The EPI datasets are not required to be aligned to an anatomical dataset although alignment is usually carried out too in a typical processing pipeline. afni_proc..py has options for handling blip-up/down dataset by using -blip_forward_dset and -blip_reverse_dset. The -blip_forward_dset is optional. The initial part of the EPI time series will be used instead if the forward dataset is not supplied. Besides afni_proc.py, you can use just the unWarpEPI.py program for unwarping outside of our standard pipelines. It calls 3dQwarp and 3dNwarpApply appropriately.