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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Pharmacia & Upjohn 18-Sep-01

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration

466 Fernandez Juncos Avenue

Puerta De Tierra

San Juan, Puerto Rico 00901-3223

September 18,2001

WARNING LETTER

SJN-01-19

CERTIFIED MAIL

Return Receipt Requested

Mr. Fred Hassan

President and Chief Executive Officer

Pharmacia & Upjohn

100 Route 206 North

Peapak, NJ 07097

Dear Mr. Hassan:

From April 3 through July 12 and again on July 30 through August 8, 2001,

investigators from this office conducted an inspection of your human drug

manufacturing facility Pharmacia & Upjohn Caribe, Inc. located at Hwy 2 km 60.0,

Arecibo, PR 00612. Our investigators found the drug products manufactured by your

firm to be adulterated within the meaning of Section 501 (a)(1) of the Federal Food,

Drug and Cosmetic Act. In addition, our investigators found significant violations of

the regulations covering the Current Good Manufacturing Practices for finished

pharmaceuticals as defined by Title 21, Code of Federal Regulations, Part 210 & 211).

These violations cause the drug products manufactured by your firm to be further

adulterated within the meaning of Section 501 (a)(2)(B) of the Federal Food, Drug and

Cosmetic Act.

The deficiencies found during the inspection, and reported on the lists of Inspectional

Observations, FDA-483, presented at the conclusion of each of the inspections include

the following:

Failure to control microbiological contamination in products not required to be sterile as

required by 21 CFR 211.113. On several occasions, finished Glyburide tablets were

released and distributed containing high counts of fungi including Penicillium spp.,

Aspergillus spp, Botryotrichum spp. and Paecilomyces spp. The investigators found

that in 1995, [redacted] lots of Glyburide tablets were contaminated with fungi with counts as high as 320 colony-forming units (CFUs)/tablet. The contamination was traced to [redacted] the used to manufacture the finished product. In 1997, your firm again detected fingi contamination in [redacted] lots of Glyburide tablets with results as high as 140 CFUs/tab, again tracing the source of the contamination to the DCPH used to manufacture the lots. In 2000, your firm founds [redacted] lots of Glyburide tablets to be contaminated with fungi and another [redacted] lots in 2001. In each instance, the contamination was traced to the [redacted] used to manufacture the Glyburide tablets. All 51 lots listed above for released by your firm for commercial distribution.

Failure to perform adequate investigations into the cause of the contamination of the

Glyburide tablets with fungus and to extend the investigation to other lots of Glyburide that were manufactured with the same lot of [redacted] found to be contaminated with

fungi as required by 21 CFR 211.192.

Failure to appropriately sample and test components of as required by 21 CFR 211.84. After, [redacted] a component of Glyburide tablets, was found to contain large numbers of fungi in l995, 1997 and 2000, your firm failed to take appropriate action by sampling ant testing the [redacted] in such a manner that the contamination, if present, would be detected. Subsequently, in 2001, a lot of [redacted] was received and used to manufacture Glyburide tablets and was latter determined to be contaminated with fungi at a level to numerous to count.

Failure to submit a NDA Field Alert Reports as required by 21 CFR 314.81. You did

not submit any NDA Field Alert Reports to the SJN-DO district after you became aware

that Glyburide tablets were contaminated with fungi described above.

We acknowledge receipt of your response dated July 27, 2001 to the FDA-483 dated

July 12, 2001 and your response dated September 6, 2001 to the FDA-483 dated

7/12/01. Our evaluation of the response finds that, except for the items listed above, the

proposed corrections will satisfactorily address the observations if adequately

implemented.

Neither this letter nor the list of inspectional observations is meant to be an all-inclusive

list of deviations at your facility. It is your responsibility to ensure that your facility is

in compliance with the provisions of the Federal Food, Drug and Cosmetic Act and all

applicable regulations and standards. Federal agencies are advised of the issuance of all

Warning Letters about drugs so that they may take this information into account when considering the award of contracts.

Please notify the San Juan District office in writing, within 15 working days of receipt

of this letter, of you response to the violations identified in this letter. Corrective

actions addressed in your letter may be referenced in you response to this letter as

appropriate. Failure to promptly correct these deviations may result in regulatory

action, including seizure, injunction, and/or prosecution, without further notice.

Your reply should be sent to the Food and Drug Administration, San Juan District

Office, 466 Fernandez Juncos Avenue, San Juan, PR, 00901-3223, Attention: Mary L.

Mason, Compliance Officer.

Sincerely,

Mildred R. Barber

San Juan District Office