Working with Susy 2 syntax.

_layout.scss

//Grid-wide settings

$columns                        : 4;

$break-large                    : 50em;

$break-medium                   : 35em;

//Ulitities

$show-grids                     : hide; //show-grids or hide

//Basic Padding
@mixin grid-padding {
  @include background-origin(content-box);
  @include background-clip(content-box);
  padding: rhythm(0.25) 1.5em;
}

//Grid Setup

div[role="content"] {
  @include container;
  @include grid-padding;


  @include breakpoint($break-large) {
    @include use-grid(16 1/4) {
      @include container;
      @include grid-padding;
      max-width: 65em;
    }
  }

  @include breakpoint($break-medium) {
    @include use-grid(16 1/4) {
      @include container;
      @include grid-padding;
      max-width: 65em;
    }
  }

  div[role="content_main"] { 

    @include breakpoint($break-medium) { @include span(48% no-gutters); }
    @include breakpoint($break-large) { @include span(48% no-gutters); }

  }

  div[role="content_second"] { 

    @include breakpoint($break-medium) { @include span(last 48% no-gutters); }
    @include breakpoint($break-large) { @include span(last 48% no-gutters); }

  }

}

Looks good, but you can simplify. If you want smooth container transitions the whole way up, I only bother setting the largest. All it really does is add a max-width and a clearfix, anyway. Column count doesn't matter if you are setting an outer width yourself.

div[role="content"] {
  @include container(65em); 
  @include grid-padding; // This may be a good idea to roll in to Susy...
}

And you may as well take advantage of the mobile-first approach with your nested content. Don't bother with a large breakpoint for settings that are identical to the medium. 48% is 48%, not matter what the context, so leave it alone:

div[role="content_main"] { 
  @include breakpoint($break-medium) { @include span(48% no-gutters); }
}

div[role="content_second"] { 
  @include breakpoint($break-medium) { @include span(last 48% no-gutters); }
}

That should give you exactly the same setup, in a fraction of the code. :)