TWELVE PAGE, TEN ITEM 483 COMPLEMENTS 483 ISSUED EARLIER IN 2011
Ben Venue Laboratories received a second audit by four FDA investigators from Nov 7 thru Dec 2, 2011 and received a twelve page Form FDA 483 with ten Observations. While several of the Observations were similar to those previously received in the May 2011 audit, new Observations were also noted as part of the audit. The “Media Fill Program Parameters and Specifications” document was reviewed a second time and several of the Observations are again noted within Observation 2 (see “a” through “i”). Other issues include providing a comprehensive environmental monitoring performance for only part of and not the entire manufacturing facility as well as EM Trend data and a failure to identify the source(s) of the contaminants. Still other concerns existed with the Company failing to follow procedures and ensure validation group employees complete required training in a timely period. Please go to the CDER Electronic Reading Room to review the entire FDA 483.
2. The “Media Fill Program Parameters and Specifications” document #030-SOP-D-29, dated 19 Aug 2011 defines media fill as “A process conducted in order to demonstrate the acceptability of aseptic processes from the point of filtration of the product of the completion of the filling and closing of the aseptic container system, including aseptic equipment assembly steps.” The procedure requires “Interventions are planned and performed to ensure that the routine procedures involved in the manufacturing process are supported by the performance of an acceptable media fill.” Routine planned ‘worst-case” interventions are those interventions that occur less frequently but are potential aseptic interventions.” Furthermore, “an employee must have been an active participant in a media fill while completing the intervention which they would be performing during the routine filling operation” and “All employees must perform the interventions associated within their job function Despite the establishment of the aforementioned requirements, the media fill records do not document (b) (4) ” Despite the establishment of the aforementioned requirements, the media fill records do not document that the interventions are performed by all of the individuals listed in the manufacturing batch record (MBR). Rather, the Senior Manager North Facility confirmed that the requisite manual interventions are successfully completed if one of the listed individuals (in the media fill MBR) performs the intervention. In addition,
a. After performing the requisite manual interventions the media filled vials that were within or near area where the manual intervention was performed are discarded (e.g., approximate -of media filled vials) and not (b) (4) included with the incubated vials. There is no record to document that the manual interventions performed during aseptic media fill adequately “demonstrate the acceptability of aseptic processes form the point of filtration of the product of the completion of the filling and closing of the aseptic container system, including aseptic equipment assembly steps”;
b. Discarding the media filled vials precludes the Quality Unit from adequately assessing and assuring that the manual interventions do not create or provide adverse conditions that can result in having microbial and/or nonviable contamination during the aseptic filling process to “ensure that the routine procedures involved in the manufacturing process are supported by the performance of an acceptable media fill”;
c. The Senior Manager North Facility confirmed that the media filled vials within their so-called manual intervention “zone clearance” are discarded and not included with the incubation of the media fill batch. The Senior Manager North Facility confirms that they do not have a scientific rationale to demonstrate how the removal and discarding of the media fill vials following the manual interventions is an acceptable practice in support of the aseptic process;
d. The “Simulation of Aseptic Processes” document #028-0CP-00074, dated 01 Jun 2006 defines interventions as “All interventions that may be encountered during a routine process must be appropriately simulated during any media fill run, for example, line stoppages, shift changes, equipment exchanges or interventions by maintenance personnel.” The corporate procedure does not provide language with respect to the removal and discarding vials following the manual interventions performed within the so-called “zone clearance”;
e. The Senior Manager North Facility explained that during routine aseptic filling operations of finished products there exists a practice of having multiple manual interventions that are occurring simultaneously. The Senior Manager North Facility confirmed that a similar practice is not performed during the aseptic media fill process, which documents that the company is not adhering to the aforementioned corporate wide established written procedure;
f. The routine operations described in the aforementioned observations also apply to the aseptic media fill processes performed in the South and Phase-IV manufacturing facilities;
g. The manufacturing fill equipment (FILLR-FLOS) used for the media fills performed in 2011 for the South manufacturing facilities has not met the periodic requalification;
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