Allergan gets green light after pre-license probe.

Allergan BOTOX, Westport, Ireland.

An announced pre-license inspection of Allergan BOTOX turned up three reportable observations, each of which the company was able to correct to clear the way for production of final dosage forms of botulinum toxin Type A (BOTOX) for marketing in the U.S., recently released inspection documents show.

The EIR noted that the plant used two lots of bulk toxin in its production, only one of which was approved for use in the U.S. Center for Biologics Investigators Julia Gorman and Ann Sutton stated in the report that the firm had taken precautions to avoid mix-ups between its two stock concentrates.

The firm had planned to produce a BOTOX lot from bulk toxin during the inspection, which FDA conducted in October 1995. However, the formulation had to be aborted when a biosafety hood went into alarm status, the EIR said.

Although the alarm stopped after some alcohol used in cleaning evaporated, - Allergan decided to avoid possible disqualification of the lot by switching to production of a saline placebo instead, the report said.

However, Gorman and Sutton still were able to observe compounding, filling, loading and unloading of the lyophilizer, capping, ink jetting and off-loading, the EIR said.

The document added that Allergan had suffered a "mass contamination problem" in May 1995. A company probe blamed faulty construction of a sink in an area used for producing Vitrax, an ophthalmic surgical device. Chemicals used as surface disinfectants became contaminated, spreading microorganisms throughout the plant, the EIR said.

Allergan corrected the problem by fixing the sink and sterile-filtering the disinfectants before use, the report stated.

One item on the 483 was an identity test that could identify botulinin toxin, but could not distinguish between each of the two stock concentrates. During discussion with management, Sutton suggested re-examining process controls to ensure that BOTOX from the two concentrates was manufactured separately, the EIR stated.

Sutton also suggested including the product code on unlabeled vials to undergo identity testing and requesting an "equivalent method waiver of the requirement for a specific final container identity test," inspection records said.

Allergan agreed to include a product part number on the vials as part of the ink-jet imprint and modify its SOP to specify when during inspection the imprint should be verified, the EIR said.

The investigators also found reagents labeled with incorrect expiration dates, a situation corrected during the inspection, the EIR added.

It took FDA six months to reach a decision on the firm's corrective actions. While Allergan and its contract testing lab, Biological Laboratories Europe, each submitted responses to the 483 in November 1995, the memo from Gorman and Sutton did not come until in April 1996, recommending consideration for licensure.

Allergan BOTOX, Westport, Ireland, Oct. 16-20, 1995, Doc. 107805M, $10.50 plus handling.