Idec is considering using a third-party certification as a short cut to resolving FDA's remaining questions about Catalytica's fill/finish manufacturing process for the lymphoma therapy Zevalin .

The biotech company believes that Lilly may have gone the third-party certification route to receive final approval for the sepsis agent Xigris , which is also finished at the Catalytica facility.

"Certification from a third-party company would be sufficient and a good surrogate for re-inspection," Idec CEO Bill Rastetter, PhD, told a Jan. 9 conference call. Manufacturing issues are the only remaining items holding up approval of Zevalin, Idec said (see ¹ Also see "Idec Zevalin Approval Delayed By Manufacturing Issues At Catalytica" - Pink Sheet, 14 January, 2002.).

"The potential alternative to re-inspection was suggested by the agency, perhaps because they used this for Lilly," Rastetter said.

The Idec CEO emphasized that he does not know whether Lilly used the third-party certification. "I have asked on three different occasions for information on that from the agency. Appropriately, since it is a different company's product, they have not commented."

"From the so-called 'approvable' letter to the actual approval was...five or six weeks," he said. Xigris was approved Nov. 21 after a "complete response" letter dated Oct. 26 citing unresolved manufacturing issues (² Also see "Lilly Xigris Price Is $6,800 Per Dose; Sepsis Agent Clears FDA" - Pink Sheet, 26 November, 2001., p. 34).

The rapid turnaround on Xigris appears remarkable, given the number of manufacturers claiming to have supply problems resulting from GMP issues at Catalytica. Lilly, however, says it did not need a reinspection or a third-party certification for final approval of Xigris. The company says it submitted the information requested by FDA in its complete response letter and received approval.

Four different manufacturers (GlaxoSmithKline, King, Falcon and Abbott) report having supply difficulties as a result of the Catalytica problems.

The problems stem from DSM Catalytica's September 2000 discovery "of insufficient documentation practices by an analyst at its Greenville, N.C. facility," the company said. DSM acquired Catalytica in August 2000 (³ Also see "DSM Entering U.S. Via Catalytica: European Bulk Firms Going Global" - Pink Sheet, 14 August, 2000., p. 17).

"Within a week of [DSM's] notice, FDA visited the Greenville site and eventually in late January 2001 issued a warning letter," the company said. The company says it "did not have to stop production as a consequence of the warning letter." Catalytica was also the subject of a warning letter in 1999.

The Zevalin pre-approval inspection took place July 23-Aug. 30, and resulted in an FDA 483 report.

"We and Catalytica put together answers to the Catalytica 483 and submitted them to the agency," Rastetter said. "As far as we know, those responses are acceptable to the agency."

However, beginning in September, Catalytica began "substantial compliance and validation upgrades that were triggered by a third-party compliance expert," KMI, he said. The changes related to "all products and all operations at Catalytica."

From September through December there was a "tremendous amount of work and focus in that organization on things like environmental monitoring, rewriting of SOPs...fill-line revalidations, and so forth," Rastetter continued. "In essence, the organization that exists today at Catalytica is a different one, even in terms of some of the upper management in the organization, than existed in August when it was reinspected."

Production of Zevalin was halted from September to December during the upgrade of the facility, but Catalytica began manufacturing the product again in January, Idec said.

"We are back in manufacturing of Zevalin and Zevalin components, because we, [KMI] and Catalytica believe that manufacturing...is currently being done under compliance with GMP," Rastetter said. "We believe most of the compliance upgrades and validations...are behind us and were accomplished during the shutdown in the fall and early winter of 2001."

The third-party certification approach would rely on FDA's level of comfort with KMI, Rastetter indicated. "I guess the agency's view seems to be, 'hey, these guys are people that we know, they are staffed by a lot of ex-FDAers that we trust. They are going to know that organization and the systems better because they have been living there.'"

"There may be a possibility - it was suggested to me yesterday - of doing something by certification where they are rock solid, hard, done-deal things, and then to use inspection for things that are still in development...where certain post-approval commitments can be made," Rastetter said.

He observed that the Xigris approval included "many, many such post-approval commitments as it relates to Catalytica."

The production disruption during the fall appears to have affected a number of Catalytica's partners. Apart from the brief delay in final approval, Lilly says it has not had any difficulties at Catalytica.

GSK, however, reports that it has experienced some disruptions in the supply of products from Catalytica. The Greenville facility was a former Glaxo Wellcome plant that Catalytica acquired in 1997, and Catalytica produces oncologic, antiviral, and CNS drugs for GSK.

King Pharmaceuticals says that fill-finish manufacturing of their Cortisporin products at Catalytica will recommence by Feb. 1. Catalytica informed King on Jan. 8 that the production problems, which prompted recalls of King's products, have been addressed.

Production of Cortisporin (neomycin/polymyxin B/hydrocortisone) products were halted late last year following several company-initiated recalls: a Nov. 26 Class II recall on Cortisporin ointment for subpotency in the polymyxin B sulfate component; and Dec. 18 recalls of the otic suspension/solution and the ophthalmic suspension products due to a lack of sterility assurance.

King says that because Cortisporin products are generally in higher demand in the summer, the company is less concerned about the temporary stoppage in production during the winter. Cortisporin products are approved to treat bacterial infections and irritation of the skin, ear and eye.

Generic manufacturer Falcon Pharmaceuticals has also experienced problems with the Catalytica facility.

Falcon's neomycin/polymyxin B sulfate and hydrocortisoneotic suspension and solution products were recalled Dec. 19 due to a lack of sterility assurance and because a batch of bottles was damaged during shipment.

Two injectable general anesthetics made for Abbott at the Greenville plant were also recalled. Abbott initiated a recall of Nimbex (cisatracurium) and Mivacron (mivacurium) on Dec. 7 because of sterility concerns.

Catalytica Manufacturing Problems Cited In Recalls, Approval Delays

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