The revised United States Pharmacopeia (USP) chapter <1116> (3) states that when operators are present in the aseptic processing operation, an expectation of zero contamination
at all locations during every operation is not technically possible and is, therefore, unrealistic. This statement is problematic
because, while scientifically correct, regulatory guidance (such as FDA’s 2004 Aseptic Processing Guide and Annex 1 of the
EU GMPs) give “less than one colony forming unit (CFU)/m3 or per plate as the limit for an ISO 5 (Grade A/class 100) area,
and FDA goes further, stating that ISO 5 should routinely yield zero counts. Indeed, it is true that in today’s aseptic processing
environment it should be possible to routinely yield zero counts, which does not contradict the USP statement that zero at
all locations during every operation is impossible. However, in order not to mislead newcomers to a highly regulated environment,
it is important to emphasize the regulatory limits as stated. This means that any count at all in an ISO 5 area would require
a product impact assessment of some kind if there were production activity when the count was retrieved.
The breakthrough in the USP chapter is the statement that “assessment of risk associated with aseptic operation must be assessed
over a significant period of time and the contamination recovery metric based on actual data collected in the facility. The
contamination rate can then be used to track the state of control of the facility/the ongoing performance and to allow early
identification of trends and corrective actions and refinements to the overall control strategy” (3).
The USP chapter states that once optimal conditions are established (not necessarily immediately after performance qualification
[PQ] is finished—optimal conditions may come later when operators are more experienced and therefore more competent), the
contamination recovery rate should become stable within a known range of variability. This concept is a basic tenet of quality
assurance, and at that point, even small excursions from the range should be treated as alarm signals requiring close scrutiny
and possible aggressive corrective actions to return to the previous state of control. The point being made is that when there
is a change in the recovery rate, this is generally indicative of breach of one or more of the risk mitigation measures described
above and, therefore, signals a potential breakdown of the control strategy. It is a serious matter and must be addressed.
The revised USP chapter requires a carefully documented investigation when recovery rates increase, description of corrective
actions, and monitoring of effectiveness. A change in the contamination recovery rate might be a reason to convene a multidisciplinary
task force that would be disbanded only after confirmation that the previous levels of recovery have been achieved once again.
The focus should be on containment measures to ensure uniformly low recovery rates and a company should be vigilant in trying
to reduce the recovery rates over time.
Cautions when reading the revised chapter
The number 15 cfu is mentioned in a manner which, in the absence of an understanding of the issue, might be misinterpreted
as suggesting product could be released if a single recovery of 15 cfu were found in an ISO 5 area, provided there was a uniformly
low recovery rate for all preceding days in the same month. This author does not believe that is the USP’s intent—certainly
not without exceedingly robust safeguards—and it will be interesting to hear regulators respond to the revised chapter. In
any case, the ultimate and sole responsibility for the safety of product released to the marketplace is that of the company
producing it; therefore, there must be a documented impact assessment for any excursion outside the predetermined acceptance
ISO 14644-1 and 2 guidelines address the design and operation of cleanrooms and are currently under revision. These guides
only address particulate contamination of clean environments and do not discuss microbial contamination. They are often mistakenly
quoted as addressing air velocities, changes, airflows, and pressures, which is not the case. The current revisions are intended
to simplify testing to remove the need for evaluating the 95% upper confidence limit (UCL) at 2–9 locations, which is common
practice. The target date for publication of the ISO documents is December 2013–January 2014. There is a proposal to delete
the requirement for testing greater than or equal to 5 micron particles, which will take the EU Grades A and B out of the
scope of the guide for classification purposes if the proposal passes into the final standard. Current issues still under
- The number of locations is still not class sensitive
- How random locations should be selected
- How to deal with risk-based critical locations
- How to handle large cleanrooms.
Maintaining the quality of the environment in a cleanroom requires continual and relentless investment of energy in the facility
and equipment maintenance and cleaning; in personnel competence (not just check the box “training and qualification”); in
a garmenting program; in cleaning and disinfection; and in environmental control. Maintaining quality is about continual improvement.
The environmental monitoring program provides the data to assess how well a risk management program is working. Response to
risk must be rapid, and aggressive, and one must monitor the effectiveness when contamination recovery rates change.
1. Sun L., “Compounding Pharmacy Linked to Meningitis Outbreak Knew of Mold, Bacteria Contamination,” Washington Post (Oct. 26, 2012).
2. ICH Q10, Pharmaceutical Quality System (ICH, June 2008).
3. USP, General Chapter <1116> Microbiological Control of Cleanrooms and Other Controlled Environments, USP-NF, 35, May 2012.