme angle. It is also a well known cause for chain rub.
And just because you have 21 possible combinations doesn't mean that you have 21 meaningfully different gears, but probably somewhere around 15-17. If you're in the middle front - once you begin to approach either end of the cassette it's usually a good idea to shift the forward end as well. If you're in big/small at the front this becomes even more important.