The currently valid interpretation of the GMP specifications in the area of aseptic manufacture by the FDA "Guideline On Sterile Drug Products Produced By Aseptic Processing" dates from June 1987. Much of what it contains no longer conforms to the modern requirements as regards the manufacture of aseptic products. After the industry had been waiting for many years for a new version and an unauthorized version had been known to exist since 1998 FDA published last year a preliminary concept paper "Sterile Drug Products Produced By Aseptic Processing". The discussion of the contents was very intense and in some cases even controversial, and several associations (e.g. the PQRI) had submitted to FDA suggestions for improvements via working groups. Since September 3, 2003 FDA has now published an official draft "Guideline On Sterile Drug Products Produced By Aseptic Processing" which at first glance differs greatly in content from the concept paper and has adopted a surprisingly large quantity of items from commentaries by the industry. The draft is now available for official discussion and commentaries must be submitted to FDA by November 4. Now for a few remarks on the topics of Buildings and Facilities, Process Simulation and Environmental Monitoring:

I. Buildings and Facilities 
The most important changes in this part concern the definition of the cleanroom classes see Table 1 "Air Classifications". New is the comparison with the classifications according to ISO 14644-1. The units in which the values are shown have been changed from ft³ to m³ and the values themselves, e.g. particles measuring 0.5µm, Class 100 and ISO Class 5 have been corrected from 3500 to 3520. In addition, the microbiological limits have been adjusted in the values and renamed "Active Air Action Levels". Action levels for sedimentation plates have also been included. In addition, reference is made to the measurements to be carried out in Class 100 and it is pointed out that they are to be carried out where the greatest risk is to be expected. "Air pattern analysis" or "Smoke studies" are to be carried out, documented and then evaluated. It is also pointed out that the pressure stages between individual cleanroom classes are to be monitored and the time that doors are left standing open is to be checked. Further changes concern formulations and examples in the individual chapters. 

II. Process Simulation (Media Fill) 
The main points which stand out in comparison with the concept paper are the concrete values for the size of Media Fills (subchapter 4 "Size of Runs"), for temperature for incubation (subchapter 8) and for recommendations for acceptance criteria in the evaluation of the test results (subchapter chapter 9). As to the size of the media fills the draft describes the range between 5000 - 10000 units as the " generally acceptable starting point for run size". In the case of batch sizes < 5000 units the number of filled units is to be the same as the batch size. However, the central statement remains that the scope of the runs is to be so large that the commercial production conditions and contamination risks are simulated. The incubation temperature of the media fill units is now directly specified in the draft with tolerances (20 - 35 °C +- 2.5 °C). When 2 temperatures are used the draft stipulates that each sample is to be incubated for at least 7 days. 
As regards the interpretation of the test results the draft, unlike the concept paper, now gives acceptance criteria: 

• With the filling of fewer than 5000 units: no contaminated units 
• With the filling of 5000 - 10000 units : 
  • 1 contaminated unit should trigger an investigation and a repeat run 
  • 2 contaminated units lead to revalidation, after a relevant investigation 
• With the filling of more than 10000 units : 
  • 1 contaminated unit should trigger an investigation. 
  • 2 contaminated units lead to a revalidation, after a relevant investigation. 

Of course this chapter also contains a large number of "minor" changes in comparison with the concept paper. 

III. Environmental Monitoring
The structure of this chapter has hardly been changed. The reference to alternative microbiological methods has been added. Reference is always made to a written specification document and scientific methods. Here a few statements and changes in comparison with the concept paper:

General Written Program 

• When identifying critical sites to be sampled, consideration should be given to the points of contamination risk in a process, including factors such as difficulty of setup, length or processing time, impact of interventions 
• It is also clearly stated that the proof of microbiological contamination in the monitoring need not necessarily lead to the batch being placed on hold. However, the contaminated critical site sample should be investigated with an awareness of the potential for a low incidence of false positives and should include an assessment of operational information and data 

In the absence of any adverse trend, a single result above an action level should trigger an evaluation and a determination about whether remedial measures may be appropriate. In all room classes, remedial measures should be taken in response to unfavorable trends 

Establishing Levels and a Trending Program 

• Significant changes in microbial flora should be considered in the review of the ongoing environmental monitoring data Sanitization Efficacy 
• Therefore a sound disinfectant program also includes a sporicidal agent, used according to a written schedule and when environmental data suggest the presence of sporeforming organisms 

Active Air Monitoring 

• ...the air sampler should be evaluated for its suitability for use in an aseptic environment based on cleanability .... ... ensure that such devices are calibrated.... Because devices vary, the user should assess the suitability of all monitoring devices before they are placed into service.

We recommend the conference of the European Compliance Academy Qualification and Validation in Sterile Manufacturing  in Munich from November 25-26, 2003.

We are also organising the following events which also concern the implementation of the Draft Guidance:

• GMP/FDA Requirements on Environmental Monitoring, 
  3-4 November 2003, Amsterdam, The Netherlands
• Microbiology for Non-Microbiologists, 13-14 October 2003, Dublin, Ireland

Authors:
Dr. Andreas Mangel
Harald Martin
Sven Pommeranz
CONCEPT HEIDELBERG