FDA queries Novocol drug sterility; company follows with voluntary recall.

A 10-page warning letter issued to Schein subsidiary Novocol Pharmaceutical of Canada by CDER=s Division of Manufacturing and Product Quality (DMPQ) questioned whether the firm=s dental anesthetics were sterile as purported. The inspectional findings led DMPQ to recommend placing the products on import alert and disapproval of applications listing the plant as a sterile drug supplier.

Schein followed the Jan. 8 letter with an announcement on Jan. 11 that Novocol would voluntarily recall certain batches and temporarily suspend shipment of the drugs to the U.S., adding that the company was Aworking closely with FDA to resolve these issues as quickly as possible.@

AFDA is extremely concerned about the likelihood of non-sterility of batches of injectable product which are currently in U.S. distribution,@ the warning letter said. Citing Athe urgency of this matter,@ FDA faxed Novocol a copy of the letter on the day it was issued B albeit two and a half months after the inspection concluded.

Citing the shipment of Anumerous lots@ based on retesting after sterility failures, FDA said the Cambridge, Ontario, firm had Alittle or no data@ to justify blaming repeated sterility failures on Ainadvertent contamination while performing the sterility test.@ The agency added that an unreliable laboratory, in itself, constitutes an objectionable condition.

FDA also faulted test failure investigations, asserting that Novocol Afailed to address the correlation between microorganisms found in the manufacturing environment and those found in units which tested positive.@ In addi-tion, the investigations ignored the possibility of personnel contamination, often provided no corrective measures and ignored evidence that pointed to the manufacturing operation as the contamination=s source, FDA said.

The letter identified further deficiencies in the following areas:

* Personnel monitoring. Glove sampling was random and infrequent, with data collected Afor information only.@

In addition, the firm did not trend monitoring data, routinely identify microorganisms and monitor employees who conducted batch sterility testing, FDA said.

* Personnel control. The agency cited gowns that provided inadequate facial coverage, too many people in a proc-essing room during simultaneous filling operations and poor advice to employees following gowning qualification failures.

* Environmental monitoring. Citing a lack of trending, the agency discounted Novocol=s argument that some sur-faces did not require monitoring because the formulation inhibited microorganism growth. Instead, formulations such as mepivicaine showed Asubstantial levels of bioburden,@ the letter said. Further deficiencies involved active air sampling, written sampling procedures and monitoring nonviable particulates.

* Quality control unit. The unit Afailed to prevent the shipment of injectable product lots which appear to have a high likelihood of non-sterility,@ FDA said.

* Sterility test method validation. Bacteriostasis and fungistasis validation did not follow USP monograph require-ments, according to the letter.

* Plant design. Use of a single filling room for multiple filling lines, additional processing functions and storage led to Aunnecessary equipment and extra personnel load@ in a room used for producing injectable products. FDA said the room had been Aa persistent source of microbiological contamination over the last 18 months.@

* Media fill validation. The agency said media fills did not properly simulate the processing operation and acceptance criteria permitted high contamination rates.

FDA considered Novocol=s written response and subsequent updates inadequate. The agency inspected the facility Oct. 19-23, 1998. Ster, OOS, Val