FDA's System-based Approach to Inspections as Reflected in the Warning Letters

GMP News No. 329

GMP News
21 July 2003

FDA'sSystem-based Approach to Inspections
as Reflected in the Warning Letters

Since February 2002, the FDA has been following a new inspection approachthat aims at conducting and evaluating inspections with regard to specificsystems. In doing so, the Agency distinguishes between the followingsystems:
  • Quality System
  • Facilities and Equipment System
  • Materials System
  • Production System
  • Packaging and Labeling System
  • Laboratory Control System

The idea underlying this approach is that deficiencies in one systemwill affect all other systems as well.

Therefore, these systems are not congruent with the subparts B - K of21 CFR 211.

As an example, we will have a look at the "Quality System."One can assign the following paragraphs of the CFR 211 subparts to theindividual parts of the quality system:

Failure Investigations

211.22 ("Responsibilities of quality control unit")

Training / Qualification

211.25 ("Personnel qualifications")

Validation / Computer

211.68 ("Automatic, mechanical, and electronicequipment")


211.89 / 110 ("Rejected Components, drug product containers,and closures"/ "Sampling and testing of in-processmaterials and drug products")

Validation / Manufacturing

211.110 ("Sampling and testing of in-process materials anddrug products")

Change Control

211.100 / 160 ("Written procedures; deviations" /"Lab controls - General requirements")

Reprocessing / Rework

211.115 ("Reprocessing")

Quarantine Products

211.142 ("Warehousing procedures")

Stability Failures

211.166 ("Stability testing")

Product Reviewers

211.180 ("Records and Reports - General Requirements")

Validation / Lab. Method

211.194 (Laboratory records")

Complaint Files

211.198 ("Complaint Files")

Returns / Salvages

211.204 / 208 ("Returned drug products"/ "Drugproduct salvaging")

The new inspection approach is reflected by the kind and frequency ofthe citations in the Warning Letters issued since February 2002.

Practically all of the CFR paragraphs (except for 211.89; 211.115; 211.204;211.208) appeared with increasing frequency in the Warning Letters issuedafter February 2002, reaching a peak in the second half of 2002.

This trend can be verified quite well with the example of the"Laboratory Controls" system. There was e.g. a rapid increase inthe Warning Letter references to paragraph 211.165 ("Testing and release for distribution")towards the end of 2002. Batch release testing is certainly one of themost important tasks of the QC laboratory, and it is no wonder that theFDA inspectors have more and more often an especially critical look atthis point within the framework of the new inspection approach.

The same is true of 211.166 ("Stability testing"), which isalso more and more frequently referenced in Warning Letters.

Dr Gerhard Becker


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