Dr. Christopher Joseph Devine, President, Devine Guidance International
Devine Guidance

Poor Cleanroom Controls + Non-Validated Sterilization Process = Recipe for a Warning Letter!

By Dr. Christopher Joseph Devine
Dr. Christopher Joseph Devine, President, Devine Guidance International

If an establishment is manufacturing finished medical devices that are sterile, there should never be any excuses for not properly maintaining and monitoring the cleanroom or CER.

Environmental controls and the subsequent monitoring of clean rooms, coupled with product sterilization are of immense importance to medical device manufacturing establishments. In fact, the agency also takes the application of environmental controls and the validation of sterilization activities extremely seriously. 

The doctor is just not sure how an establishment that fails to control their cleanroom or fails to properly validate their sterilization processes can call their product sterile, safe and effective in its intended use. Me thinks it is not possible as the potential for those tiny little things called “bugs and bad germs” have the ability to leave their tiny-little skeletal remains on finished devices, yuck! 

An FDA inspection can clearly have a “fissiparous” (look-it-up) effect on device establishments that fail to comply with the quality system regulation, including control of environments and the validation of sterilization processes. Once the agency awards offending establishments with one of those prized warning letters; all bets are off as organizations begin the mad scramble to become whole again in the eyes of FDA. That being said, Dr. D hopes you enjoy this week’s guidance. 

FDA Warning Letter Dated – 01 April 2014

In January of this year, FDA visited East Troy, Wisconsin for 17 frigid days. The doctor’s guess is that the ice fishing must have been excellent to keep the agency around for so long. Seriously folks, ice-fishing in a snow storm, with plenty of good bourbon to keep warm, it just doesn’t get much better than that; unless it is a snow storm and an FDA inspection.

During a visit to a device establishment in East Troy, FDA identified six observations that when compiled into one inspection report was deemed worthy of a warning letter. On a serious note, FDA did go fishing in East Troy; however, it wasn’t for Walleye, it was for Form 483 Observations. The fishing must have been pretty good because the observations were whoppers.

One of the observations that Dr. D found particularly disturbing was the offending establishment’s failure to adequately control their cleanroom environment. Equally disturbing was an inspectional observation that was rooted in the sterilization process not being adequately validated. Now wait just a darn minute Dr. D, we have a cleanroom not being adequately controlled and then the sterilization process not validated. Considering the offending establishment manufactures bone-void fillers, can you say that these types of system failures can result in serious product safety and efficacy issues? Can you say an increase in the potential for infection?

Warning letter

1. Failure to adequately establish procedures to control environmental conditions, as required by 21 CFR 820.70(c).

a. Your firm failed to investigate clean room environmental monitoring results that reached the alert or action limits as required by your procedures:

  • “Air Particle Monitoring,” Doc # CR 02-001, Revision 08, Effective 3/4/2013;
  • “Air Microbial Monitoring,” Doc # CR 02-002, Revision 07, Effective 3/4/2013;
  • “Contact Microbial Monitoring,” Doc # CR 02-005, Revision 05, Effective 3/4/2013. 

The procedures require QA and/or Executive Management notification if results are above the limits and an investigation must be conducted. When the action limit is reached, a start-up cleaning procedure must be performed and retesting completed prior to production resuming. 

The following results were observed to have reached the action or alert limits. An investigation was not performed; nor was the start-up cleaning procedure and re-testing completed prior to production activities resuming when the action limits were reached. 

  • Air Particle: (b)(4) out-of-specification result for alert limits reached 1/10/2014 for (b)(4) testing;
  • Air Microbial:  (b)(4) out-of-specification result for bacteria action limits reached 1/16/2014; one out-of-specification result for bacteria alert limits reached 12/23/2013;
  • Contact Microbial:  (b)(4) out-of-specification results for bacteria alert limits reached 11/18/2013 and 12/23/2013.

b. Your firm failed to establish parameters for monitoring room temperature and humidity in your clean room. Your procedure “Temperature and Humidity Monitoring,” CR 02-003, Revision 03, lacks acceptance criteria to ensure the clean room is operating in a controlled environment. 

c. Your firm failed to establish alert limits and action limits for air particle, air microbial and contact microbial testing performed in the “Gowning Room.” The Gowning Room is part of your firm’s clean room environment. 

2. Failure to adequately validate a process whose results cannot be fully verified by subsequent inspection and test according to established procedures, as required by 21 CFR 820.75(a). 

Specifically, your firm failed to validate the sterilization process to ensure the following parameters were included, per the ISO 11137 standard, which you referenced as following in the validation plan “(b)(4) Validation Plan for the Bone Void Filler” approved 4/19/2010.

  • Dose mapping was not performed; 
  • (b)(4) production units were not submitted for dosing at (b)(4) to substantiate the minimum sterilization dose of (b)(4); 
  • Product was not submitted for testing in August 2010 to maintain assurance that a change in product bioburden did not occur as required by the standard. 

Your firm lacks the following specifications for your sterilization process as required by the standard:

  • The description of packaged product, including dimensions, density and orientation of product within the package and acceptable variations; 
  • The loading pattern of product within the irradiation container; 
  • The conveyor path(s) to be used; 
  • For product that supports microbial growth, the maximal interval of time between manufacture and completion of irradiation; 
  • The routine dosimeter monitoring position(s); 
  • The relationships between the dose at the monitoring position(s) and the minimum and maximum doses; 
  • For product that is to be given multiple exposures to the radiation field, any required re-orientation between exposures.” 

Subpart G – Production and Process Controls

Sec. 820.70 Production and process controls
(a) General. Each manufacturer shall develop, conduct, control, and monitor production processes to ensure that a device conforms to its specifications. Where deviations from device specifications could occur as a result of the manufacturing process, the manufacturer shall establish and maintain process control procedures that describe any process controls necessary to ensure conformance to specifications. Where process controls are needed they shall include:

  1. Documented instructions, standard operating procedures (SOP’s), and methods that define and control the manner of production; 
  2. Monitoring and control of process parameters and component and device characteristics during production; 
  3. Compliance with specified reference standards or codes; 
  4. The approval of processes and process equipment; and 
  5. Criteria for workmanship which shall be expressed in documented standards or by means of identified and approved representative samples. 

(b) Production and process changes. Each manufacturer shall establish and maintain procedures for changes to a specification, method, process, or procedure. Such changes shall be verified or where appropriate validated according to 820.75, before implementation and these activities shall be documented. Changes shall be approved in accordance with 820.40. 

(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.

(d) Personnel. Each manufacturer shall establish and maintain requirements for the health, cleanliness, personal practices, and clothing of personnel if contact between such personnel and product or environment could reasonably be expected to have an adverse effect on product quality. The manufacturer shall ensure that maintenance and other personnel who are required to work temporarily under special environmental conditions are appropriately trained or supervised by a trained individual.

(e) Contamination control. Each manufacturer shall establish and maintain procedures to prevent contamination of equipment or product by substances that could reasonably be expected to have an adverse effect on product quality.

(f) Buildings. Buildings shall be of suitable design and contain sufficient space to perform necessary operations, prevent mixups, and assure orderly handling.

(g) Equipment. Each manufacturer shall ensure that all equipment used in the manufacturing process meets specified requirements and is appropriately designed, constructed, placed, and installed to facilitate maintenance, adjustment, cleaning, and use.

  1. Maintenance schedule. Each manufacturer shall establish and maintain schedules for the adjustment, cleaning, and other maintenance of equipment to ensure that manufacturing specifications are met. Maintenance activities, including the date and individual(s) performing the maintenance activities, shall be documented. 
  2. Inspection. Each manufacturer shall conduct periodic inspections in accordance with established procedures to ensure adherence to applicable equipment maintenance schedules. The inspections, including the date and individual(s) conducting the inspections, shall be documented. 
  3. Adjustment. Each manufacturer shall ensure that any inherent limitations or allowable tolerances are visibly posted on or near equipment requiring periodic adjustments or are readily available to personnel performing these adjustments. 

(h) Manufacturing material. Where a manufacturing material could reasonably be expected to have an adverse effect on product quality, the manufacturer shall establish and maintain procedures for the use and removal of such manufacturing material to ensure that it is removed or limited to an amount that does not adversely affect the device’s quality. The removal or reduction of such manufacturing material shall be documented.

(i) Automated processes. When computers or automated data processing systems are used as part of production or the quality system, the manufacturer shall validate computer software for its intended use according to an established protocol. All software changes shall be validated before approval and issuance. These validation activities and results shall be documented. 

Complying with the regulation

Now granted Dr. D will be the first to admit, he is not a microbiologist, so the doctor’s extent on understanding the importance of cleanrooms is limited to the basic understanding that germs are bad things, yuck! However, the doctor does understand the salient concept of placing proper cleanroom controls in place, including the monitoring tools to ensure the sterility of finished medical devices. 

For starters, cleanrooms and Controlled Environment Rooms (CERs) must be validated before the manufacturing of production finished medical devices commences. There are two states that require serious validation, California and Illinois (just kidding). Seriously, the two states are: (a) no activity being performed (inactive state) a.k.a., empty cleanroom/CER; and (b) personnel actually performing work, a.k.a., active state. Dr. D. recommends obtaining and reading the ISO 14644 series of standards that govern cleanroom environments. 

Furthermore, there are organizations that can actually perform all of the testing/monitoring of cleanrooms/CERs for device establishments. For you industry stalwarts, you already know the drill. For you novices, there are companies that specialize in cleanroom testing and monitoring services. So let’s talk about the content of the procedure and what device establishments need to consider for their cleanrooms/CERs controls and monitoring. Dr. D recommends assessing the following requirements for inclusion into a well-written procedure:

  • Temperature and humidity; 
  • Surface microbial; 
  • Airborne microbial; 
  • Airborne particulate; 
  • Bioburden requirements; 
  • Validated alert and action limits; 
  • Corrective action requirements for retesting when alert and action limits are exceeded; and 
  • Requirements when the sterile area is violated, e.g., emergency evacuation of the cleanroom/CER. 

Additionally, there is no point in having controls in place if there are no procedures for gowning/personal hygiene and the actual cleaning/maintenance of cleanrooms/CERs. For example, there are industry-acceptable standards for gowning such as washing one’s hands after visiting the restroom. 

It is now time for a quick Dr. D story. Several years ago Dr. D had the pleasure of investigating a surface microbial action limit failure that resulted in so many Colony Forming Units (CFUs), the lab was unable to count the CFUs. I believe the comment was; “Off-the-charts baby!” The lab ultimately identified the offending material as fecal matter. In short, it appeared someone crapped on their hands and then started assembling medical devices. Excuse me, but what about washing your hands people. Fuel for thought, the next time you let someone borrow your cell phone, just maybe this person left the restroom in a hurry.

Furthermore, the janitorial staff (typically contractors) must be properly trained in cleanroom/CER etiquette, including proper gowning techniques. Did the doctor mention that this training needs to be documented? Finally, all of the activities performed by the janitorial staff should be documented in a janitorial log, including the germicides being employed to wipe down surfaces (please do not forget to change the surface cleaners frequently). Why, because these bad germs can eventually become immune to solutions such as alcohol diluted with water. In fact, if the germs could talk, after a few months of using alcohol and water, they would probably say; “Hey dude a little less water and more alcohol please.” 

Folks, please remember, managing an environment, cleanroom, CER, or other, is not rocket science. The monitoring and maintaining of environmental conditions should never result in Form 483 observations or in a warning letter. Although the doctor is not a big fan of “football metaphors” one that is quite appropriate for the monitoring and measuring of cleanrooms and CERs is basic blocking and tackling. In football, as in medical devices, poor execution will result in an unsatisfactory outcome, e.g., a loss in football or an agency warning letter if the FDA believes the violations are egregious. 


For this week’s guidance, the doctor will leave the readers with just two takeaways. One – please wash your hands after leaving the restroom. Two – if an establishment is manufacturing finished medical devices that are sterile, there should never be any excuses for not properly maintaining and monitoring the cleanroom or CER. It is Dr. D’s strong opinion; “If the cleanroom is not being properly maintained and monitored, then it will be problematic guaranteeing device sterility, especially if the sterilization process is not validated.” 

In closing, thank you again for joining Dr. D and I hope you find value in the guidance provided. Until the next installment of DG – cheers from Dr. D. and best wishes for continued professional success. 


  1. Code of Federal Regulation. (2013, April) Title 21 Part 820: Quality system regulation. Washington, D.C.: U.S. Government Printing Office. 
  2. Devine, C. (2011). Devine guidance for complying with the FDA’s quality system regulation – 21 CFR, Part 820. Charleston, SC: Amazon. 
  3. FDA’s enforcement page. (2014, April). FDA.gov Website. Retrieved April 25, 2014, from http://www.fda.gov/ICECI/EnforcementActions/WarningLetters/ucm393126.htm 
  4. ISO 14644-1:1999. (1999). Clean rooms and associated controlled environments – Part 1: Classification of air cleanliness. 
  5. ISO 14644-2:2000. (2000). Clean rooms and associated controlled environments – Part 2: Specification for testing and monitoring to prove continued compliance with ISO 14644-1. 
  6. ISO 14644-3:2005. (2005). Clean rooms and associated controlled environments – Part 3: Test methods.

About The Author

Dr. Christopher Joseph Devine, President, Devine Guidance International