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An FDA warning letter to a Pfizer Inc. plant in McPherson, Kansas, where Sandoz International GMBH and Momenta Pharmaceuticals Inc. had decided to outsource fill/finish operations wound up costing them a first-to-market advantage for their generic of Teva Pharmaceutical Industries Ltd.'s Copaxone 40 mg (glatiramer acetate) multiple sclerosis treatment.

That warning letter was "our core challenge in 2017," Momenta CEO Craig Wheeler said during a Feb. 21 earnings call. "The delay of getting Glatopa 40 mg product to the market due to the warning letter issued to Sandoz's fill/finish contractor … coupled with Mylan's aggressive entry into the market in October, make it clear that the level of revenues we had planned for from this product will most likely not be realized."

The expected reduction in revenues from Glatopa 40 mg is a major reason why Momenta is conducting a strategic review of its business "to live within our means, " Wheeler said. This could mean slowing the firm's biosimilars programs and selling assets like the Humira biosimilar it has been developing.

Vasant Narasimhan, who was about to take the reins as CEO of Sandoz's parent Novartis AG, told investors during a Jan. 21 earnings call that the delayed launch of the Glatopa 40 mg generic was one of three big risks for 2018 "that are top of mind for me."

The Choice Of Contractor
The episode strikes home the importance of choosing contract manufacturers that don't have serious, unresolved manufacturing issues like particulates in parenteral drug products, as the warning letter said was the case at the Pfizer Hospira Inc. unit's McPherson plant.

It also underscores the possibility that firms can make missteps in outsourcing without turning to low-cost manufacturing facilities in Asia that have sketchy compliance records. In Sandoz/Momenta's case, they were relying on a facility in the US that had been acquired by a global US-based manufacturer with a reputation for quality.

The February 2017 warning letter stemmed from a June 2016 inspection of the McPherson plant that identified issues with investigations into complaints about particulates. The warning letter cited a continuing inability of Hospira to prevent visible particulates from winding up in parenteral drug products despite multiple complaint investigations. (Also see "Pfizer Suffered 'Significant Loss Of Control' At McPherson Plant, US FDA Warning Letter Says" - Pink Sheet, 28 Feb, 2017.)

The persistence of the visible particulates showed a loss of control of the plant's manufacturing process that put patients at risk, according to the warning letter. What's more, FDA noted that it had identified similar violations at other Hospira plants in four warning letters issued over the previous six years. This suggests that in FDA's view, the problem was not specific to the McPherson plant but rather part of a broader, more difficult to correct pattern throughout Hospira's quality system.

The warning letter did not prevent Hospira from continuing to manufacture Glatopa 20 mg for Sandoz/Momenta at the plant, but it did put a hold on approval of the 40 mg formulation, which the firms had expected to launch that month. (Also see "Pfizer Warning Letter Trips Up Sandoz/Momenta’s Expected Glatopa Launch" - Pink Sheet, 23 Feb, 2017.)

The Reinspection
When Mylan announced Oct. 3 that FDA had approved its generic of Copaxone 40 mg, Sandoz/Momenta were still waiting for Pfizer to resolve the issues raised in the warning letter. (Also see "Surprise! Mylan's Copaxone Generic Sets Teva Up For A Struggle" - Scrip, 4 Oct, 2017.)

During an Oct. 22 earnings call, Momenta CEO Craig Wheeler said Pfizer was reporting significant progress with the remediation and the facility was prepared for reinspection.

In fact, the reinspection was underway.

Wheeler told investors that Momenta and Sandoz had prepared for several possible outcomes of the reinspection: FDA could lift the warning letter or change the facility's status from official action indicated to voluntary action indicated, either of which would allow the agency to grant marketing approval, probably in late 2017 or early 2018. Or FDA could leave the warning letter and OAI status in place.

If the Pfizer manufacturing hold remained in place, Sandoz and Momenta were prepared to switch to another fill-finish contractor they had identified – but this would further delay launch, likely to the second half of 2018.

The Approval

When three investigators completed the reinspection on Oct. 27, they gave the plant a Form 483 report that described 10 observations, and FDA changed the plant's status to voluntary action indicated, allowing the agency's review of Glatopa 40 mg to resume.

The Form 483 report, which FDA's Office of Regulatory Affairs published Feb. 15, called attention to what it termed inadequate investigations into 139 complaints of ineffective bupivacaine HCl with dextrose, 15 complaints of particulates in hydromorphone HCl that turned out to be silicone-related, and one complaint of a hair partially embedded in a vancomycin HCl vial's stopper section.

The 483 also identified issues with visual inspection training, design of labeling equipment, visual examination of reserve samples, cleaning procedures, field alert reporting, complaint follow-up reporting and complaint handling procedures.

Even though there were still issues with complaints, particulates and investigations, the agency was sufficiently satisfied with the extent to which the firm had taken control of the situation to let it proceed with voluntary corrections, and therefore to release its hold on the Glatopa review.

What Now

Sandoz and Momenta finally launched Glatopa 40 mg upon receiving FDA approval Feb. 13. (Also see "Sandoz's Less Frequently Dosed Copaxone Generic Glatopa Hits Teva Two Months Early" - Scrip, 13 Feb, 2018.)

What happens next depends on market factors such as how Teva tries to retain Copaxone market share, how Mylan competes and other factors.

"It's going to take some time to really figure out how this market evolves because it is a second generic entry into the marketplace," Wheeler said. "Everything seems to be going well so far from what we're seeing from Sandoz, but it's going to take some time until we're really clear in terms of the total opportunity here."

One thing is clear, though: that opportunity was diminished by an FDA warning letter to the venture's contract manufacturer.

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