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Effective Execution of the Microbial, Environmental, & Utility Testing in Cleanroom Qualification

Kevin Heiser
Effective Execution of the Microbial, Environmental, & Utility Testing in Cleanroom Qualification

The commissioning of a cleanroom is a complex and crucial process with many stages that start after the rooms are designed and built. The ultimate goal of cleanroom commissioning is to confirm that the controlled space will have a robust, clean and safe environment for the processing of drug products, medical supplies, or other manufactured products.

The first step of commissioning is the qualification of the air handling systems and HEPA filters, which involves establishing the appropriate airflow rates, patterns and pressure differentials. Airflow should move from a cleaner classification to a less clean one. Smoke studies are also sometimes implemented during this stage to visually confirm that the airflow is acting appropriately within the space. It is always appropriate to consider performing a smoke study within spaces where open processing will occur. Next, temperature and relative humidity will be confirmed to be within the appropriate parameters required for the clean space. Having the correct temperature and relative humidity, along with a robust cleaning program, will help to contain the introduction and growth of bacteria or mold species. If all of these requirements are met, the commissioning process will move onto the final step – the comprehensive testing associated with the qualification of the environment through environmental monitoring (EM) and utilities monitoring.

There are many different approaches for EM, to show cleanroom spaces are in control. The most common approach contains three specific stages. It begins with baseline surface sampling, where the goal is to confirm in the cleanliness of the clean room following the construction cleaning. These samples are expected to have microbial recovery. Next, once the facility has been triple cleaned, static monitoring of air and surfaces begins. This stage of the qualification process demonstrates that the air handlers and disinfection procedure utilized for the facility are working properly, and that the microorganisms recovered during the baseline are no longer present. Expected results are low to no microbial recovery, and particle counts below specification. Last is dynamic sampling, where the same sampling types used during static monitoring are used, but with more people present and simulated manufacturing processes ongoing. During this operational condition, the goal is to confirm that results collected from the rooms are still within the required specifications. All phases of the qualification should be performed in replicate to ensure enough data points are present to see an overall picture of the cleanliness and operation of the clean room.

Here are some of the efficiencies that have been developed at Boston Analytical to ensure a smooth cleanroom qualification process:

  • A deep understanding of the regulations that must be followed to build a qualification – USP, EP, JP, ISO 14644 all have bits and pieces to the puzzle. The best place to go is PDA technical report 13, which brings everything together. It’s important to design the qualification study to meet the most stringent requirements for the regulations.

  • Effective EM protocol development – Commissioning protocols tend to focus on the air handling capabilities and design of the cleanroom, and often do not contain much instruction for the EM qualification portion of the process. It is important to ensure that sufficient detail is contained in the EM sampling protocol to handle the process from an execution standpoint.

  • Selection of sampling sites – The main purpose of sampling should be to provide meaningful data that can help uncover potential contamination problems associated with personnel flow, material flow, and the processes occurring within a cleanroom. Air sites, both air viable and air non-viable are typically setup following ISO chapter 14644 in a grid like manner, but a risk assessment should also be performed during site selection so that sites are placed in areas close to operations and/or open processing. Surface sites should be selected based on the location of process operations, in areas that demonstrate the equipment and personnel flow into the space is controlled, and in places that demonstrate that the disinfection process is working.

  • Execution of the sampling events – Work with a company that can help plan for all of the things that are involved during the sampling event. Is all of the equipment present in the facility prior to start of execution? Can the environment be truly static during sampling? How can you ensure that? Have you defined the maximum amount of people that can be present at a given time within a room during dynamic sampling? Do you need office and contract lab personnel in order to fill the suites?

  • Documentation of sampling – Definition of the parameters that are important for you to document (e.g. number of people in the room, sampling times, instrument calibration information, operations occurring during dynamic monitoring, etc.). If using a contract lab, will you need calibration certificates, or other forms of documentation? Many of these pieces are often overlooked, and can lead to a critical gap in your documentation.

  • How will you respond to alert and/or action level excursions? This should be defined in your qualification protocol. Will there be additional cleaning before resampling can occur? How many times will the site need to be resampled if a failure occurs?

  • Final reporting of data – Contract labs can work with you to provide a data deliverable that is fit for your purpose. Find out if they have the expertise to put together a comprehensive summary report that can be filed as an attachment to the overall commissioning report. There is no need to create a report from CofAs if your executing lab has the expertise.

While qualifying the environment of the clean room itself is important, understanding the performance and quality of the gases you employ in your manufacturing facility is also something that should be considered. Similar to the EM sampling that goes into clean room qualification, system release for a gas system should also follow a strategic approach. Because gases are in a closed system, there is no need for static or dynamic testing. Rather, the focus should be on testing in replicate to gain a solid picture of the control and cleanliness of the gas being qualified. Here are some things to think about when starting a gas monitoring qualification.

  • Typically, you want to look at viable air, non-viable air (particulates), moisture/dew point, and hydrocarbon when qualifying gas system.

  • Don’t do hydrocarbon testing if the air compressor you employ doesn’t use oil – it is useless data.

  • If using a flammable gas source in your process (e.g. 100 % oxygen), you will not be able to evaluate particulates, and that’s okay. Particle counters use a laser to count particles as they pass through the machine and are not intrinsically safe. If there were to be a spark as the oxygen passed through this laser, it could cause a fire and/or explosion within the unit and gas line.

Commissioning of cleanrooms is a complex process, and finding the correct partner to develop or execute the testing is important. Whether you need a protocol written, sampling performed, or risk assessment done, Boston Analytical has the expertise and industry experience to help you meet your goal.