The Agency

What the FDA is looking for…

Top Ten of 483 GMP Findings by the FDA

in Fiscal Year 2003

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.

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.

#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 211.188): referenced on 178 of the 483 forms

#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 483 forms

#2 reason for 483

"RESPONSIBILITIES OF THE QUALITY CONTROL UNIT" (21 CFR 211.22 (d)): referenced on 247 of the 483 forms

#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   

FDA Warning Letters

http://www.fda-compliant.net/fda-warning-letter.html

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.

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.

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.

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]

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.

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

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

Trending

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

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.

Questions