Q. We find ourselves spending a significant amount of money every year to certify our cleanrooms and laminar flow devices. Is it necessary to do this testing twice a year?
The short answer is yes, USP chapters and regulators mandate certification be done every six months. This answer, however, ignores the real reasons certification twice a year is required. Environmental conditions change with the seasons and these changes potentially affect HVAC and other building services. Filters load, seals degrade, airflows change. Testing only once a year in the same season every year does not provide adequate confidence in the maintenance of a “state of control” over a critical sterile compounding environment.
Q. What is a “state of control” and how does it affect our facility?
The primary function of a cleanroom is to maintain ISO Class under dynamic operating conditions. For example, an ISO Class 7 buffer room must maintain a particle count level below 352,000 0.5 micrometer particles per cubic meter while the room is in full operation. This is accomplished by delivering adequate airflow via the heating, ventilation, air conditioning system (HVAC) through HEPA filters located in the ceiling to dilute particles in the room and remove them through return or exhaust grilles located low on the wall. It should be verified in the commissioning process that the certified air change rate will, in fact, result in adequate particle removal to maintain the desired room cleanliness. The amount of air supplied to the room versus the amount removed through return/exhaust grilles and leakage at the doors or other openings will result in a room pressure which must be continuously monitored.
Q. Why is the room pressure so important that it must be monitored, and the pressures logged daily?
Monitoring the room pressures is the easiest and most economical method of verifying that the amount of airflow delivered to and removed from the room has not changed. If the room pressure remains constant or returns to the same value after an excursion, we can be confident that our state of control has not changed. Therefore, we are maintaining the required room cleanliness level for the work being done in that room.
Q. When we open our door, the room pressure goes to neutral. Does that mean we lost our state of control?
You might lose your state of control if you left that door open for more than the few seconds it takes to walk through it. However, you can prove that the room maintains ISO class during the time the door is open for people and materials to be transferred by conducting particle count testing under dynamic conditions. The amount of time the door is open during this testing should be used to set the alarm delay function on the room pressure monitor. This time is typically 45 seconds, but you can validate shorter or longer delay times for your facility. Remember that the monitoring of room pressure is important because it proves you are maintaining a state of control over the cleanroom environment, not because a specific room pressure is critical.
Q. What pressures are required to maintain our state of control and why the difference between negative and positive pressure requirements?
USP chapters require a minimum pressure of 0.020" water column (w.c.) for positive pressure rooms and a range of 0.010" to 0.030" w.c. negative pressure for a hazardous compounding room. There is no cap on the positive pressure because there is little potential for contamination to a room at elevated positive pressure. There is, however, significant impact on the performance of a negative pressure cleanroom when operating at too much vacuum. After the 2008 changes to Chapter <797> were passed, the required negative pressure for a hazardous buffer room was simply a minimum of 0.01" w.c. negative with no cap. This resulted in many hazardous drug buffer rooms operating at a very negative pressure relative to the ante room. As a result, microbiological contamination was common. By restricting the low-end of the negative pressure range, most hazardous drug buffer rooms are negative to the ante room but slightly positive to the ceiling and other non-classified areas. The tight range of negative pressure between the hazardous drug buffer room and the anteroom is admittedly difficult to maintain but imperative for room performance. The primary function of any sterile compounding room is sterility of the product, so a buffer room can only be negative to rooms that are at least as clean as it is.
Q. What standards should our sterile compounding facility be certified to meet?
A 503B registered outsourcing facility will be inspected by the FDA to current Good Manufacturing Practices (GMPs). A 503A facility will be inspected by state boards of pharmacy, the Joint Commission, or departments of health to either their own standard or to USP Chapters <797> and <800>. The Controlled Environment Testing Association has developed an application guide (CAG-003) for certification of sterile compounding facilities. This application guide was developed to outline the certification process for compliance with USP chapters, but it can also be followed when testing a 503B facility.
Q. How can we get more out of the certification process?
Certification for compliance to USP Chapters <797> and <800> has become an interactive process between the compounding personnel and the certification team. The certifier can no longer provide a compliant certification without interacting with the compounding team. The dynamic particle count surveys, smoke studies, and environmental monitoring all are required to be done under dynamic conditions, which is “the actual compounding staff performing actual compounding processes using surrogate materials.” The compounding staff must work with the certifier to make this happen. Often, like most other industries, compounding operations are short-staffed, so giving up a trained compounding technician even for a few minutes for this regulatory required testing is looked at as a burden and is treated as a time-wasting task. This deprives the compounding team of a tremendous training tool for the proper use of “first air” in developing good aseptic technique. The dynamic tests should be looked at as an opportunity to better understand your facility and to train your personnel. For example, we often see the same person perform all aseptic operations during the dynamic smoke studies every certification cycle. Ideally, a different compounding technician should participate or even multiple technicians for different devices and for different test cycles. A dynamic smoke study can be the best aseptic technique training tool you have if you plan for it. If you rush through it or go into it with an attitude that it’s a waste of your time, it will be. If you use it as a valuable training tool, it will be that too. You must do it so you might as well embrace it and allow it to be a beneficial tool.
Q. My certifier says that there are no accommodations for leak testing the HEPA filters. Can they certify the room?
USP Chapter <797> (2019) Section 5 establishes the minimum requirements for the certification of ISO classified areas. Section 5 references the Controlled Environment Testing Association’s (CETA) certification guide for sterile compounding facilities for specific procedures. Section 5 also lists HEPA filter integrity testing as one of the specific tests that MUST be conducted at every certification (six-month intervals). Historically, this is one test that was not always completed as part of certification by every certification provider. The reason given was often “our facility was not designed to accommodate filter leak testing.” While this may be true, it never was an acceptable justification to not do this important test. Any time a HEPA filter is relied upon as a part of the critical facility state of control, that filter MUST be proven to be leak free. It is ultimately the designated persons responsibility to ensure that certification is done correctly. In this case, that means ensuring that accommodations are provided for integrity testing every HEPA filter. There are several remote-challenge systems available on-line if accommodations are not already provided. They can be installed by your certifier or by an HVAC contractor.
Q. Are there any specific tests required for the initial certification after new construction?
After the construction phase is complete, consider functional testing by “commissioning” the rooms. Commissioning can be carried out by your certification vendor or a commissioning engineer. It should be performed before operational compounding can begin. Commissioning verifies that the cleanroom suite is operating according to the facility design requirements as well as meeting regulatory requirements. The commissioning report is similar to a certification report but is intended to ensure the mechanical systems are performing to the specific facility design, not general guidance provided in USP chapters. A certification report is intended to prove the facility meets regulatory requirements. Both are important but the commissioning report is more valuable for ensuring you got what you paid for from the installer.
More testing may be required for a commissioning project than routine certification. The acceptance criteria should be based on the facility design parameters, not necessarily the minimum criteria found in USP chapters. For example, if a negative pressure hazardous buffer room was designed to have 60 air changes per hour (ACPH), it must have 60 ACPH when it is commissioned to design, but if it was certified to USP minimum values, it could be certified to 30 ACPH. Additionally, if the design for that same facility’s non-hazardous buffer room was for 1,000 CFM through the HVAC system and the room is commissioned to be delivering 1,050 CFM which results in a room pressure of 0.050" w.c., the room pressure monitor should be set to alarm at approximately 0.040" w.c., not 0.020" w.c. (the USP minimum). The state of control point for that room will have been commissioned to a meaningful and relevant number for that room. The acceptance criteria used in the commissioning process should then become the state of control based certification parameters for future certifications. The commissioning agent should be contracted directly to the owner, not the contractor.
Jim Wagner, President, Controlled Environment Consulting (CEC)
Jim Wagner, the president of Controlled Environment Consulting (CEC), has been involved in the controlled environment performance evaluation industry since 1979. His consulting includes design and evaluation of sterile compounding facilities, containment facilities, and other engineering controls. Jim conducts international training on cleanroom and containment device design and certification. Prior to founding CEC, Jim was the president of Micro-Clean, a certification and validation company. Jim led the Controlled Environment Testing Association’s (CETA) efforts to develop guidance documents for compliance with USP Chapter <797>. Jim was a member of the USP Compounding Expert Committee (2005-2010, 2015-2020). Jim is a steering committee member for NSF/ANSI standard 49 Biosafety Cabinetry: Design, Construction, Performance, and Field Certification. Jim was a two-time president of the Controlled Environment Testing Association including being CETA’s first president in 1991-92. Jim was awarded CETA’s Mel First award for outstanding contributions to the advancement of certification and testing of controlled environments.
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