McGuff Pharmaceuticals Inc Warning Letter 12/28/10

McGuff Pharmaceuticals Inc 12/28/10

Warning Letter

CGMP Violations

1. “Your firm’s qualification of the Getinge Model 4300 autoclave and Grieve CLE-500 oven are inadequate in that you have not qualified this equipment with representative loads.  Your firm’s practice is to qualify the equipment using minimum loads as oppose to actual loads during routine operation (e.g., Grieve CLE-500 oven was qualified to depyrogenate glass vials using (b)(4) tray when the actual load is a maximum of 60 trays). 

In addition, your use of biological indicators and penetration thermocouples in the qualification studies are inadequate.  Your firm has not used any penetration thermocouples during the qualification of Getinge Model 4300 since February (b)(4) nor have you incorporated the use of biological indicators.  During the maximum load configuration study, your firm only used a (b)(4) penetration thermocouple and failed to use any biological indicators. 

In your response, your firm commits to evaluate the adequacy of your current procedure, to qualify your minimum and maximum load on each of your manufacturing operations, and to include penetration thermocouples and biological indicators in appropriate areas and in appropriate quantities.  However your response is inadequate because you did not explain how you will determine the appropriate locations and quantities for the thermocouples and the biological indicators.  Since your firm is currently manufacturing sterile drug products using unqualified equipment, your response fails to include any additional controls to assure the quality of your drug products while you are evaluating your current procedures.”

COMMENTS 

Minimum loads do not permit the determination of an adequate cycle for either an autoclave or a dry heat oven.  With minimum loads the cycles are typically shorter in duration and do not assure that all of the containers being sterilized in a full load will receive the intended sterilization time and temperature.    

When an autoclave or oven is validated, the initial tests are performed only with thermocouples to determine the “coldest” spot within each.  Following this confirmation, thermocouples are then distributed throughout both a minimum and maximum load to assure that the “coldest” spot has not migrated because of the autoclave containing components.  The maximum load is validated three or more times to assure the F_o. Following this determination, appropriate Biological Indicators are placed within the units based on a predetermined load pattern and formulated against a Master Autoclave or Dry Heat Validation Plan. In each case, the Biological Indicators should not occlude the components’ pathways.  (Please also see Health Canada “Process Validation: Moist Heat Sterilization for Pharmaceuticals”.)  

Further, use of equipment to continue to manufacture product with components that have been derived from non-validated cycles is unacceptable.  If the validation cannot be accomplished in a rapid fashion (during a shutdown), alternative sources for validated, sterilized product should be sought.