Pfizer revalidates systems to become compliant following 70-item 483 for Pharmacia Sweden facility.

Pfizer last year revalidated its computers and "instituted. a corporate-wide program to upgrade aseptic manufacturing operations in all our plants" following a blistering 2000 inspection of then-Pharmacia facilities in Sweden, which FDA audited prior to the Pfizer-Pharmacia merger.

Referring to the 2002 follow-up audit, Pfizer spokesman Bryant Haskins said in an interview that the upgrade of aseptic processing "included new equipment and processes as well." He said the plants, which were making active pharmaceutical ingredients (APIs), were all given a clean bill of health by FDA following the 2002 follow-up visits.

According to the 483 and EIR of the 2001 inspection, Thomas Arista and chemist Robert Tollefsen from the Center for Drugs Office of Compliance, visited facilities in Strangnas, Brunna and Stockholm. The audit, initially carried out to investigate four NDAs, resulted in a 42-page, 70-item 483 and a January 2001 warning letter (Doc. 9911W).

According to the documents, Pharmacia was cited for deficiencies ranging from changing stability conditions without notifying FDA, failure to keep commitments in NDAs, and numerous software and documentation deficiencies.

Highlights from the 483 include:

* The firm's Quality Unit failed to perform a comprehensive review "to adequately address many of the established operations and supporting data that are used to support the production operations for Caverject, Cyklokapron, Genotropin and Fragmin.

* "Failure to keep commitments in New Drug Applications." Specifically, the 483 stated that with respect to NDA 20-287, Fragmin solution for injection 10,000 IU product, an amendment commits to change stability storage conditions by changing humidity levels. However, stability samples for an unnamed batch were "found maintained in a stability chamber, which does not control humidity."

* The networked computer system used for manufacturing Caverject, Cyklokapron, Genotropin and Fragmin, and used by QA for the control/release of raw material and finished API had numerous validation issues raised. The program is used at the Strangas, Stockholm, Uppsala, Helsingborg and Brunna facilities, and is not controlled via revision number. Although significant changes and modifications have been made to the system since 1985, complete system design documentation has not been maintained or updated throughout the life of the software. Ten objectionable conditions related to maintenance of software, including design specifications not maintained, functional design, program code documentation, and diagrams and text descriptions were cited.

* "Change control documentation was found lacking indication of review or approval." For example, change control forms utilized to initiate changes were found, which had been sent electronically, with no electronic or hard copy signatures.

* Validation was incomplete or missing with respect to the firms system that connects all Local Area Networks (LANs). Examples of functions performed by these applications include recording and approval of testing data, materials management functions to include approval/rejection of raw materials, in-process materials and finished API. Complete system definition documentations was not maintained and the quality unit "failed to ensure that procedures are in place, which define all system definition documentation," the 483 stated.

* LANs that connect local manufacturing, testing and warehouse departments at each site were not validated. For example, the quality unit failed to put procedures in place to ensure that LANs for each site were controlled. The firm produced no approved LAN diagrams identifying all sites and equipment on the LAN, and LAN site listings were not maintained or controlled, the 483 stated.

* Validation documentation failed to include complete and updated system design documentation. The 483 also stated that validation documentation failed to include complete wiring and network diagrams to identify all computers and devices connected on the system.

* Regarding qualification of the stability chambers, the room designated for storing samples all three Fragmin NDA 20-287 products, was not qualified. For example, no temperature distribution studies were conducted. In another example, a stability room designated for Genotropin also was not qualified for the same reasons stated above.

* Raw data of standard preparations for the monthly stability tests for Genotropin were found being recorded directly into a computer that was not "protected in that analysts using this equipment utilize shared usernames and passwords."

* For stability testing operations at Uppsala for Caverject and Fragmin API, qualifications for the stability room where samples were stored had "no approved study protocols." Additionally, the qualification report did not define the loaded conditions of the room at the time when qualifications were being performed.

* For filling operations at Uppsala, for the Gentropin product, the filled non-stoppered or partially stoppered containers "are not kept under Class 100 conditions during the transfer process." For example, the transfer cart that transports the cartridge "does not provide controlled conditions to prevent the ingress of viable or non-viable particles from entering into the transfer cabinet." Nine other such examples related to environmental conditions in aseptic areas were listed on the 483.

Other deviations regarding filling operations at Uppsala were cited, including employees failing to wear facial covers in filling areas and to remove gloves in between procedures to avoid cross contamination.

Documents stated that the filling equipment's computer retained equipment errors that occured during filling operations; however after the filling operations, "the computer information is 'overwritten.'" As explained, the electronic data was not kept due to the storage capacity of the equipment's hard drive. In addition, there was no written established procedure that describes an evaluation process of the equipment error "in order to determine the more frequent or problematic filling operation equipment errors."

The 483 also stated that there was no approved list of individuals or users who have access to the equipment computer control system. Nine more examples of electronic data issues concerning the filling area system follow in the 483.

Numerous alarm documentation deficiencies are cited in the 483 that include failure to put procedures in place to review alarm printouts, failure to include the year on the date the alarm occurred and incorrect dates on alarm printouts.

In addition, observations involving validation of the monitoring system used for filling areas for finished products were cited on the 483. For example, the system was initially validated and approved in January 2000; however, due to a computer system failure, the system was reconfigured in March 2000 and no additional test was performed that demonstrated that the March 2000 configuration did not adversely affect the initial validation of the system.

In the interview, Haskins said said with respect to the computer validation issues raised, the firm revalidated some systems and replaced others to be compliant.

The other major issue raised by FDA in the 2000 inspection, focused on cross-contamination that was related to a penicillin manufacturer located next to the Stockholm plant. To deal with that issue, Haskins said Pfizer monitored and tested for contamination and found none, but still made some changes to prevent cross-contamination. The plant also relocated, which made it a non-issue anyway, Haskins said.

Pharmacia, Stockholm, Sweden, 6/27-7/12/00, Doc. 109433M, $23.00 plus retrieval.

[check] The Checklist--Pfizer

[check] computer validation deficiencies

[check] failure to keep commitments in NDA's

[check] stability conditions

[check] validation documentation deficiencies