Maintain EM Compliance Post-Construction

June 2022 - Vol.19 No. 6 - Page #20
Category: Environmental Monitoring Consulting

Environmental monitoring (EM) testing is a requirement of USP compounding standards and for facilities operating under FDA current Good Manufacturing Practice (cGMP) regulations. However, intending to meet only the minimum standards will quickly cause a challenge for compliance. Prioritizing your EM program at all stages of cleanroom design, construction, and beyond will ensure your classified spaces are continuously operating under a state of control.

The April 2022 PP&P article “EM Solutions within Cleanroom Design” discusses EM considerations during cleanroom design and construction. A key component of this early process is the ongoing multidisciplinary review and deployment of appropriate materials and construction methods as the cleanroom is designed and constructed. These measures are equally important following construction to ensure long-term EM integrity. Routine testing and ongoing oversight are key to maintaining EM compliance immediately following cleanroom construction and beyond.

Post-Construction Acceptance and Testing

Following the construction phases of classified spaces, the cleanroom project then moves into the acceptance and testing phase. The cleanroom should undergo a thorough cleaning performed as specified in the ultra-clean portion of the clean construction protocol (see SIDEBAR). A post-construction triple clean with an EPA registered one-step disinfectant and an EPA registered one-step sporicidal disinfectant cleaner is also necessary prior to certification and commissioning.1

The systems supporting the cleanroom must undergo any required testing, certification, and commissioning processes prior to the start of compounding. At a minimum, the following systems must be included in these processes:

  • Static air sampling
  • Dynamic air sampling
  • Cleanroom and PEC certification
  • Test and balance
  • Fire alarm testing
  • Generator switchover and back
  • Commissioning of all heating, ventilation, and air conditioning (HVAC) systems

A Controlled Environment Testing Association (CETA) certified testing agency should be used throughout the testing phase to oversee and perform the IQ/OQ/PQ testing, or the as-built, at-rest functional testing, and the dynamic operational testing.

Consider performing an Environmental Monitoring Performance Qualification (EMPQ) after construction as part of the acceptance and testing phase. While this is not a USP <797> requirement for post-construction testing and certification, nor is it commonly performed in pharmacy, such testing of the environment will establish how long the cleanroom environment can remain within a state of control during downtime. This is especially valuable during unplanned downtimes and supports the fine-tuning of cleanroom reaction time and recovery, which in turn can help identify issues such as HVAC system volumes and pressures not returning to operational levels as expected. An EMPQ can be performed by the pharmacy team partnering with the EM vendor and contractor to simulate the downtimes. Your cleanroom consultant may also be able to guide the development and design of your EMPQ and oversee the testing and analysis of data. If possible, connecting to the building automation system to enable remote monitoring also adds significant value to operational efficiencies and helps in assessing risks around environmental monitoring due to unexpected downtimes.

Ongoing Oversight

Ensuring your classified spaces are continuously operating under a state of control will contribute to the success of your EM program. This can be achieved through the following 4 steps:

  1. Create a preventative maintenance standard operating procedure (SOP)
  2. Establish cleaning and disinfecting practices and SOPs
  3. Create the environmental sampling and testing program
  4. Appoint an EM committee

A preventative maintenance SOP should be written, maintained, and updated in conjunction with your facilities department and cleanroom consultant. The life cycle of all HVAC components, equipment, primary engineering controls (PECs), refrigerators, lighting, and more should be part of the preventative maintenance SOP and should inform the schedule for planned preventative maintenance downtimes. For example, routine inspection of refrigeration unit condensate pan heaters should be included on the preventative maintenance schedule. Microbial proliferation and EM findings are commonly traced to refrigerator condensate pans located within cleanrooms.

Cleaning and disinfecting, as well as sampling and testing are required by USP <797> for the ongoing maintenance of your facility. The distinction that will ensure the success of the program is the selection of appropriate cleaning and disinfecting products and thoughtful consideration of sampling locations for your EM monitoring program, as even cleaning techniques themselves can lead to mold infiltration. For example, during monthly wall cleaning poor technique or oversaturated wall mops can permit moisture seepage behind the coving or walls, which can rapidly result in microbial proliferation.

An ongoing evaluation of testing frequency and locations is necessary to ensure the value of the data collected. Consideration should be given to increasing the frequency of air and surface EM testing, especially with the anticipated changes to USP <797>. Methods should be developed for investigating out-of-specification (OOS) events through a corrective action and preventive action (CAPA) program involving root cause analysis and remediation as necessary, unless your local state board of pharmacy or department of health has developed mandatory requirements for remediation. Documentation for all CAPA, Root Cause Analysis (RCA), and remediation efforts is critical and ensures readiness for audits. As is frequently noted in the regulatory world, “If it is not written down, it did not happen!”

Another key component to developing a strategy for monitoring and maintaining a strong EM protocol is the establishment of an environmental monitoring committee to review results and trends. Ideally, this group should be a multidisciplinary committee that includes infection control staff, an environmental microbiologist or an industrial hygienist, key pharmacy team members, and perhaps contracted external subject matter experts. An EM committee is a mainstay in cGMP pharmaceutical research and manufacturing facilities and is a crucial element of the overall quality management system. The committee is tasked to respond in real time when EM findings arise to ensure the CAPA response and RCA investigation are appropriate. Not only is it critical to have a multidisciplinary team to support with identification and remediation, it also ensures that the ultimate decision making does not lay only with a director of pharmacy or designee. This team approach provides significant support for future regulatory inspections.

Conclusion

The ideal design for a compliant cleanroom is one that goes beyond meeting the minimum compounding standards. This requires the involvement of multiple stakeholders throughout every step of building or renovating a cleanroom. Pharmacy should engage experts in order to fully understand the impact of all decisions, from choosing cleanroom finishes to selecting disinfection products. Post-construction, thorough testing should be completed to ensure that design decisions will maximize the state of control. Similarly, SOPs should be maintained and updated as needed to ensure that EM protocols created early in the process continue to protect and promote and state of control within the cleanroom.

References

  1. Critical Point. Cleaning and Environmental Monitoring After Construction to Achieve a State of Microbial Control. Critical Point Pearls of Knowledge Newsletter. April 2018.

Elaine Strauss, PharmD, MS, BCSCP serves as the senior consultant for cleanrooms and sterile compounding at WorkingBuildings, a Trinity Consultants Company. She received her doctor of pharmacy degree in 2010 from the University of Georgia and a master of science in health system pharmacy administration from the University of Pittsburgh in 2012. In 2021, Dr. Strauss achieved Board Certification as a sterile compounding pharmacist.

Lilit Smith, PharmD, MBA, BCSCP is the manager for compounding and compliance at Baptist Health South Florida. She received her doctor of pharmacy degree in 2007 and master of business administration in 2015 from the University of Connecticut. In 2019, Dr. Smith achieved Board Certification as a sterile compounding pharmacist.

 

A clean construction protocol (CCP) describes the practice of employing increasingly clean construction methods and processes throughout construction to prevent excessive non-viable and viable particles from being introduced into and left behind within the facility as it is constructed. The CCP includes establishing a controlled access entrance, required actions for equipment and supply delivery (such as establishing an equipment wipe down area), specification of sporicidal and disinfecting agents used to wipe down all equipment, and garbing procedures specific to each of the four clean stages. The CCP stages are:

1. Normal Clean - Phase I (pre-ceiling installation)

2. Normal Clean - Phase II (ceiling installation)

3. Very Clean

4. Ultra Clean

 

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