TNT’s “Rizzoli & Isles” hits the 100-episode mark with its July 25 episode, the first of two milestones this year as the cable hit prepares to end its seven-season run on Sept. 5.

The 100th episode, directed by series star Angie Harmon, follows Boston police detective Jane Rizzoli (Harmon) and medical examiner Maura Isles (Sasha Alexander) during the investigation of a murder at a biker bar. In a nod to the series reaching 100 episodes, showrunner Jan Nash says it will use the official Warner Bros. production number, 2M7258-100, as both the title and a prisoner number within the segment.

“As we [planned] the final season of the show, we had watched the pilot again, and we did give some thought to doing something that isn’t exactly like the pilot but had some of the same tone of the pilot, which was a much darker version of the show than had existed for much of the show’s history,” Nash says. “So it is darker, with deeper themes in it, and it serves as a launching pad for the end of the season. At the end of it you’ll see something that we follow for the [remaining] five episodes.”

Despite directing the episode, Harmon’s Jane Rizzoli is featured prominently ­— Nash says Harmon had a lighter acting load in the previous episode to give her more prep time for directing the 100th. Co-star Alexander also directed an episode in the seventh season.

“I was very excited, but my biggest concern was that it didn’t look like all our other episodes,” Harmon says. “Achieving 100 episodes, especially nowadays, is an accomplishment. Today you’re lucky if you can get 100 minutes into a series.”

Warner Bros. Television Group president Peter Roth echoed Harmon’s sentiment. “Reaching the coveted 100-episode milestone is a remarkable achievement for any series,” he says, “Accomplishing that feat in the basic cable universe, wherein the order patterns are considerably less, is even more significant.”

And while the show, based on the novels by Tess Gerritsen, hasn’t switched up the format much over 100 episodes, its characters have evolved. Alexander says she was surprised when, in the first episode after the pilot, Maura was on a date and started to obsess over her date’s dry hands. “She starts to diagnose what the possible diseases could be,” Alexander says. “I remember asking [then showrunner] Janet Tamaro if [Maura] had Asperger’s. The fact that this woman would totally fall out of line with the norm — which would be to just enjoy your date with a handsome man who’s flirting with you — and instead she breaks the moment with scientific randomness. I will really miss playing Maura because she has such a funny, curious disposition.”

For Harmon, Jane’s softer side came as a welcome surprise. “As big, tough, ballsy and fearless and courageous → as Jane is, when it comes to men she blushes and gets coy and tucks her chin in,” Harmon says. “Love excites her, and I don’t think when we first met Jane she wanted any part of that. As those walls started to crack and her heart started to be exposed, she was giddy when it came to love and she still is.”

Executive producer Bill Haber says the show’s legacy will be the friendship between its lead characters, which was also what convinced Nash to accept the offer to be the series’ showrunner in season five. “That relationship existing at the center of the show was not something you see a lot of in television drama,” Nash says. “You see it in comedies, but not a lot of dramas have a strong female friendship as one of their central elements.”

Alexander says the showrunner shift from Tamaro to Nash did change “Rizzoli & Isles.” “Janet was the voice of the show and when the showrunner leaves and a new person comes in with a new perspective — they can’t imitate what’s been done, it wouldn’t be fair to their own creative process — naturally they’ll write to their own strengths and what they prefer,” she says. “Jan has done a lovely job, but it has been a different show. Just like any company, you change ownership and the company changes.”

While Alexander notes recent seasons have been more procedural-based, Harmon says friendship has always been the third character on the series and compares the women’s bond to the role New York City played on “Law & Order” and “Sex and the City.” “That was hugely important to me because I wanted to put it out there to women and girls and teenagers that women can be for women,” Harmon says. “We’ve managed to keep that going for seven years.”

As for the timing of the show’s exit, cast and crew have mixed feelings. “I accept that’s what’s going to happen, but it’s terribly sad,” Nash says. “This is the nicest place I’ve ever worked.”

Alexander says “Rizzoli & Isles” could continue, but she feels like seven seasons is a good number on which to exit. “Personally, it’s bittersweet,” she says. “I’m ready to move on, but I also loved doing it.”

Nash says producers anticipated that season seven might be the end of the line for the series even before TNT president Kevin Reilly announced the show’s cancellation during the January Television Critics Assn. winter press tour. “So many series are high-profile, but nobody watches,” says Haber. “I love [that] this was something that was successful — 6 million people still watch it.”

As they near the finish line, Nash says producers will bring back several characters from the show’s past, including a guest turn by Sharon Lawrence as Maura’s biological mother. “We tried to figure out what would be a satisfying way for all of these characters to move into that moment of black frame that is what happens after the show ends,” Nash says. “This is not just the audience saying goodbye to the characters, it’s the characters and the actors saying goodbye to the audience and the experience of making this show.”

Both Harmon and Alexander say they’re pleased with where the series leaves their characters. “It’s going to be a really good send-off,” Alexander says. “It’s quite emotional, but I do like where they’ve taken Maura this year. Jan has done a lovely job of giving us human obstacles to get through that remind us why we love [‘Rizzoli & Isles’] and I’m very happy with where they’ve gone.”

Nash says she’s confident viewers will have a reaction to the show’s finale. “I have no illusion everybody will find the conclusion we have [is] the right conclusion, and all that shows is how much they love the show,” Nash says. “If people vigorously disagree with what we’ve done then that means they were invested in something.”