FDA Draft Guidance for Industry: Sterile Drug Products Produced by Aseptic Processing

GMP-News Nr. 347

8 September 2003
FDA Draft Guidance for Industry: 
Sterile DrugProducts Produced by Aseptic Processing

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

I. Buildings and Facilities 
The most important changes in this part concern the definition of thecleanroom classes see Table 1 "Air Classifications". New is thecomparison with the classifications according to ISO 14644-1. The units inwhich the values are shown have been changed from ft³ to m³ and the valuesthemselves, e.g. particles measuring 0.5µm, Class 100 and ISO Class 5 havebeen corrected from 3500 to 3520. In addition, the microbiological limitshave been adjusted in the values and renamed "Active Air ActionLevels". Action levels for sedimentation plates have also beenincluded. In addition, reference is made to the measurements to be carriedout in Class 100 and it is pointed out that they are to be carried out wherethe greatest risk is to be expected. "Air pattern analysis" or"Smoke studies" are to be carried out, documented and thenevaluated. It is also pointed out that the pressure stages betweenindividual cleanroom classes are to be monitored and the time that doors areleft standing open is to be checked. Further changes concern formulationsand examples in the individual chapters. 

II. Process Simulation (MediaFill) 
The main points which stand out in comparison with the concept paper arethe concrete values for the size of Media Fills (subchapter 4 "Size ofRuns"), for temperature for incubation (subchapter 8) and forrecommendations for acceptance criteria in the evaluation of the testresults (subchapter chapter 9). As to the size of the media fills the draftdescribes the range between 5000 - 10000 units as the " generallyacceptable 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 batchsize. However, the central statement remains that the scope of the runs isto be so large that the commercial production conditions and contaminationrisks are simulated. The incubation temperature of the media fill units isnow directly specified in the draft with tolerances (20 - 35 °C +- 2.5°C). When 2 temperatures are used the draft stipulates that each sample isto be incubated for at least 7 days. 
As regards the interpretation of thetest results the draft, unlike the concept paper, now gives acceptancecriteria: 

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

Of course this chapter alsocontains a large number of "minor" changes in comparison with theconcept paper. 

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

General Written Program 

  • When identifying critical sites to besampled, consideration should be given to the points of contaminationrisk in a process, including factors such as difficulty of setup, lengthor processing time, impact of interventions 
  • It is also clearly stated that the proofof microbiological contamination in the monitoring need not necessarilylead to the batch being placed on hold. However, the contaminatedcritical site sample should be investigated with an awareness of thepotential for a low incidence of false positives and should include anassessment of operational information and data 

In the absence of any adverse trend, asingle result above an action level should trigger an evaluation and adetermination about whether remedial measures may be appropriate. In allroom classes, remedial measures should be taken in response to unfavorabletrends 

Establishing Levels and a TrendingProgram 

  • Significant changes in microbial florashould be considered in the review of the ongoing environmentalmonitoring data Sanitization Efficacy 
  • Therefore a sound disinfectant programalso includes a sporicidal agent, used according to a written scheduleand when environmental data suggest the presence of sporeformingorganisms 

Active Air Monitoring 

  • ...the air sampler should be evaluatedfor its suitability for use in an aseptic environment based oncleanability .... ... ensure that such devices are calibrated....Because devices vary, the user should assess the suitability of allmonitoring devices before they are placed into service.
Here you can download the FDA Draft Guidance Document: Sterile DrugProducts Produced by Aseptic Processing: http://www.fda.gov/cder/guidance/1874dft.pdf

Dr. Andreas Mangel
Harald Martin
Sven Pommeranz

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