STILL ANOTHER INDIAN FIRM IS CITED FOR ITS MANAGEMENT OF ITS ISO 5 ENVIRONMENT (8/09/13)

 

EXTENSIVE CORRESPONDENCE STILL RESULTS IN A WARNING LETTER

During the time frame of March 25, 2013 through April 3, 2013 the FDA inspected Promed Exports Private Limited located at Promed Exports Private Limited, Khera Nihla Village, Tehsil Nalagarh, Solan District, Himachal Pradesh, 174101, India.  Investigator(s) from the U.S. Food and Drug Administration (FDA) identified significant violations of current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations caused the drug product to be adulterated.

The investigator(s) observed specific violations during the inspection, which included the following:

1.    “Your firm failed to establish adequate systems for monitoring environmental conditions and for cleaning and disinfecting the room and equipment in aseptic processing areas (21 CFR 211.42(c) (10)(iv)and (v)).

1. The aseptic processing environment is not adequately monitored.  For example, there is no viable air monitoring inside of the Class 100 (ISO 5) filling barrier on the “(b)(4) Line (b)(4).”  This is the critical area where drug product and pre-sterilized components are exposed and it is important that your firm collect air samples that adequately represent filling conditions.”

COMMENT:

Within an Aseptic Processing Area (APA), the ISO 5 environment should be monitored in at least three critical locations to include a) where the vials/bottles are positioned to be filled, b) where the vials/bottles are being filled, and, c) where the stoppers are inserted into the necks of the vials/bottles.  If the product will be sold only within the EMA, no requirement exists for active monitoring – only for passive monitoring. 

Please review the FDA-guidance entitled Sterile Drug Products Produced by Aseptic Processing – Current Good Manufacturing Practice (September 2004) located at the following link: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM070342.pdffor additional background. 

Moreover, outside of the line (b)(4) filling area, the three air samples taken in the Class 100 (ISO 5) area were not taken under dynamic conditions. These active samples were instead taken after line set-up and before any filling.

COMMENT: 

Taking samples after set-up and before any filling represent only the “tip of the iceberg”.  Total airborne viable and non-viable particulates should have monitoring initiated at time of set-up and not cease until only the individuals completing the sampling remain is the ISO 5 environment.

We are concerned that the environmental monitoring (EM) program is not adequate to ensure the environment is suitable for aseptic processing of sterile product. The data generated does not sufficiently demonstrate that an ISO 5 environment is maintained.

In your response, you commit to improving sampling in your aseptic operation lines.  Specifically, you commit to revising the environmental monitoring procedures for aseptic processing lines (N/QC/066 and N/QC/180) to add the requirement of the performance of extensive EM. Additionally, you commit to re-establish the sampling locations of the EM program, to provide a scientific rationale for the selection of appropriate EM sampling, and to routinely review the EM trend data from a holistic, risk-based perspective. In response to this letter, provide a copy of the summary report identifying the critical active air sampling locations and their frequency.

COMMENT: 

A Risk management, scientific based rationale is required before any sampling is performed.  In addition, background sampling is often required before the revision of any environmental monitoring protocol to assure that the viable and non-viable airborne testing that will be implemented can be demonstrated to have validity.  

1. Your firm did not use a sporicidal disinfectant for cleaning inside of the Class 100 (ISO 5) filling areas. The inspection documented that your firm uses (b)(4) ((b)(4)) alone, which is not effective against spore-forming organisms such as Bacillus spp. The September 2011 media fill failure investigation for the (b)(4) Line (b)(4) identified the contaminating organism as Bacillus pumilus. Additionally, you did not sufficiently evaluate the disinfectant (b)(4) on surfaces inside the Class 100 (ISO 5) area including (b)(4).

Your response indicates that the disinfectant procedure will be revised to include using a sporicidal disinfectant agent on a (b)(4) along with (b)(4) to clean and disinfect the machine parts in the Class 100 (ISO 5) filling area and that you scheduled qualification completion for May 2013.  Please note that it is essential that the sporicidal agent be used regularly to ensure a suitable ISO 5 (Class 100) environment.  Additionally, you indicate that (b)(4) will be evaluated on the other surfaces in the Class 100 (ISO 5) filling area.  In response to this letter, provide a copy of the disinfectant program qualification reports for the (b)(4) and the sporicidal agent to adequately address all surface types in the Class 100 (ISO 5) filling area.

COMMENT: 

Too frequently, investigators find that firms that are working within an APA are using sanitizers/disinfectants that will not kill spore-forming bacteria and fungi.  In addition, the use of a sporicide without the use of a cleaner prior to the sporicide is required to assure that the sporicide will function as required.  All that is required is a thin film to prevent a sporicide from properly functioning. 

The investigators also indicated that other surfaces should be examined to demonstrate that all surfaces may meet the disinfection/sporicidal properties.  While this seems like a simple task, small details to include the size of the coupon, the drying of the sample, the method of application of the microorganism as well as its concentration are areas that require understanding prior to developing a protocol.  With upwards of a half dozen surfaces requiring testing as well as both ATCC and “house bugs” involved at various application times, this simple appearing test can become quite involved and often is required to be repeated if not performed satisfactorily the first time.