In our USP <797> Q&A Series, we’ve mentioned cleanrooms a few times but haven’t gone too deeply into the topic. As in other areas, the revised USP <797> standard includes a few changes. Some tighten up the requirements, while others leave things open to interpretation. Here are answers to some of the more frequent questions we get on USP <797> cleanroom standards.
Note: For the purposes of this discussion, we are focused on requirements for compounding sterile preparations. cGMP cleanroom standards for pharmaceutical manufacturers and other industries are different.
Before we jump into the first question, I want to remind everyone that one of the more significant changes to USP <797> was the redefinition of risk categories. Categories for compounding used to be designated low-, medium-, and high-risk, based on factors such as complexity of the preparation and exposure risk. The new Categories 1, 2, and 3 are now defined by the environmental conditions under which CSPs are compounded. These changes impact decisions like the kind of cleanrooms or sterile spaces needed, what the requirements are within those areas, which compounding activities can occur in those spaces, and what impact those spaces have on CSPs.
Q: How are USP <797> cleanrooms classified?
USP <797> uses the International Standards Organization (ISO) ISO 14644-1:2015 classification for air cleanliness by particle concentration. It’s important to keep in mind that this standard is applied across many industries, such as pharmaceutical manufacturing, food processing, semiconductor fabrication, healthcare, and more. ISO 14644 is focused on limits for non-viable particulate matter. An ISO Class 5 cleanroom, for example, must have a non-viable particulate air count of no more than 3520 particulates of 0.5 microns and larger per cubic meter of air.
However, since USP <797> is focused on minimizing viable microorganisms, compounding pharmacies are also required to prove that they meet additional requirements for air cleanliness, air changes, temperature, relative humidity control, and proper ingress and egress of air from one controlled area to the other. They must also show that they’ve accounted for the risks associated with the flow of personnel and products and waste in and out of those same spaces. This is proven through defined SOPs, documentation, and last but not least, viable CFU counts below the defined action levels.
Q: What areas need to be certified?
Section 4.2 of USP <797> states that “The designated person(s) is responsible for ensuring that each area related to CSP preparation meets the classified air quality standard appropriate for the activities to be conducted in that area.” As you can see in the list of relevant areas below, devices and connecting areas must also meet cleanroom standards.
Anteroom – An ISO Class 8 or cleaner room with fixed walls and doors where personnel hand hygiene, garbing procedures, and other activities that generate high particulate levels may be performed. The anteroom is the transition room between the unclassified area of the facility and the buffer room.
Primary Engineering Control (PEC) – A device or zone that provides an ISO Class 5 air quality environment for sterile compounding.
Buffer room – An ISO Class 7 or cleaner room with fixed walls and doors where PEC(s) that generate and maintain an ISO Class 5 environment are physically located. The buffer room may only be accessed through the anteroom or another buffer room.
Pass-through chamber – An enclosure with sealed doors on both sides that should be interlocked. The pass-through chamber is used to minimize particulate transfer while moving materials from one space to another. Cleanroom standards for pass-throughs are not defined in USP <797>; however, the industry standard best practice is to ensure the pass-through meets the standards of the cleaner of the environments connected.
Read: USP <797> Q&A: Sampling Pass-Throughs
Q: How often do we need to recertify our cleanrooms?
Section 5 of USP <797> mandates cleanrooms be independently certified before compounding can begin and then recertified every six months thereafter or whenever changes are made that could impact airflow or air quality. This section also delineates the minimum tests that must be included in the certification and recertification.
My friends in the cleanroom certification business tell me this is one of those areas where some independent thought is required. For example, PECs and pass-through chambers can include mobile devices such as a laminar flow hood on wheels. If you move the flow hood a couple of feet, does the room now need to be recertified? Perhaps not, but it depends on your risk assessment.
Of course, there are even less black and white examples, but questions like these emphasize the need to form a relationship with a cleanroom certification organization that has experience with USP <797> requirements. They can help you work through some of the grey areas.
From the lab’s perspective, I’d also add that if your trending data is headed the wrong direction and the source of contamination cannot be traced back to something like cleaning procedures or garbing, you may want to consider accelerating your recertification schedule. An upward trend in viable microorganisms may indicate a pending failure of engineering controls, such as air exchange systems or HEPA filters. Keep in mind that any tinkering with environmental controls, even for testing or recalibration purposes, could impact airflow or air quality and is therefore grounds for recertification under USP <797>.
Data trends inform effective environmental monitoring and personnel competency strategies.
Q: Why did USP <797> remove any references to CETA?
As many of you probably know, the previous version of USP <797> referenced a couple of third-party organizations in the environmental monitoring space, but the revised standard has removed these references. We most often get asked about the Controlled Environment Testing Association (CETA), an organization that specializes in certifying technicians and professionals who conduct testing, certification, and performance verification of controlled environments. The National Environmental Balancing Bureau (NEBB) was also removed. This well-known organization certifies firms and individuals involved in the testing, adjusting, and balancing of HVAC systems, cleanroom certification, and environmental monitoring.
We’re not entirely sure why the US Pharmacopeia removed references to these organizations. It’s possible they wanted to appear impartial. However, in our opinion, these organizations remain in good standing within the industry. The materials they produce can be extremely useful in helping USP<797> DPs (Designated Persons) select the right cleanroom certification partner and understand what to look for in cleanroom (re)certification reports.
Final Tips from the Lab
Finally, I’ll end with my usual statement about USP <797> being a standard of minimums. Cleanroom standards and certifications should be part of your risk assessment discussions. Know your plan. Understand the data you've collected via your partners: your certification firm, your facilities and infection control teams, and your trusted analytical laboratory partner. It's important to build working relationships with and between each of these partners as they work together to create a meaningful living document and system that ensures the health and safety of your personnel and the patients you serve.