REVIEW OF SELECTED OBSERVATIONS FROM BEN VENUE FDA 483 (5/25/11)

MEDIA FILL OBSERVATION GATHERS 8 “SUBOBSERVATIONS”

COMMENT

Enclosed are the initial four Subobservations from the audit surrounding the Media Fill Program.  Where possible FDA’s 2004 Aseptic Processing Guidance is referenced.  

OBSERVATION 3

The “Media Fill Program Parameters and Specifications” document #030-SOP-029, and the “Outlining Test Parameters and Specifications Required For Process Simulations” document #030-SOP-D-29, effective dates 06 Apr 2011 and 01 Jun 2010, respectively “outline the test parameters and test specifications required for media fills” and establishes the media fill acceptance criteria.  A Regulatory Deviation Report TRK #11 0926, dated 1/4/11 document that “During manufacture of lot 1012-60-2017296 on 12/31/10 in filling suite (b)(4) the minimum count requirement was not satisfied.”  The manufacturing batch record document the media fill consisted of filling (b)(4) vials and the deviation report documents “The batch size for these products is less than the (b)(4)   minimum requirement outlined in the validation protocol. This media is recommended for acceptance.”  Despite the written procedures established in the aforementioned standard operating procedures the media fill was passed and deemed acceptable.  In addition;

COMMENT

FDA’s Guidance for Industry Sterile Drug Products Produced by Aseptic Processing — Current Good Manufacturing Practice (September 2004) states on Page 23, Section IX.  Validation of Aseptic Processing and Sterilizations, A. 4. Size of Runs that “operations with production sizes under 5,000, the number of media filled units should at least equal the maximum batch size made on the processing line.”

a. The “Media Fill Validation Master Plan” document #VMP33709M, dated 9/20/2010, establish the media fill test requirements, which references the rationale for the media fill size” is documented in the “Process Validation Process Simulation Testing Rationale for the Establishment of a Representative PST Size”, document #RAT23509M, dated 06/11/09. The PST rationale establishes “a maximum media fill size on compendial guidance, PDA recommendations and industry baseline information. “However, the aforementioned procedures do not contain language or establish provisions with respect to having less (e.g.,  (b)(4), than the requisite media filled vials (i.e., established by the media fill protocols;

COMMENT

One of the reasons that the FDA is concerned about “having less than the requisite media filled vials” is because there exists a possibility that one of those few less vials used could potentially represent a contaminated vial.  Similar logic is now used to select media fill vials following the 14 day incubation period as opposed to removing vials at the initiation of the incubation period.

b. The “Intervention Conducted During Operations in the Aseptic Processing Area (APA)”, document #030-SOP-D-01155, define intervention as “an aseptic manipulation or activity that occurs at a critical area.” The media fill records lists the manual interventions that are required to be performed by the specified individuals (i.e., job functions). However, 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 MRB) performs the intervention;

COMMENT

Ben Venue creates their own problems in this section by requiring all “specified individuals (i.e., job functions)” to perform all of the interventions listed in the manufacturing batch record.  Most Aseptic Filling Areas require the successful completion of the intervention by a member of the team, not by each member of the team.  Taking the interpretation to excess, while admirable, creates difficulties within the organization if the task is not performed as exactly written. 

c.  A Regulatory Deviation Report TRK #114581 was initiated due to an operator error which occurred during the 3/8/11 Media Fill lot #1 038,.71-2036542 in filling suite #(b)(4).  The documentation for Intervention #14, “Reconfiguration of Trays”, was not performed as required in the Master Production Record “Routine Interventions” section RINT1 OOA, which requires the operator to record the identification number of the “Reconfigure Trays” on the lyophilization chamber shelves after loading said chamber. Concurrently, the original and relocation of the trays were not documented on the Chamber Loading Data Sheet MPR 66L by the operator. The Senior Manager North Facility could not confirm that the operator performed the requisite manual intervention as described in the Master Batch Production Record.

COMMENT

Performance of activities such as the “requisite manual intervention” require documentation.  If the FDA could readily find this lack of documentation, the question remains how many others they did not find.  Wherever possible, the simplification of documents may eliminate these possible problems.

d.  A 1/20/2010 CAPA, TRK# 93875, was implemented to address execution of varied manual interventions (b)(4) specifically defined interventions) performed during aseptic filling operations. However, not all of the personnel that are currently engaged in the manufacture of finished products have completed the CAPA’s requisite training. The number of employees and manual interventions range, for example, from (b)(4) employees performing “stopper bowl change out” and “use trayer plastic to tray vials, respectively (Note: aforementioned examples are not intended to be an all inclusive lists of the number of employees and manual interventions to be accomplished);

COMMENT

This Observation represents a “gray” area where the facilities’ QA management should have “pushed back”.  Just because personnel “are currently engaged in the manufacture of finished products” does not necessarily require them to have CAPA training — unless the facility possesses documentation that states that it is needed.  Quite often personnel training documentation within a facility will indicate which positions require various SOP training.