BEN VENUE FAILS TO FOLLOW FDA’s GUIDANCE FOR INDUSTRY RE: STERILE DRUG PRODUCTS (09/04)

A REVIEW OF ADDITIONAL BEN VENUE 483 OBSERVATIONS (5/25/11) 

COMMENT 

A review of additional Ben Venue Form FDA 483 Observations suggests that many of these observations relate to either not following or following incorrectly the FDA’s Guidance for Industry Sterile Drug Products (September 2004).  The Observations that follow include comments regarding where the Company’s documentation either “falls short” or “exceeds” the requirement of the Guidance.   

e. The (b)(4) Product Specific media  manufacturing batch record #1105-08-2125730, dated 9/19/10, document process simulations with manual interventions of the lyophilization pre-chilled vial steps, which is performed prior to the aseptic filling process.  However, the media fill process failed to include the requisite manual interventions established by the ” Media Fill Validation Master Plan” (VMP), document #VMP22709M dated 8/30/10, “Media Fill Program Parameters and Specifications” document #030-SOP-D-29, effective date 01 Jun 2010, and the 9/19/2008 assessment document #RA31208M. The observation is applicable for all (b)(4) product specific media fill processes; 

COMMENT 

21CFR 211.113(b) states that “Appropriate written procedures, designed to prevent microbiological contamination of drug products purporting to be sterile, shall be established and followed.  Such procedures shall include validation of any sterilization process.”  In addition, FDA’s Guidance for Industry Sterile Drug Products (September 2004), SECTION IX. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION, A.  Process Simulations, 1. Study Design states that “Representative number, type, and complexity of normal interventions that occur with each run, as well as nonroutine interventions and events (e.g., maintenance, stoppages, equipment adjustments)” and lyophilization, when applicable be used to include the “requisite manual interventions”. 

f.  The media fill manufacturing batch records do not accurately account for the number of vials that are filled and there is no reconciliation to assure that all media filled vials are accounted for. The CAPA TRK #107148, dated 10/15/10 provides Regulatory Deviation Reports, for example TRK #105923, dated 7/6/10 describes, “During the (b)(4) and (b)(4) day reads it was discovered the documented amount of units received for incubation varied from the amount actually incubated. There is currently no specification for accountability of media filled units.” The TRK chronology of event document a similar concern occurred for (b)(4)  media fills dated from 5/27/10 to 8/20/10. In addition, the aforementioned  accountability for media filled vials applies to the following media fill lots;

i. 12/31/10-#1012-60-2017196, < (b)(4) media filled vials of  (b)(4)

ii. 03/08/11-#1038-71-2036541, <(b)(4)  media filled vials of  (b)(4)

COMMENT 

FDA’s Guidance for Industry Sterile Drug Products (September 2004), SECTION IX. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION, A.  Process Simulations, 8. Incubation and Examination of Media-Filled Units states “appropriate criteria should be established for yield and accountability (reconciliation of filled units).  Media fill record reconciliation documentation should include a full accounting and description of units rejected from a batch”. 

g.  “Media Fill Program Parameters and Specifications” document #030-SOP-0-29, effective date 06 Apr 2011, establish “the test parameters and test specifications required for media fills” and “Each intervention should be documented such that growth positive test results may be appropriately correlated to a designated tray of media filled units.  However, after performing the requisite manual interventions the media filled vials are discarded and not included with the incubated vials. Discarding the media filled vials precludes the company from adequately assessing and assuring that the manual interventions do not create or provide adverse conditions that result in positive media fill vials. (Note: refer to the air flow pattern evaluations and upward movement of air in Observation #7); 

COMMENT 

FDA’s Guidance for Industry Sterile Drug Products (September 2004), SECTION IX. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION, A.  Process Simulations, 8. Incubation and Examination of Media-Filled Units states “Written procedures regarding aseptic interventions should be clear and specific (e.g., intervention type; quantity of units removed), providing for consistent production practices and assessment of these practices during media fills. If written procedures and batch documentation are adequate to describe an associated clearance, the intervention units removed during media fills do not need to be incubated. Where procedures lack specificity, there would be insufficient justification for exclusion of units removed during an intervention from incubation. For example, if a production procedure requires removal of 10 units after an intervention at the stoppering station infeed, batch records (i.e., for production and media fills) should clearly document conformance with this procedure. In no case should more units be removed during a media fill intervention than would be cleared during a production run.” 

h.  The ¹¹ Media Fill Validation Master Plan” (VMP), document #VMP22709M dated 8/30/10 establish, the general approach for developing the media fill schedule and is designed to meet the requirements set forth in procedure 030-SOP-D-29, Media Program Specifications and Parameters.” The procedure establishes the media fill acceptance criteria, for example, 

i.  “When filling fewer than (b)(4)  units, no contaminated units should be detected. One (1) contaminated unit is considered cause for revalidation, following an investigation.”

ii. When filling from (b)(4) units, One (1) contaminated unit should result in an investigation, including consideration of a supplemental media fill. Two (2) contaminated units are considered cause for revalidation, following an investigation,” “, And,

iii.  When filling more than (b)(4) units, One (1) contaminated unit should result in an investigation. Two (2) contaminated units are considered cause for revalidation, following an investigation.”

     However, the preceding objectionable conditions precludes the company from having _ the supporting data to document that they can meet the acceptance criteria established by the standard operating procedure and the VMP Statement of Commitment, “that the aseptic manufacturing process consistently produces product meeting an acceptable level of sterility assurance.”

COMMENT 

FDA’s Guidance for Industry Sterile Drug Products (September 2004), SECTION IX. VALIDATION OF ASEPTIC PROCESSING AND STERILIZATION, A.  Process Simulations, 9.  Interpretation of Test Results states that “recurring incidents of contaminated units in media fills for an individual line, regardless of acceptance criteria, would be a signal of an adverse trend on the aseptic processing line that should lead to problem identification, correction, and revalidation.” 

9.  The sterility failure found on 01/20/10 associated with (b)(4) lot# 2378-44-1157184 {TRK #93890) identified Paenibacillus woosongensisas as the contaminant. This lot was manufactured on 01/25/08 in fill room (b)(4)  the North facility. The environmental monitoring program, from dates 12/10/07 through 07/17/08 identified the recovery of Paenibacillus from Class 100 personnel monitoring and from Class 10,000 area and it was not recovered from the sterility tests isolator. The Senior Microbiologist explained that they believe that the microbial contaminant was due to concerns with the sterility test isolator. The aforementioned locations were not considered as a source for the microbial contamination. 

COMMENT 

There appears to be an inconsistency within this Observation or a misunderstanding as to what the Investigator desired.  It is difficult to understand how a sterility test isolator could create this problem unless the isolator did not maintain its integrity (NOTE: no microorganisms were recovered from the isolator) or the personnel used poor technique since the microorganism, Paenibacillus woosongensisas, was also identified on personnel within the Class 100 and from the Class 10,000 environment. 

11.  The 01/21/11 sterility failure associated with (b)(4) lot #2499-49-2055596 (TRK #111988), identified Propionibacterium acnes as the contaminant. The investigation (TRK #111988) attributes that the anaerobic contaminant came from the isolator gloves, which failed the integrity testing after the sterility tests were performed. However, the environmental monitoring program does not include an assessment for the presence of anaerobes. In addition, a root cause analysis has not been performed to determine the source of the anaerobic microorganism.

COMMENT 

Propionibacterium acnes represents an isolate frequently found as part of the skin microflora.  Few facilities monitor for this microorganism and typically find it within Fluid Thioglycollate Medium (FTM) during sterility testing (see USP<71> Sterility Tests) or during the cultivation of cell culture.  Accugenix, Inc has included this microorganism as one of their “Top Fifteen Bacteria” isolated during 2010 (see my Blog from May 17, 2011).  Even in an ISO Class 5 environment, there is a high probability of finding this bacterium because of the presence of personnel.  Thus, to associate the isolator gloves as the “root cause” of the microorganism is “iffy”, given that no anaerobic environmental monitoring is performed. 

13.  The firm has recovered at least 1,171 microbial contaminants between 01/01/10 and 03/30/11, including 1,047 actions of gram-positive organisms, 108 actions of gram negative organisms, and 16 actions of mold organisms from various locations within the firm’s classified areas, including the Class 100 and Class 10,000 manufacturing areas. However, the firm has not investigated these microbial contaminants to determine the root cause of the contamination, nor have they initiated any corrective action to address the contamination.

COMMENT 

FDA’s Guidance for Industry Sterile Drug Products (September 2004), SECTION X. Laboratory Controls, B. Microbiological Media and Identification states “the goal of microbiological monitoring is to reproducibly detect microorganisms for purposes of monitoring the state of environmental control. 

Characterization of recovered microorganisms provides vital information for the environmental monitoring program. Environmental isolates often correlate with the contaminants found in a media fill or product sterility testing failure, and the overall environmental picture provides valuable information for an investigation. Monitoring critical and immediately surrounding clean areas as well as personnel should include routine identification of microorganisms to the species (or, where appropriate, genus) level. In some cases, environmental trending data have revealed migration of microorganisms into the aseptic processing room from either uncontrolled or lesser controlled areas. Establishing an adequate program for differentiating microorganisms in the lesser-controlled environments, such as Class 100,000 (ISO 8), can often be instrumental in detecting such trends. At minimum, the program should require species (or, where appropriate, genus) identification of microorganisms in these ancillary environments at frequent intervals to establish a valid, current database of contaminants present in the facility during processing (and to demonstrate that cleaning and sanitization procedures continue to be effective).  

Genotypic methods have been shown to be more accurate and precise than traditional biochemical and phenotypic techniques. These methods are especially valuable for investigations into failures (e.g., sterility test; media fill contamination). However, appropriate biochemical and phenotypic methods can be used for the routine identification of isolates.”