Manufacturing Problems Again Hold Up FDA Approval of Genzyme's Large-Scale Production of Lumizyme

Following a five-week inspection of Genzyme's plant in Allston Landing, MA, the US Food and Drug Administration is still not satisfied with the company's large-scale manufacturing of Lumizyme. The agency issued a complete response letter on Friday afternoon indicating that manufacturing deficiencies at the plant must be corrected before the application can be approved. At the same time, the FDA issued a Form 483 outlining the deficiencies, which were mainly related to fill–finish operations.

Lumizyme (also marketed as Myozyme), the only available treatment for Pompe disease, is approved by the FDA at the 160-L pilot production scale, but Genzyme has been seeking US approval for product made at the 2,000-L commercial scale at the Allston site. Genzyme had to submit a new BLA because of differences in the carbohydrate structure between the product manufactured at 2,000-L and 160-L scales.

Genzyme no longer wishes to manufacture Lumizyme at the 2,000-L scale at Allston, however. That plant was temporarily shut down this summer for decontamination following the detection of bioreactor contamination with Vesivirus. That shutdown led to shortages of Cerezyme and Fabryzyme, two of the company's other drugs.

"It's clear to everybody that producing Lumizyme or Myozyme in the Allston plant is not the right decision, because we want to focus that plant on Cerezyme and Fabryzyme," said Genzyme CEO Henri Termeer during a conference call yesterday. "Actually, the introduction of the production of Myozyme in Allston was a very significant factor in the complications that we have experienced there."

Instead, Genzyme will request a meeting with the FDA to discuss the fastest path to US approval of Lumizyme produced at the 4,000-L scale at Genzyme's facility in Geel, Belgium, which already supplies the drug to other markets. That plant, and the company's fill–finish facility in Waterford, Ireland, both recently passed FDA inspections.

Addressing the fill–finish deficiencies at Allston, including particulate contamination concerns announced on Friday, will be a multistep effort, explained David Meeker, MD, an executive vice president at Genzyme.

For the near term, the company will temporarily halt filling operations at Allston to update equipment and implement additional internal controls.

Meeker said the particulates came from metal-on-metal contact in older equipment, so the company will replace components where that contact occurs. "The technology continues to improve, so the replacement parts that we are bringing in now will, we believe, decrease the amount of particles that are shed," he said. They are also enhancing vial inspection procedures. "We currently inspect 100% of the vials, but there are things we can do to make that process even more robust," he said.

Meeker emphasized, however, that the particulates can be removed by filtering the product before administration. "That's why our communication to the [medical] community was very focused on reinforcing the label, which says that these vials should be inspected and a filter should be used," he said.

In the medium term, Genzyme will seek to expand filling at existing contract manufacturers and use some excess filling capacity at the company's own facility in Waterford, Ireland.

For the longer term, they are expanding filling capacity in Waterford. A new filling line is already being tested there, and engineering runs on the new line are expected to be carried out in the first quarter of 2010.

The other observations in the Form 483 were mainly related to items such as documentation and training, Meeker said.

"These are elements that we knew about . . . [and] had developed a comprehensive plan and had submitted that plan to the FDA in advance of their inspection as part of our overall remediation effort," he said, adding that the FDA had shown "a strong willingness" to work with the company to continue to address these issues.

The agency also asked for additional documentation around the decontamination procedure used to address the Vesivirus contamination of the bioreactors, which he said the company will provide.

"There was nothing about the other 483 items that should impact our ability to produce [drugs]," he said.

Previous coverage:

FDA Warns of Genzyme Product Contamination

Gaucher Patients Can Be Treated with Protalix's Drug During Cerezyme Shortage

Protalix's Gaucher Drug May Fill Gap Left from Genzyme Plant Closure

Genzyme Detects Virus Contamination of Bioreactor, Halts Production