Hi,
after couple of hours of investigating, reading tons of discussions on internet and applying all possible solutions I have found the way that works for me.
Remember that this problem is complex and there is not one good solution for all situations. But maybe somebody will find it helpful.
Info about hw+sw:
iMac late 2013
proc: 3,2GHz Intel Core i5
RAM: 16GB 1600 MHz DDR3
MOTU 4PRE
El Capitan
Pro Tools 11
iZotope RX 4 Advanced plugin
When I was working in window iZotope RX 4 (through plugin iZotope Connect in ProTools) I had often issue with MOTU reconnecting. If that happened I had to close iZotope RX 4 and Pro Tools. Then I opened both programs and I continued till next MOTU reconnect. Meanwhile there were clicks and pops 😟.
My solution: Open "Audio MIDI Setup". In "Audio Devices" window add two fresh new Aggregates. I have called them "Aggregate for ProTools" and "Aggregate for RX". Set up them in the same way - select in column "Use" "MOTU 4pre" first and then "Built-in Output" as second. This order is important, I am not sure why... Then set Clock Source for both aggregates as Built-in Output. Sample Rate keep the same as you are using. In my case 48000Hz.
Now use "Aggregate for ProTools" in Pro Tools and "Aggregate for RX" in iZotope RX 4 as Audio device (or Playback engine). Also set in both programs Buffer size to 256.
Everything works fine for me now. No more reconnecting MOTU and no more clicking and buzzing.
Maybe it is worthless to use two same Aggregates maybe it is enough to create only one new. But I am not expert about all this, so I am just happy it is working now 🙂.
I hope it helps somebody to be happy too 🙂