Mobile Edition
Print
Get the Mag
Weekly UpdatesNovartis Vaccines and Diagnostics, Marburg, Germany CBER
The FDA inspection team of Omotunde Osunsanmi, Mihaly Ligmond and Robin Levis surveyed operations at Novartis Vaccines and Diagnostics in Marburg, Germany, Oct. 15-23, 2008, issuing a 15-item 483 at the close of inspection for multiple problems in its quality and laboratory control systems, cleaning and production issues.
The FDAers found that the company had no justification for using a type of analysis to change a result for the validation of rabies vaccine processing times that had been previously classed as "failed to pass." A deviation report indicated that after the validation failed to pass it was then approved and "no further actions were initiated in regard to product impact assessment." The inspectors reported that, in regard to Novartis' investigation into the vaccine process time validation, a company official stated that "the validation process was incorrectly written and executed; as such, quality assurance oversight, including the review and approval of the written protocol, the execution of the protocol and approval of the final validation report is inadequate."
FDA found that the company's "corrective action to prevent future and similar deviation occurrences is deficient in that the only CAPA opened was to check if validation can be marked in the system. However, there is no documentation that additional CAPA has been opened, or corrective/preventive actions initiated that will formally address future occurrences of the QA oversight of product validation issues."
An initial investigation into metallic particles found on the tops and undersides of filled rabies vaccine stoppers was incomplete "and not conducted in a timely manner," the 483 stated. The problem was first documented Jan. 26, 2008, when 100 vials were rejected. No investigation took place until after 241 vials were rejected on Feb. 21, 2008. Although several investigations were conducted, none was undertaken "to determine the presence of particles in the product or on the undersides of the stoppers" which would be exposed to the product in the vials. A later in-depth investigation begun in April found that the metallic particles on the undersides of the stoppers could potentially have contaminated the vaccine.
The FDA team also observed that rabies vaccine deviation investigations were not always conducted or closed within the established limit of 30 days, and in some cases CAPA to prevent future occurrences of such deviations were not implemented in a "timely manner." There was no set time frame for completion of product deviation CAPAs, the report noted.
Manufacturing procedures did not reflect actual procedures in use, the FDAers wrote. For example, the written standard procedure for handling eggs, which details storage conditions and times for eggs, had not been updated following a change in the procedure.
An investigation into action level excursions of burkholderia in tetanus toxoid "did not specifically discuss an evaluation of product impact in regard to endotoxin," the FDA team wrote. "No evaluation was documented as to the impact (other than microbiological) the presence of this may have had."
A product impact assessment into failed aseptic media fill, which resulted in two contaminated filled vials, was inadequate to assure the sterility of the products filled since the previous aseptic media fill simulation. "There was no documentation that the sterility, animal release testing, complaints and adverse events of any of the affected lots that were manufactured since the previous media fill simulation were reviewed to assure the sterility of distributed products," the FDAers observed.
The firm's pharmacovigilance unit requested a medical review of previously assessed adverse events from October 2007 through August 2008, "to identify cases of potential transmission of infectious agent due to a failed media run which might have affected the released lots." That report determined that all the AEs involved "extended injection site reactions and do not provide evidence for manufacturing-related issues." However, the 483 noted, three AEs were found--one involving an injection site abscess and two cases of injection site inflammation--that were not originally identified and investigated in relation to the media fill failure.
The investigators also found that at the end of a media fill simulation conducted in February 2007, "the staff detected a slight clouding" in some of the medium remaining in the bottle. The report stated that there was "no justification for the invalidation of the aseptic media fill simulation" in this case and, further, that the media fill was inadequate because "only two additional media fills were conducted. Three additional aseptic media runs were not performed to assure the sterility of the products that were filled on the filling line since the last aseptic media fill."
Three out of six media/buffers from a total of eight used in rabies vaccine manufacturing that were reviewed during the inspection had not been adequately validated, the FDAers stated. The storage container used in one hold time study was not the same as the container currently used, and another hold time study failed to meet acceptance criteria. There was no validation hold time study for the diptheria fermentation process, the team added.
No documented assessment supporting the container/ closure system used for sterile tetanus toxoid concentrate had been performed, the FDA inspectors observed. Further, no container/closure validation studies had been conducted to justify the expiry for a different type of container in which the tetanus toxoid concentrate is held. The small-scale containers used in a separate study to justify storage of tetanus toxoid concentrate without preservative were not representative of the type of bottle in which the product was actually stored.
No validation of the mixing process for diptheria and tetanus toxoid concentrates had been performed to justify the mixing of these products in a vessel. "No other documented mixing of the sterile tetanus material is performed" before it is dispensed, the report stated.
During setup for aseptic filling of Menjugate vaccine, the FDAers observed an operator in the area "with exposed skin near the chin. After the operator was informed of the gowning issue, the operator was observed to pass through" another area to leave the room and adjust the gowning.
FDA found that Novartis did not maintain adequate control of reagents and standards in its quality control laboratories. For example, one lot of beta-propriolactone was rejected due to a failed test for content, but a bottle of material from this lot was used in the QC laboratory as a standard for several months.
No validation had been performed or was ongoing regarding the maximum number of uses of filters used in purification operations. Cleaning validation had not been done for the lifetime of these or other filters used in a different application, FDA observed.
FEED