FDA WARNING LETTER TO

ERCROS S.A.

(A glimpse of what not to do

when running a
manufacturing facility.)

When the FDA speaks, you better

listen!

Dear Ms. Cruzado,

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.