Uncommon Sense in Execution of Process Simulations

• Interventions always mean increased risk to the patient.
•  There is no truly safe intervention
•  Interventions are to be eliminated if at all possible; if they can’t be eliminated, then their frequency should be reduced as far as possible; simplified with respect to their execution in all instances.
• The “perfect” intervention is the one that is designed out or eliminated from the process!

The length or duration of a media fill has always been a point of regulatory concern. In the 1970s, media fills rarely exceeded 3,000 units.1 When the statistical implications of using an acceptance criterion of a maximum 0.1% contamination rate were understood, media fills started to exceed 4,700 units. The FDA’s 2002 draft Aseptic Processing Guideline brought an increase to 5,000 units.13  More recently, there have been EMA and FDA expectations for media fills that exceed the maximum batch size allowed on the line. This premise behind these increasing size simulations is apparently rooted in the regulatory belief that the microbial conditions on the line slowly deteriorate over the course of the fill such that units filled at the end of the batch have a higher potential for contamination. There is ample evidence that this is not the case, and if one considers the fundamentals of aseptic process system design why such a concern is incorrect.14 The typical manned aseptic filling line whether conventional or RABS is designed to continuously eliminate contamination by the unidirectional downward flow of air through the critical zone. There are no reports of microbial contamination trending upward during an operational day, and clear support to the contrary. The appropriate duration for a process simulation should be longer than the operators’ continuous presence in the fill room, or 5,000 units — whichever comes first.  
 

One of the more puzzling aspects of process simulation execution is the continued use of 2 different (20-25°C and 30-35°C) incubation temperatures for seven days each for the filled units. The trouble lies in the dichotomy of the temperature sequence. Industry surveys beginning in 1980s indicated that the industry was split almost equally among firms that incubate first at 20-25°C and then at 30-35°C, and those that began at 30-35°C and then switched to 20-25°C. The arguments posed for doing this in either fashion are largely theoretical. Noting this, PDA suggested and FDA agreed to the use of a single temperature between 20-35°C with an allowable range of ±2.5°C.7 Using a single temperature simplifies the execution, eliminates the need for large incubators and more closely mimics what occurs with many products anyway. The persistence of the antiquated practices across the industry is puzzling given the operational advantages and regulatory acceptance of a single temperature.
 

Perhaps the most confusing aspect of all with respect to media fill execution is that of operator participation. The FDA’s 2004 aseptic guidance includes the following: 

“All personnel who are authorized to enter the aseptic processing room during manufacturing, including technicians and maintenance personnel, should participate in a media fill at least once a year. Participation should be consistent with the nature of each operator’s duties during routine production.” (7) 

On the surface, this seems completely clear. However, what exactly does “participation” in this context mean? For those individuals that do not perform interventions in the critical zone, the expectation is actually excessive. To mandate that supervisory personnel participate to the same extent they routinely do means they should stand to the side and little else. For other gown-qualified personnel sanitization staff, instrument mechanics and so on, that do not intervene on an operating line they should also be exempted from any direct involvement in the media fill program. That leaves the set-up personnel (if different from the operating staff), line operators and environmental monitoring staff (if present) as those whose participation is necessary to meet the regulatory expectation.  
 

The implementation of the regulatory desire is still not without some difficulty. In a single line facility, with a staff of four, two media fills would afford ample repetitive opportunity for the four operators to perform each of the permitted interventions without difficulty. Applying the guidance to a larger plant is far more complicated. Consider the following real world parenteral facility — eight filling lines, two operating shifts and approximately 50 line operators. Ignoring the participation concern, the facility would perform 32 media fills per year (8 lines X 2 shifts X 2 fills per year = 32). If there are 10 interventions to be included and they are performed on average five times each in the media fill, then 1,600 total interventions would be performed each year. Considering the 50 qualified operators, that converts to an average of 3.2 interventions per operator per year! Those 3.2 interventions would in theory support each operator’s participation on all lines for all of the different interventions. The confidence provided by this approach is clearly compromised and an alternative approach is necessary. Increasing the number of media fills to match the intervention numbers performed in the smaller facility would require 400 media-fills-per-year levels and is not a realistic alternative. 

The most appropriate means to address participation at larger sites is reliance on procedural conformance. If the means to execute the intervention is sufficiently detailed and the operators well trained in the procedure, then the aseptic process should be considered adequately qualified despite every operator not having performed every intervention on every line multiple times. As the individual operators can be gown-qualified and separately demonstrated to be proficient in the aseptic techniques necessary, their participation is assured through the procedural controls. 
 

The execution of process simulations is an essential part of the sterile product compliance demonstration. The details of their execution have been addressed in industry guidance documents, however the structure of those documents precludes detailed examination of the methods as afforded here.

 

1) PDA, "Technical Monograph No. 2, Validation of Aseptic Filling for Solution Drug Products," 1980.
2) Technical Report No. 6, Validation of Aseptic Drug Powder Filling Processes," 1984.
3) Process Simulation Testing for Aseptically Filled Products", PDA Technical Report #22, PDA Journal of Pharmaceutical Science and Technology, Vol. 50, No. 6, supplement, 1996.
4) Process Simulation for Aseptically Filled Products", PDA Technical Report #22, 2011 Revision, PDA, 2011.
5) PHSS, PS Technical Monograph No.4, The Use of Process Simulation Tests in the Evaluation of Processes for the Manufacture of Sterile Products, 1993.
6) ISO 13408-1:2008, Aseptic processing of health care products -- Part 1: General requirements, 2008.
7) FDA, Guideline on Sterile Drug Products Produced by Aseptic Processing, 2004.
8) EMA, Annex 1 - Manufacture of Sterile Medicinal Products, 2008.
9) PIC/S, PI 007-6, Validation Of Aseptic Processes, 2010.
10) Agalloco, J., “Management of Aseptic Interventions”, Pharmaceutical Technology, Vol. 29, No. 3, p. 56-66, 2005.
11) Agalloco, J., & Akers, J., “The Truth about Interventions in Aseptic Processing”, Pharmaceutical Technology, Vol. 31, No.5, p. S8-11, 2007.
12) Agalloco, J., & Akers, J., “Revisiting Interventions in Aseptic Processing”, Pharmaceutical Technology, Vol. 35, No.4, pp 69-72, 2011.
13) FDA, draft Guideline on Sterile Drug Products Produced by Aseptic Processing, 2002.
14) Cundell, A.M., Bean, R., Massimore, L. & Maier, C., “Statistical analysis of environmental monitoring data: does a worst case time for monitoring clean rooms exist?”, PDA J. Pharm Sci Technol. , Vol. 52, No. 6, pp 326-330, 1998.
15) Agalloco, J., Akers, J., & Madsen R., "Current Practices in the Validation of Aseptic Processing - 2001", PDA Technical Report #36, PDA Journal of Pharmaceutical Science and Technology, Vol. 56, No. 3, 2002.