Warning Letters Report 2005

GMP News No. 702

GMP News
5 April 2006
 
Warning Letters Report 2005
 
The analysis of the warning letters issued in the fiscal year 2005 (from Oct. 2004 to Sept. 2005) and referring to the Code of Federal Regulations (CFR) Part 211 yields a surprising result: while in the previous year 33 warning letters were issued, the number decreased by almost half in 2005 to 17. The number of letters for firms processing blood or blood products and manufacturing biologic products as well as for manufacturers of medical devices remained the same, as the following table shows:
 
 

FY 2004

FY 2005

WLs relative to Part 211 (Drugs)

33

17

WLs relative to Part 600, 606, 610, 630, 640, 680 (Blood, Blood Products, Biologicals)

9

9

WLs relative to Part 820 (Medical Devices)

104

107

Comparing the most frequently mentioned deficiencies in the two years also shows some striking differences, as the following summary demonstrates:

  • Similar to last year, Production Record Review (211.192) and Responsibilities of the quality control unit (211.22) are at the top of the frequent GMP deficiencies. However, Control of microbiological contamination (211.113) climbed from position 6 to 3 in the top ten findings in 2005.
  • Compared to last year, the agency also found more deficiencies in batch documentation: Batch Production and Control Records (211.188) rank 4th in the top ten list compared to 8th in the fiscal year 2004.
  • FDA investigators also focused on Equipment cleaning and maintenance (211.67), which was mentioned in this year's warning letters almost as often as last year.

The following table compares the most frequent deficiencies in 2004 with 2005.

The ten most frequent GMP deficiencies in the fiscal years 2004 and 2005 warning letters

Top Ten List No.

Fiscal Year 2004

Fiscal Year 2005

1

211.100

Subpart F – Production and Process Controls

Written procedures; deviations

211.192

Subpart J – Records and Reports

Production record review

2

211.67

Subpart D – Equipment

Equipment cleaning and maintenance

211.22

Subpart B – Organization and Personnel

Responsibilities of quality control unit

3

211.22

Subpart B – Organization and Personnel

Responsibilities of quality control unit

211.166

Subpart I – Laboratory Controls

Stability Testing

211.113

Subpart F – Production and Process Controls

Control of microbiological contamination

4

211.192

Subpart J – Records and Reports

Production record review

211.67

Subpart D – Equipment

Equipment cleaning and maintenance

211.100

Subpart F – Production and Process Controls

Written procedures; deviations

211.160

Subpart I – Laboratory Controls

General requirements

211.188

Subpart J – Records and Reports

Batch production and control records

5

211.160

Subpart I – Laboratory Controls

General requirements

211.165

Subpart I – Laboratory Controls

Testing and release for distribution

211.42

Subpart C – Buildings and Facilities

Design and Construction Features

211.166

Subpart I – Laboratory Controls

Stability Testing

211.198

Subpart J – Records and Reports

Complaint files

6

211.113

Subpart F – Production and Process Controls

Control of microbiological contamination

211.165

Subpart I – Laboratory Controls

Testing and release for distribution

7

211.84

Subpart E – Control of Components and Drug Product Containers and Closures

Testing and approval or rejection of components, drug product containers, and closures

211.25

Subpart B – Organization and Personnel

Personnel qualifications

211.68

Subpart D – Equipment

Automatic, mechanical, and electronic equipment

8

211.188

Subpart J – Records and Reports

Batch production and control records

211.84

Subpart E – Control of Components and Drug Product Containers and Closures

Testing and approval or rejection of components, drug product containers, and closures

211.122

Subpart G – Packaging and Labelling Control

Materials examination and usage criteria

211.137

Subpart G – Packaging and Labelling Control

Expiration dating

9

211.186

Subpart J – Records and Reports

Master production and control records

211.46

Subpart C – Buildings and Facilities

Ventilation, air filtration, air heating and cooling

211.94

Subpart E – Control of Components and Drug Product Containers and Closures

Drug product containers, and closures

211.110

Subpart F – Production and Process Controls

Sampling and testing of in-process materials and drug products

211.125

Subpart G – Packaging and Labelling Control

Labelling issuance

10

211.25

Subpart B – Organization and Personnel

Personnel qualifications

211.42

Subpart C – Buildings and Facilities

Design and Construction Features

211.63

Subpart D – Equipment

Equipment design, size, and location

211.80

Subpart E – Control of Components and Drug Product Containers and Closures

General requirements

211.130

Subpart G– Packaging and Labelling Control

Packaging and labelling operations

211.167

Subpart I – Laboratory Controls

Special testing requirements

211.176

Subpart I – Laboratory Controls

Penicillin contamination

211.180

Subpart J – Records and Reports

General requirements

211.204

Subpart K – Returned and Salvaged Drug Products

Returned drug products

FDA inspections are based on a systems oriented approach, mainly focusing on the quality system. Accordingly, the agency often finds failures and neglected duties in the quality unit. Related topics like insufficient Production Record Review or the handling of deviations and written procedures are also frequent matters of objections. Most likely, these findings will also be on the top of the list in the future, together with inadequate control of microbial contaminations or equipment cleaning.

Among the companies receiving a warning letter last year were 4 outside the US: one in Puerto Rico, one in Canada and two companies in Europe – in Italy and in Switzerland.

In the same period, 2 (US-based) API manufacturers received a warning letter, coming down from 3 the year before (one in the Czech Rep. and two in China).
 

The European Compliance Academy will organise the following conferences and intensive courses relative to the FDA Top Deviations:
  

Environmental Monitoring - Compliant and Reasonable

18./19. May 2006, Copenhagen, Denmark

FDA's and ICH's New Quality Systems Approach

1./2. June 2006, Prague, Czech Rep.

FDA Compliance in Analytical Laboratories

4.-6. October 2006, Prague, Czech Rep.

How to Pass EU and FDA Inspections - GMP-Compliance Auditor

4.-6. October 2006, Barcelona, Spain

GMP and FDA Compliance in Quality Assurance Units

8.-10. November 2006, Prague, Czech Rep.

Microbial Contamination - Corrective Actions, Preventive Actions

23./24. November 2006, Vienna, Austria

 
Author:
Dr. Gerhard Becker
On behalf of the European Compliance Academy (ECA)

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