The odds of getting a complete response letter (CRL) from the FDA citing manufacturing problems are about as good these days as getting a closeout letter stating that a company has adequately resolved all the manufacturing concerns raised in a warning letter.

That's because the number of CRLs issued due to good manufacturing practice (GMP) violations is climbing, while many companies are waiting years for a closeout letter. According to the FDA, GMP violations resulted in 14 CRLs for novel drugs last year. But only four drug CRLs issued from 2010 to 2015 cited GMP issues. (See BioWorld Today, Jan. 6, 2017.)

Since privately held companies don't have to disclose CRLs, it's hard to say exactly how many rejections related to GMP issues the FDA has given out this year. However, a fair number of public companies have reported receiving a CRL that cited manufacturing problems, David Rosen, a partner at Foley & Lardner LLP, told BioWorld.

Meanwhile, the FDA has sent just 10 closeout letters so far this year resolving GMP issues at drug manufacturing plants, compared with 24 closeout letters involving the manufacture of medical devices and four involving diagnostics.

Part of the problem is that a company's response to a warning letter can be "very detailed and voluminous," Rosen said, and it can include a "lot of moving parts." Thus, it may take the FDA considerable time to review the responses and schedule a second inspection, if necessary.

Of the drug-related closeout letters sent this year, the average time from the warning letter to the closeout was more than 20 months. The longest time involved a Feb. 22, 2012, warning letter to APP Pharmaceuticals LLC, which is now part of Fresenius Kabi USA LLC. The FDA closed out that warning letter a few weeks ago.

The shortest closeout for a drug manufacturer took six months. It involved Japan-based Nippon Fine Chemical Co. Ltd., which received a warning letter in September 2016 after being put on import alert. However the time between the inspection, during which a plant official had employees stand shoulder-to-shoulder to prevent the FDA investigator from inspecting parts of the quality control lab, and the warning letter was another nine months.

The wait is even longer on the device and diagnostics side of things, where the average time between GMP-related warning and closeout letters is more than 30 months. China's Omron (Dalian) Co. Ltd. received a closeout letter in June – more than five years after getting a warning letter citing issues related to the manufacture of its blood pressure monitors.

The quickest turnaround for device GMP issues involved Valeant Pharmaceuticals International. The FDA sent the firm a closeout letter in June, just seven months after issuing a warning letter citing quality control problems at the company's Rochester, N.Y., plant regarding Valeant's Small Particle Size Aerosol Generator (SPAG-2), used to administer Virazole (ribavirin), and the Orapharma Onset Mixing Pen. In Valeant's case, the warning letter was sent just a few months after the inspection.

Delayed launches

In its warning letters, the FDA cautions companies that approval of new products may be held up until the issues cited in the letter are resolved. "Companies shouldn't be surprised" by a warning letter or CRL citing manufacturing problems, especially if they've been working closely with the FDA, said Rosen, a former FDA official.

But the letters can come as a surprise to a company that's using a contract manufacturer. For instance, an expected approval of Glatopa 40 mg, a generic of Copaxone (glatiramer acetate injection, Teva Pharmaceutical Industries LLC) developed by Momenta Pharmaceuticals Inc. and Sandoz Inc., was delayed earlier this year when the FDA delivered a Valentine's warning letter to the contracted manufacturing plant owned by Pfizer Inc. The letter stemmed from an inspection that had occurred more than eight months earlier at Pfizer's facility in McPherson, Kan.

In Momenta's second quarter earnings report this month, President and CEO Craig Wheeler said he remained optimistic that Glatopa 40 mg could still launch later this year.

The same Feb. 14 warning letter, which cited contamination problems with sterile drugs at the McPherson plant, resulted in a second CRL for Pfizer's Retacrit, a biosimilar to Amgen Inc.'s Epogen (epoetin alfa), in June – a month after the FDA's Oncologic Drugs Advisory Committee (ODAC) unanimously recommended approval of the biosimilar. No concerns about the manufacturing issues were raised at the ODAC meeting or in the briefing materials for the meeting. (See BioWorld Today, May 26, 2017, and July 14, 2017.)

No compromise

"There's no compromise on product quality," Rosen said, noting that U.S.-based companies are just as likely to get a warning letter as those in other countries. And getting a closeout letter can take just as long, regardless of where a plant is located.

Los Angeles-based KS Choi Corp. received a closeout letter last month, more than four years after it got a warning letter citing its handling of imported acupuncture needles. And Baxter Healthcare Corp. worked with the FDA for more than three years to clear up a warning letter involving a plant in Illinois that manufactures dialysis systems.

The APP Pharmaceuticals plant that was the subject of the 2012 warning letter that took 65 months to resolve is located in New York.

Although they can take years to get, closeout letters are important, Rosen said, adding that drug and device companies need to know that their response to the warning letter is satisfactory. A company may get oral confirmation that everything looks good, but what counts is what FDA investigators see when they walk through the door to reinspect a facility.

To shorten the time to a closeout – or avoid a warning letter altogether – Rosen advised drug and device companies "to really hear what FDA is saying" on the follow-up to an inspection so they understand what the material issues are that can affect the safety, efficacy and quality of their products. They also need to make sure the agency understands what they're saying.