18 February 2020
GMP News No. 348
18 September 2003
FirstConsequencesfor Process Validation and Equipment Qualification
As we already wrote in our GMP News of 8 September, the FDA published theDraft Guidance for Industry "Sterile Drug Products Produced by AsepticProcessing - Current Good Manufacturing Practice" on 3 September.
But what are the consequences?
In the following, we will compare the first part of chapter IX"Process Validation and Equipment Qualification" of the ConceptPaper that had initially been published by the FDA with the version in thenow published Draft.
While the introduction to part A "Process Simulation" of theConcept Paper considers environmental monitoring data to be "integralto the validation of an aseptic processing operation," the Draft justsees it as a potential source of "useful information."
In subchapter 1 "Study Design," the Draft does no longerrequire a validation protocol that describes in detail the way ofproceeding, the test equipment and the acceptance criteria. However, it doesrequire the integration of contamination risk factors into the media fillprogrammes. As in the Concept Paper, the Draft gives a detailed list ofissues that should be taken into account during media fill. Compared to theConcept Paper, two requirements are missing on this list:
Whereas the Concept Paper states that media fills cannot be used to"validate" an unacceptable practice, the Draft just advises thatthis should not be done.
The subchapter 2 "Frequency and Number of Runs" of the Draftpoints to the fact that "activities and interventions representative ofeach shift, and shift changeover, should be incorporated into the design ofthe semi-annual qualification." As an example, the Draft mentions thateach shift should be evaluated according to time-related and operationalfeatures. Moreover, it strongly recommends that participation in a mediafill should be consistent with the nature of each operator’s duties duringroutine production.
The topic "Size and Duration of Runs", to which the ConceptPaper dedicates just one subchapter, has been divided into two separatesubchapters in the Draft. There are only minor changes regarding theduration of runs (subchapter 3). The only thing that has been added is therequirement that interventions that commonly occur should be routinelysimulated.
The greatest part of subchapter 4 ("Size of Runs") has beenre-formulated. However, the central statement remains the same: the size ofthe runs should be large enough to simulate the commercial productionconditions and contamination risks.
According to the Draft, the "generally acceptable starting point forrun size" lies between 5,000 and 10,000 units. If the batch size issmaller than 5,000 units, the number of media-filled units should be equalto the batch size. Here, the text contains a reference to the PQRI AsepticProcessing Working Group.
Depending on the contamination risk, the new Draft considers thepossibilities of filling a larger number of units (e.g. manually intensivefilling lines) or a smaller number of units (e.g. when using an isolator).If a processes involves shift changeovers or unusually large numbers ofunits, media fill size and duration should be determined in the media fillprogramme so as to mimic real-life conditions and risks adequately.
In subchapter 5 "Line Speed," a sentence has been deletedsaying that in some cases more than one line speed should be evaluatedwithin the framework of the study.
In subchapter 6 "Environmental Conditions," the formerrequirement to cover also worst case conditions (Concept Paper) has beentoned down to "adequately representative of ranges under which actualmanufacturing operations are conducted."
Just two small changes have been made to subchapter 7 "Media"
In subchapter 8, the incubation temperature of the media fill units isnow expressly fixed in the Draft together with tolerances (20 - 35°C +/-2.5°C). If two different temperatures are used, the samples should beincubated for at least 7 days at each temperature.
In contrast to the Concept Paper, the Draft suggests acceptance criteriafor the interpretation of the test results (subchapter 9):
If fewer than 5,000 units have been filled:
Between 5,000 and 10,000 filled units:
More than 10,000 filled units: