1. The Agency
What the FDA is looking for…

2. Top Ten of 483 GMP
Findings by the FDA
in Fiscal Year 2003

3. The FDA's analysis of the 483s
is very informative, as these
forms are not available on the
Internet.
 In FY 2003, the FDA conducted 259
inspections abroad. 162 of them
ended with the issue of a "483.

4.  The FDA does not consider every finding as so
critical or relevant that it issues a warning letter
(some of the findings are even dismissed!)
 Depending on the analysis, the "deficiency groups"
are defined differently. A missing SOP for the
validation of a water facility can e.g. either be
classified as a "failure to follow and/or document
written production and process control procedures"
or as a deficiency in the "validation" category.
However, this kind of deviation will be less frequent
in the future since recently issued warning letters
always mention the CFR paragraph to which they
refer.

5. #10 reason for 483
"PRODUCTION RECORD REVIEW" (21
CFR 211.192): referenced on 141 of
the 483 forms

6. #9 reason for 483
"COMPLAINT PROCEDURES are not
established or followed" (21 CFR 198
(a)): referenced on 142 of the 483
forms

7. #8 reason for 483
 "LABORATORY CONTROLS" (21 CFR
211.160 (b)): referenced on 163 of
the 483 forms

8. #7 reason for 483
 "PERSONNEL QUALIFICATIONS" (21
CFR.25 (a)): referenced on 166 of the
483 forms

9. #6 reason for 483
 "VALIDATION" (21 CFR 211.110 (a)):
referenced on 173 of the 483 forms

10. #5 reason for 483
 "Failure to maintain complete and
accurate BATCH PRODUCTION AND
CONTROL RECORDS" (21 CFR
211.188): referenced on 178 of the
483 forms

11. #4 reason for 483
 "TESTING AND RELEASE FOR
DISTRIBUTION" (21 CFR 211.165 (a)):
referenced on 183 of the 483 forms

12. #3 reason for 483
"WRITTEN PROCEDURES FOR
PRODUCTION AND PROCESS
CONTROLS" (21 CFR 211.100 (a)):
referenced on 185 of the 483 forms

13. #2 reason for 483
 "RESPONSIBILITIES OF THE QUALITY
CONTROL UNIT" (21 CFR 211.22 (d)):
referenced on 247 of the 483 forms

14. #1 reason for 483
"FAILURE TO FOLLOW AND/OR
DOCUMENT WRITTEN PRODUCTION
AND PROCESS CONTROL
PROCEDURES" (21 CFR 211.100 (b):
referenced on 317 of the 483 forms

15. FDA Warning Letters
http://www.fda-
compliant.net/fda-warning-
letter.html

16. Facility Cleaning
 During the investigator's visual inspection of
the manufacturing facility, layers of dust
and dried white powder were observed on
the surface of the lyophilizer, tables,
compounding tanks, water storage tanks,
filter housing, water purification equipment
and the walls of the building.
 This dust was also observed on various
components of the water purification
system.

17. Clean your facility
 Cobwebs were observed between the
[redacted] C freezer, the walls surrounding
it and the water purification system.
 The investigator noticed a white dried
crystallized powder on the top opening of
the tanks as well as the outside wall of the
tanks. The firm had no designated area for
the tanks to be cleaned properly.
 The firm gave no reply when asked the last
time the facility was cleaned.

18. Maintain your equipment
 Prior to performing process validation of the
lyophilizer in 2004, the firm noticed there
was damage to the equipment.
 More specifically, the firm's process
validation report indicated that the wires on
the lyophilizer were damaged.
 This physical damage was observed by the
investigator during the current inspection.

19. Qualify your equipment
 The firm failed to establish procedures to
ensure that all equipment was appropriately
designed, constructed, placed, and installed
to facilitate use.
 Failure to implement procedures for quality
audits and conduct such audits to assure
that the quality system is in compliance with
quality system regulation. [21 CFR §
820.22]

20. Follow your procedures
 Failure to establish and follow written
responsibilities and procedures
applicable to the quality control unit
[21 CFR 211.22(d)]. For example:
Written procedure 2-032, In-House
Reference Standards, dated 8/27/04,
is not followed. In house reference
standards, which are used in testing
finished product samples, are not
retested annually as required by step
7.3 of the SOP.

21. CAPA
 22 out of 37 failure investigation reports
reviewed did not include corrective actions.
 There is no procedure in place to assure
that corrective actions are actually made
– For report # xxxx, 14 months had elapsed
before the corrective action was actually
implemented

22. Inspectional Observations
(continued)
 The laboratory does not have procedures in place
for tracking and trending laboratory
investigations.
 The investigations do not include
– The corrective actions necessary, nor do they include
a review of batches with similar OOS results, or other
products affected

23. Trending
 The reported assay precision in the
analytical runs was not accurate
because the precision analysis did not
include standards.

24. Failure analysis, CAPA
 The firm does not conduct failure
investigations for every product failure
 During the failure investigation, it was
determined that the analytical method used
was not stability indicating, and therefore
the analytical results were not valid.
 No follow-up, changes or corrective
actions were instituted regarding the
analytical method.

25. Questions