Lilly is preparing alternate manufacturing facilities for Cialis (tadalafil) to expedite the erectile dysfunction product's launch despite Lilly's GMP problems.

"We believe that Cialis will not be impacted by these issues, as we have contingency capacity that should be coming online that should take manufacturing of the critical path for product launch," Senior VP-Human Resources & Manufacturing Pedro Granadillo said July 18 during Lilly's second quarter earnings call.

Cialis will be manufactured at a facility in Carolina, Puerto Rico. Cialis' finishing was slated to be completed at the dry facility in Indianapolis which is subject to a joint 483 with Lilly's parenteral facility.

When Cialis received an "approvable" letter from FDA in April, Lilly indicated that launch would take place sometime in 2003, but is now projecting a launch in the second half of 2003. The letter asked Lilly/Icos for additional clinical pharmacology studies (¹ Also see "Lilly Cialis Delay Clears Space For Bayer Nuviva: Extra FDA Caution Cited" - Pink Sheet, 6 May, 2002., p. 26).

On the call, Lilly also emphasized its attention deficit hyperactivity disorder drug Strattera (atomoxetine) as another pending product that would not be delayed by manufacturing issues. However, Lilly does appear to expect additional work on the product; the NDA was filed in October, and Lilly expects an action letter in the third quarter, but is projecting a spring 2003 launch. Strattera will be manufactured at facilities in Puerto Rico and Ireland.

Two other late-stage pipeline drugs, the non-small cell lung cancer treatment Alimta and the Zyprexa/Prozac combo OFC, also appear free of manufacturing hang-ups. "Alimta and OFC should not be impacted by these issues because none of the manufacturing will occur at the Indianapolis site," Granadillo said.

However, Lilly noted that FDA's March 2001 warning letter reserves the right to withhold approval for all Lilly drugs. "It is not yet clear whether we will receive FDA approval for any new products manufactured at our other facilities while we are under a warning letter for our parenteral facility in Indianapolis."

The company sees such delays as unlikely. "We have no indication in any of our other conversations with the agency that they are thinking about not approving products that are manufactured at sites outside of Indianapolis," Granadillo said.

FDA's inspection procedures may delay some approvals at the Indianapolis facilities, though.

"Because the FDA issued a combined 483 for the injectable and dry products plants in Indianapolis, it is possible that the FDA may not approve any new products manufactured at this facility until these deficiencies are addressed and the warning letter is lifted," Granadillo said. "The new products that, in fact, could be impacted by this are Zyprexa IM , Cymbalta and potentially Forteo ."

Lilly expects to be prepared for a FDA re-inspection of its Indianapolis manufacturing facilities in early 2003.

Four FDA inspectors examined the facilities for six weeks beginning in April and issued a form 483 citing 50 observations. The company has responded to the concerns and "we believe that we will have the agencies response in the next two to three months."

Lilly is not inclined to enter a consent decree with FDA. "To actively pursue a consent decree is something that we do not feel is in the right and in the interest for the company or the shareholders," CEO Sydney Taurel said. Lilly signed consent decrees with FDA in 1989 and 1995.

"We are talking about deep changes being made in our manufacturing and quality systems. When you operate under a consent decree, you typically have third parties taking part of that responsibility, and that's not the way to affect really controlled change inside of an organization," Taurel said.

Following its 483 in the winter, the company pledged to "affect cultural change" to its manufacturing operations (² Also see "Lilly GMP “Culture Change” Will Address Compliance Issues, Firm Tells FDA" - Pink Sheet, 4 February, 2002., p 34).

The company remains optimistic about FDA's comments. "We believe that we just need more time for the new leadership, the new talent, as well as the new work processors to impact the daily work on the shop floor," Granadillo said.

"They are not necessarily finding new issues," Chief Financial Officer Charles Golden said.

"We had a second inspection in November, and I think that's where the shocks came, where we found that the most important observation was the first one and that was one about quality control department, had not fulfilled its mission," Granadillo explained.

"The habit that we had too often, when we had a deviation [was] to focus our efforts on establishing whether the product was still safe and efficacious, whether the quality of the product was okay, rather than on the what the root cause of the deviation was [and] how to address it."

Granadillo attributed the problems to staff inexperience. "Because of the rotations that we experience at Indianapolis,...the level of the experience tends to be lower. That does not apply to our sites outside of the U.S.," he added.

To solve these problems, Lilly hired 50 scientists and "over 250 professionals into manufacturing and quality organization. These individuals bring over 2,400 years of experience to operations in Indianapolis," Granadillo noted.

"We've made deep changes in the leadership, and, at this point, in all management levels. We've changed 60% of our managers and our executives in the quality area, and more than 50% in the manufacturing area," Golden said.

The company has "also moved scientists from other areas of the company, like product development" into manufacturing, Granadillo noted.

"I think that all of the discussions we've had with the FDA today indicate that we are now on the right track," Golden said.

Lilly initiated recalls related to the Indianapolis facilities, "due to the possibility that a small number of vials could have defects such as low levels of particulates or a small vial crack," Granadillo explained. "This recall is a precautionary measure only, and is primarily in our legacy products and seven lots of Gemzar ." Lilly is not expecting any further recalls.

Lilly Cialis Using Alternate Manufacturing Facilities For 2nd Half 2003 Launch

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