Having the appropriate environmental monitoring in place to support manufacturing in a cleanroom or controlled environment room (CER), is another activity that Dr. D likes to put into the basic blocking and tackling category for quality management systems (QMS). If a device establishment is going to invest significant time and money into building a cleanroom or a controlled environment room, it makes zero sense not to perform proper monitoring of the environment. In fact, there are ISO standards that device companies can shamelessly plagiarize by cutting and pasting applicable requirements right into their very own standard operating procedure(s) (SOP). ISO 14698-1:2003 (Cleanrooms and associated controlled environments – Bio-contamination control — Part 1: General principles and methods); and ISO 14644 (Cleanrooms and associated controlled environments – Multiple Parts) can be used to quickly establish cornerstone requirements for any cleanroom or CER. However, fail to properly attend to the monitoring of the cleanroom or CER, and during one of those friendly visits from our friends from the agency, the attending investigator will have the ability to quickly “anathematize” (look-it-up) the Chief Jailable Officer (CJO) of the offending establishment. Being anathematized just does not sound like fun to old Dr. D. Enjoy!
Warning Letter – 21 August 2017
The FDA visited the offending establishment, and winner of the prized agency warning letter referenced in this week’s Devine Guidance (DG), for almost a full month back in April and May of 2017. The doctor is pretty sure that our friends from the agency were not in Wisconsin for the Walleye fishing. Now being rewarded with five Form 483 observations is nothing to write home about; however, providing the FDA with five responses that they deem to be inadequate will almost always earn a warning letter. It is not enough to just whisper sweet nothings into the ears of FDA. The agency actually wants to see written proof (e.g., documented evidence) that the transgressions are being corrected or have enough information to reach the conclusion that the offending establishment is on the correct mitigation path.
Warning Letter Excerpt
“(3) Failure to adequately establish procedures to control environmental conditions, as required by 21 CFR 820.70(c). Specifically, the firm failed to meet requirements described in the “Cleanroom Practices for Aseptic Operations” (SP1044). Step (b)(4) states: “There are strict environmental controls that must be maintained in the cleanrooms used for aseptic production: all surfaces inside the cleanroom must be sterilized prior to use, and environmental factors such as air flow velocity and pressure, non-viable particles, temperature, humidity, and the presence of microorganisms are monitored.” For example:
A. The clean rooms are not monitored for humidity.
B. The pressure differential in the clean rooms is not being monitored frequently; the pressure is checked (b)(4).
Additionally, the clean room pressure was recorded as (b)(4) on 5/9/2016; (b)(4) on 5/12/2016; and (b)(4) on 5/18/2016; the specification is (b)(4) and (b)(4). These out of specification results were not identified at the time of the firm’s record review.”
21 CFR, Part 820. 70 – Production & Process Controls
(c) Environmental control. “Where environmental conditions could reasonably be expected to have an adverse effect on product quality, the manufacturer shall establish and maintain procedures to adequately control these environmental conditions. Environmental control system(s) shall be periodically inspected to verify that the system, including necessary equipment, is adequate and functioning properly. These activities shall be documented and reviewed.”
Compliance for Dummies
Now Dr. D will be the first to tell my readers, the only thing the doctor knows about bacteria and colony forming units (CFUs) is that germs are bad things. The television commercials go a step further and call germs yucky. Typically, when Dr. D has questions pertaining to cleanroom monitoring and microbiology space; the doctor reaches out to his panel of experts, Tim Achuff (a superb microbiologist) and/or Stu McLaughlin (president) at Certification and Testing Services (CTS). All it takes to keep an establishment’s cleanroom and CER functioning, is a little bit of elbow grease and a reasonable monitoring program.
The good news is the ISO standards have already defined what the action and alert limits should be for a cleanroom premised on class (particulate size). There are a plethora of companies, scattered around the globe, like CTS that can perform the initial validation of the room, collect the samples, and perform/coordinate the testing. Dr. D has had the opportunity to review thousands of test reports over the years and some of the stuff found in cleanrooms and CERs would scare the living crap out of people. Obviously, from some of the reports the doctor has had the pleasure of reviewing over the years; actually has scared the crap out of the manufacturing operators and inspectors (literally and figuratively). Thank God for sterilization.
So what are the elements that should be monitored for an effective cleanroom or CER? Typically, the doctor sees most establishments monitoring:
- Viable and non-viable air;
- Viable surface;
- Relative Humidity (RH) and temperature (continuously monitored);
- Positive pressure (continuously) monitored;
- Compressed air; and
- The condition of the HEPA filters and filtration system.
Additionally, the frequency of monitoring that most establishments have in place is quarterly. Dr. Dr. believes that best practice would be monthly testing. Furthermore, all personnel enter into the controlled environment should receive adequate training. This includes contractors and other service personnel. Finally, the doctor recommends testing for species identification when action limits are exceeded and at least annually. Please note, these test reports are not considered to be confidential or privileged information under Part 820, so the FDA can review the contents of the monitoring reports and reach their own conclusions in regards to program effectiveness. Before the doctor forgets, make sure the janitorial staff are properly trained to actually clean in the cleanrooms and CERs; otherwise bad things can happen quickly (make sure thy janitors complete the cleaning log sheets).
For this week’s guidance, the doctor will leave the readers with just two takeaways. One – the testing and monitoring (all activities) of the cleanroom shall be documented in a well-written procedure. Two – device establishments are actually expected to adhere to the SOPs that they write. Fail at executing these takeaways, and the agency has takeaways of its own. They are called Form 483 observations. In closing, thank you again for joining Dr. D; and the doctor hopes you found value (and some humor) in the guidance provided. Until the next installment of DG – cheers from Dr. D. and best wishes for continued professional success.
- Code of Federal Regulation. (2017, April). Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office.
- Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon.
- Devine, C. (2013). Devine guidance for managing key attributes of a FDA-compliant quality management system – 21 CFR, Part 820 Compliance. Charleston, SC: Amazon.
- FDA’s enforcement page. (2017, September). FDA.gov Website. Retrieved October 06, 2017, From https://www.fda.gov/ICECI/EnforcementActions/WarningLetters/2017/ucm575367.htm