The AgencyWhat the FDA is looking for…
Top Ten of 483 GMPFindings by the FDAin Fiscal Year 2003
The FDAs analysis of the 483sis very informative, as theseforms are not available on theInternet.     In FY 2003, the FDA...
   The FDA does not consider every finding as so    critical or relevant that it issues a warning letter    (some of the ...
#10 reason for 483"PRODUCTION RECORD REVIEW" (21  CFR 211.192): referenced on 141 of  the 483 forms
#9 reason for 483"COMPLAINT PROCEDURES are not established or followed" (21 CFR 198 (a)): referenced on 142 of the 483 forms
#8 reason for 483   "LABORATORY CONTROLS" (21 CFR    211.160 (b)): referenced on 163 of    the 483 forms
#7 reason for 483    "PERSONNEL QUALIFICATIONS" (21    CFR.25 (a)): referenced on 166 of the    483 forms
#6 reason for 483   "VALIDATION" (21 CFR 211.110 (a)):    referenced on 173 of the 483 forms
#5 reason for 483   "Failure to maintain complete and    accurate BATCH PRODUCTION AND    CONTROL RECORDS" (21 CFR    211...
#4 reason for 483   "TESTING AND RELEASE FOR    DISTRIBUTION" (21 CFR 211.165 (a)):    referenced on 183 of the 483 forms
#3 reason for 483"WRITTEN PROCEDURES FOR PRODUCTION AND PROCESS CONTROLS" (21 CFR 211.100 (a)): referenced on 185 of the 4...
#2 reason for 483   "RESPONSIBILITIES OF THE QUALITY    CONTROL UNIT" (21 CFR 211.22 (d)):    referenced on 247 of the 48...
#1 reason for 483"FAILURE TO FOLLOW AND/OR  DOCUMENT WRITTEN PRODUCTION  AND PROCESS CONTROL  PROCEDURES" (21 CFR 211.100 ...
FDA Warning Lettershttp://www.fda-compliant.net/fda-warning-letter.html
Facility Cleaning   During the investigators visual inspection of    the manufacturing facility, layers of dust    and dr...
Clean your facility   Cobwebs were observed between the    [redacted] C freezer, the walls surrounding    it and the wate...
Maintain your equipment   Prior to performing process validation of the    lyophilizer in 2004, the firm noticed there   ...
Qualify your equipment   The firm failed to establish procedures to    ensure that all equipment was appropriately    des...
Follow your procedures   Failure to establish and follow written    responsibilities and procedures    applicable to the ...
CAPA   22 out of 37 failure investigation reports    reviewed did not include corrective actions.   There is no procedur...
Inspectional Observations(continued)   The laboratory does not have procedures in place    for tracking and trending labo...
Trending   The reported assay precision in the    analytical runs was not accurate    because the precision analysis did ...
Failure analysis, CAPA   The firm does not conduct failure    investigations for every product failure   During the fail...
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3 top ten fda warning letter findings by the

  1. 1. The AgencyWhat the FDA is looking for…
  2. 2. Top Ten of 483 GMPFindings by the FDAin Fiscal Year 2003
  3. 3. The FDAs analysis of the 483sis very informative, as theseforms are not available on theInternet.  In FY 2003, the FDA conducted 259 inspections abroad. 162 of them ended with the issue of a "483.
  4. 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. 5. #10 reason for 483"PRODUCTION RECORD REVIEW" (21 CFR 211.192): referenced on 141 of the 483 forms
  6. 6. #9 reason for 483"COMPLAINT PROCEDURES are not established or followed" (21 CFR 198 (a)): referenced on 142 of the 483 forms
  7. 7. #8 reason for 483 "LABORATORY CONTROLS" (21 CFR 211.160 (b)): referenced on 163 of the 483 forms
  8. 8. #7 reason for 483 "PERSONNEL QUALIFICATIONS" (21 CFR.25 (a)): referenced on 166 of the 483 forms
  9. 9. #6 reason for 483 "VALIDATION" (21 CFR 211.110 (a)): referenced on 173 of the 483 forms
  10. 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. 11. #4 reason for 483 "TESTING AND RELEASE FOR DISTRIBUTION" (21 CFR 211.165 (a)): referenced on 183 of the 483 forms
  12. 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. 13. #2 reason for 483 "RESPONSIBILITIES OF THE QUALITY CONTROL UNIT" (21 CFR 211.22 (d)): referenced on 247 of the 483 forms
  14. 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. 15. FDA Warning Lettershttp://www.fda-compliant.net/fda-warning-letter.html
  16. 16. Facility Cleaning During the investigators 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. 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. 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 firms 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. 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. 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. 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. 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. 23. Trending The reported assay precision in the analytical runs was not accurate because the precision analysis did not include standards.
  24. 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. 25. Questions
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