In the following, we will compare the first part of chapter IX "Process Validation and Equipment Qualification" of the Concept Paper that had initially been published by the FDA with the version in the now published Draft.

While the introduction to part A "Process Simulation" of the Concept Paper considers environmental monitoring data to be "integral to the validation of an aseptic processing operation," the Draft just sees it as a potential source of "useful information."

In subchapter 1 "Study Design," the Draft does no longer require a validation protocol that describes in detail the way of proceeding, the test equipment and the acceptance criteria. However, it does require the integration of contamination risk factors into the media fill programmes. As in the Concept Paper, the Draft gives a detailed list of issues that should be taken into account during media fill. Compared to the Concept Paper, two requirements are missing on this list:

• The ability to produce sterile units in case the environmental conditions represent a greater risk to the product
• The consideration of temperature and humidity at set point extremes

Whereas the Concept Paper states that media fills cannot be used to "validate" an unacceptable practice, the Draft just advises that this should not be done.

The subchapter 2 "Frequency and Number of Runs" of the Draft points to the fact that "activities and interventions representative of each shift, and shift changeover, should be incorporated into the design of the semi-annual qualification." As an example, the Draft mentions that each shift should be evaluated according to time-related and operational features. Moreover, it strongly recommends that participation in a media fill should be consistent with the nature of each operator’s duties during routine production.

The topic "Size and Duration of Runs", to which the Concept Paper dedicates just one subchapter, has been divided into two separate subchapters in the Draft. There are only minor changes regarding the duration of runs (subchapter 3). The only thing that has been added is the requirement that interventions that commonly occur should be routinely simulated.

The greatest part of subchapter 4 ("Size of Runs") has been re-formulated. However, the central statement remains the same: the size of the runs should be large enough to simulate the commercial production conditions and contamination risks.

According to the Draft, the "generally acceptable starting point for run size" lies between 5,000 and 10,000 units. If the batch size is smaller than 5,000 units, the number of media-filled units should be equal to the batch size. Here, the text contains a reference to the PQRI Aseptic Processing Working Group.

Depending on the contamination risk, the new Draft considers the possibilities of filling a larger number of units (e.g. manually intensive filling lines) or a smaller number of units (e.g. when using an isolator). If a processes involves shift changeovers or unusually large numbers of units, media fill size and duration should be determined in the media fill programme so as to mimic real-life conditions and risks adequately.

In subchapter 5 "Line Speed," a sentence has been deleted saying that in some cases more than one line speed should be evaluated within the framework of the study.

In subchapter 6 "Environmental Conditions," the former requirement to cover also worst case conditions (Concept Paper) has been toned down to "adequately representative of ranges under which actual manufacturing operations are conducted."

Just two small changes have been made to subchapter 7 "Media"

• Whereas the Concept Paper considers the use of anaerobic growth media in special circumstances to be appropriate, the Draft only states that it "would be appropriate."
• The Concept Paper demands that the filled units be inverted and swirled so that the growth medium moistens the inner container-closure surfaces completely; the Draft just requires that the units be inverted or swirled. However, the Draft adds the adverb "thoroughly."

In subchapter 8, the incubation temperature of the media fill units is now expressly fixed in the Draft together with tolerances (20 - 35°C +/- 2.5°C). If two different temperatures are used, the samples should be incubated for at least 7 days at each temperature.

In contrast to the Concept Paper, the Draft suggests acceptance criteria for the interpretation of the test results (subchapter 9):

If fewer than 5,000 units have been filled:

• no contaminated unit

Between 5,000 and 10,000 filled units:

• 1 contaminated unit should trigger an investigation as well as a repetition of the test
• 2 contaminated units should initiate first an investigation and then a revalidation

More than 10,000 filled units:

• 1 contaminated unit should trigger an investigation
• 2 contaminated units should initiate first an investigation and then a revalidation

If you would like to enhance your knowledge of this topic, we recommend you the following events:

• Qualification / Validation in Sterile Manufacturing, Munich, Germany, 
  25-26 November 2003
• GMP / FDA Requirements on Environmental Monitoring, Amsterdam, The Netherlands, 3-4 November 2003