Cleanroom Validation - what is actually required from ISO-14644

[yannmc]

Hi all,

I need guidance on validating an ISO Class 7 cleanroom. We are a startup manufacturing an implantable medical device, which will be gamma sterilized after being packaged inside the cleanroom.
Although I’ve read the ISO-14644 standard, I feel overwhelmed by its length and numerous sections. I know the FDA doesn’t mandate a specific cleanroom testing method, I’d like your advice on what tests are truly essential so I can better prioritizing what is really required.

I know that the airborne particle testing is required, and I’ve purchased settling plates to test during the operational state. However, how often should these tests be conducted?
Do we need to always monitor temperature and humidity?

P.S the cleanroom will come with a controller that will monitor the pressure difference and the air changes every 10 seconds.

Other than that what is required to be tested weekly/monthly/annually?

Thank YOU!

 

[Nichole F]

Sampling frequency depends on the stability of your controlled environment and the risk posed to your device by excursions. I would recommend non-viable particle counts and viable sampling. Settling plates are great, but viable air particles are a valuable tool as well. Make sure your culture media is appropriate. It is best practice to use two medias to test, one for bacteria and one for fungi (TSA and PDA or SabDex are commonly used). You may want to consider surface testing as well with contact or RODAC plates. Equipment and operators have a huge impact on your cleanroom. If they are not clean, your cleanroom will not remain clean.

Initially, I would recommend you start with weekly sampling so you can establish a baseline and have historical data to compare to. If you are seeing little variation in your sampling with few or no out of specification readings, you can likely decrease the frequency. Just be careful going too long as you will need to consider the impact of an out of specification reading on all product produced since the last in-spec reading.

It is good practice to monitor temperature and humidity since warm temperatures and high relative humidity are ideal growing conditions for most bacteria. You will want to understand the impact of environmental conditions on testing results.

In addition to air exchanges, you will want to periodically assess HEPA efficiency and establish a replacement cycle. You will need to determine the frequency of your cleanroom re-qualification. Other testing will depend on the results of your routine monitoring. For example, if you are experiencing loss of pressure, you may consider a smoke study. If you are experiencing frequency viable particle out of specifications, you may need to fog the room.

Lastly, be sure you have set up a way to assess and respond to out of specifications. You will have them.

 

[yannmc]

Sampling frequency depends on the stability of your controlled environment and the risk posed to your device by excursions. I would recommend non-viable particle counts and viable sampling. Settling plates are great, but viable air particles are a valuable tool as well. Make sure your culture media is appropriate. It is best practice to use two medias to test, one for bacteria and one for fungi (TSA and PDA or SabDex are commonly used). You may want to consider surface testing as well with contact or RODAC plates. Equipment and operators have a huge impact on your cleanroom. If they are not clean, your cleanroom will not remain clean.

Initially, I would recommend you start with weekly sampling so you can establish a baseline and have historical data to compare to. If you are seeing little variation in your sampling with few or no out of specification readings, you can likely decrease the frequency. Just be careful going too long as you will need to consider the impact of an out of specification reading on all product produced since the last in-spec reading.

It is good practice to monitor temperature and humidity since warm temperatures and high relative humidity are ideal growing conditions for most bacteria. You will want to understand the impact of environmental conditions on testing results.

In addition to air exchanges, you will want to periodically assess HEPA efficiency and establish a replacement cycle. You will need to determine the frequency of your cleanroom re-qualification. Other testing will depend on the results of your routine monitoring. For example, if you are experiencing loss of pressure, you may consider a smoke study. If you are experiencing frequency viable particle out of specifications, you may need to fog the room.

Lastly, be sure you have set up a way to assess and respond to out of specifications. You will have them.

We are now planning to do the following tests as an initial stage before encountering any out-of-specification results:

1. Non-viable particle testing using a particle counter.
2. Viable particle testing using settling plates.
3. Air changes and pressure differentials monitored through the cleanroom module system.
4. Temperature and humidity monitoring using sensors.

And we can then assess other test based on the results that we receive from these main tests is that right? For example, if viable particle levels exceed the acceptable limits, we will implement corrective actions such as fogging the room (which serves as a sanitization method am guesssing?).

Aside from these, is there anything else that is essential to include? Are there any mandatory tests we should account for?


Lastly I read somewhere that when you have a ISO Class 7 room at rest, airborne particle counts can be within the range of ISO Class 8 airborne particles at operation and that is considered okay, is that correct?

 

[Nichole F]

I've always preferred viable air sampling paired with contact plates over settling plates for viable particle testing. If you have a specific area of concern for viable particles, settling plates is a good measure. Settling plates rely on a very precise I'd recommend reviewing ISO 14644-3. I don't have access to a copy, but it should cover what test methods you should employ to maintain the desired production environment. There are other documents in the ISO 14644 series you might find helpful.

You absolutely can (and should!) reassess if your testing methods are appropriate based upon your historical results and the impact of an out of specifications result on your cleanroom environment and the bioburden of your end product. Just be sure when you are doing trend analysis that you are comparing like to like tests.

If you exceed the viable particle levels, fogging is certainly an option, but be sure that you do your root cause investigation before jumping to that corrective action. There may be less burdensome actions you can take.

To answer your last question, you are correct that if a room is ISO Class 7 at rest, it is highly likely it will not meet the requirements of Class 7 area in use. This is why it is critical to define your requirements for the room (or define the necessary infrastructure to support the manufacture of your device) clearly. Not every company defines in-operation limits so consider if you even need to do so (especially for non-viable particles).

I hope this information helps!

 

[yannmc]

Thank you so much! Its been great help!!