During our July 11-15, 2011 inspection of your active pharmaceutical ingredient (API) manufacturing facility, Ercros S.A. located at Paseo del Delite, 2803 Aranjuez, Madrid, Spain, investigators from the Food and Drug Administration (FDA) identified significant deviations from Current Good Manufacturing Practice (CGMP) for the manufacture of APIs. These deviations cause your API(s) to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 351(a)(2)(B)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with, CGMP. We have reviewed your firms response of August 05, 2011, and note that it lacks sufficient corrective actions.
Problems Explicitly Stated
1. Failure to validate that your water system is capable of consistently producing purified water suitable for its intended use. Began use of the purified water system in November 2004 but did not perform a validation on the system until January 2010!
What needed to be considered when
preparing USP Purified Water (PW) STERILE WATER FOR INJECTION (USP) PREPARED FROM WFI WATER FOR PHARMACEUTICAL PURPOSES (10 CFU/100 ml MAX) ENDOTOXIN (.25 EU/ml MAX) CONDUCTIVITY <645> STERILITY <71> pH <791> (5.0 7.0) PARTICULATE MATTER <788> CHEMICAL TESTS FOR AMMONIA, CALCIUM,CARBON DIOXIDE, CHLORIDE, SULFATE OXIDIZABLE SUBSTANCES
Problems Explicitly Stated
(continued) The 2010 validation conducted was retrospective and included very limited sampling data. Significantly, this 2010 study included data from only one point of use per month over a period of eleven months. The validation failed to include a thorough assessment of elements critical to the performance of the system such as an evaluation of the quality of the water at each step in the (b)(4) process, a thorough evaluation at all points of use, and a complete microbial and endotoxin analysis.
Problems Explicitly Stated
(continued) your response lacks specific methods, acceptance criteria, and does not address whether adequate retrospective data is available to establish that the system maintained daily control. In your response to this letter, please describe more fully the validation of the purified water system that you will perform, and describe how the current water monitoring program (including but not limited to frequency of monitoring) ensures the system produces water appropriate for its intended use for each batch produced by your facility.
Water Systems IQ Considerations
Major System/Controls Hardware Component Verification & Listing
Major Software / PLC Component Verification & Listing Important System Documentation Listing & Verification P&ID & Critical Drawing Walkthrough Ladder Logic / Code Comments & Dead Code Walkthrough Critical Static Configuration Parameter Walkthrough Weld Certificate Review / Verification Materials of Construction Listing & Verification Passivation Records Review (and/or Field Passivity Verifications) Critical Instrument Listing & Calibration Verification Maintenance Procedures & Use Logbooks Listing / Verification Input / Output (I/O) Verification Installed Service Utilities Listing & Verification Spare Parts Listing System SOP Listing, Suitability Review, & Training Verification
Water Systems OQ Considerations
Controls Access Security tests
HMI Screen Navigation tests Controls & Lights tests Sequence of Operations test Sequence of Sanitization Cycle test (manual & automatic; heat vs. chemical) Power Cycle tests (e.g. start, stop, E-Stop, and Power Failure Recovery) Critical Operation Alarms test (e.g. conductivity, temperature, TOC,) Fail/Safe Verifications (e.g. critical sensor failures or equipment faults) Non-Critical (Warning / Alert) Alarms test (if any)
Water Systems PQ Considerations
Daily water sampling from all practical use points with
system running & quality attribute verifications over 2week period. Some companies require 2 such tests. This validates the assumption that the system is capable of producing good quality water. Hold Time recovery test: system down for 72 continuous hours, brought back online / sanitized per company SOP on this subject, and water quality tested. This validates the assumption that the system can recover automatically from worst-case shut-down conditions, e.g. as for maintenance activities.
Water Systems PQ Considerations (continued)
Weekly water sampling & quality attribute
verifications from key use points over a 11-12 month period. This validates the assumption that the established sanitization frequency, response to seasonal, bed change, and other normal use effects, and normal QC water sampling frequency are appropriate for maintaining and monitoring the quality of water generated by the system.