How to identify the causes and establish long- and short-term solutions to eliminate these costly events in your pharmaceutical/biotechnology facility
By Elaine Kopis Sartain
I frequently visit pharmaceutical and biotechnology facilities to provide assistance in troubleshooting of microbial excursions—environmental data that is at or above established action limits for the regulated area—as well as training on cleanroom contamination control. These activities have allowed me the opportunity to develop guidelines on the key causes of microbial excursions and establish both long- and short-term strategies to address these potentially costly events.
Thousands of hours and incalculable dollars are devoted to activities related to microbial excursions, such as investigation of the root cause, implementation of corrective actions and determination of whether or not the product manufactured in these areas was placed at risk.
In some cases, product rejection may occur, greatly increasing the cost of environmental excursions. Any time there is an excursion, there is generally a question of whether or not laboratory error has occurred. While this should be investigated as a possible cause, the other areas discussed are more likely to be the causes and should be used as a guide during microbial excursion investigations.
Begin the investigation
In terms of investigating an excursion, there are several pieces of information that may be required. Knowing the identification of the microorganism detected is a key place to start. By knowing the microorganism, at least to the genus level, you can determine several things including the source—soil, water, human-borne—and whether or not your sanitization program has failed due to inappropriate product selection. This is, of course, predicated on having either a validation study conducted on the product that involves the isolated organism or a scientifically valid presumption of performance.
For example, it is well established that bacterial endospores are susceptible to oxidizing chemicals and are relatively unaffected by exposure to phenolics, quaternary ammonium compounds and alcohol. If you have in vitro data demonstrating that the product is capable of killing the organism, then it's a question of whether the product was used correctly. Product failure alone is rarely the problem, assuming that the correct product is selected in the first place.
Most disinfectants and sanitizers designed for cleanroom use have been formulated to handle fairly high levels of target microorganisms and heavy soil loads, both of which are not typically found in cleanrooms. Instead, the problem lies in product application techniques that fail to address important control parameters such as concentration, temperature, contact time and coverage.
Trouble in the SOPs
In reviewing hundreds of cleaning standard operating procedures (SOPs), I have found numerous examples of such problems, including incorrect product identification, incorrect dilution instructions and no stipulation on the volume of disinfectant to be used for a designated area.
I recently observed cleaning during which the operator saturated the mop, wrung it and proceeded to mop an extremely large area without once returning to the bucket to resaturate the mop. In this situation, some areas had sufficient wetting with the disinfectant and others did not.
Another area of concern is contact time. Most SOPs I have reviewed will stipulate a defined contact time during which the surface is to be wet with the disinfectant or sanitizer. This time period is based on either manufacturer's instructions or internal validation work. However, there is generally no control over this parameter, and in most cases, it's unknown whether or not the stipulated contact time is being met. The disinfectant will only work if it is in wet contact with the surface to be decontaminated.
As the situation above indicates, contact time and application techniques may be related.
Let me speak to your manager
The question may also arise whether the area is experiencing microbial control problems due to personnel management issues. For example, while consulting at a facility recently, it was brought to my attention that the supervisor of one manufacturing area had directed his staff to place concentrated disinfectant directly from the one-gallon product container onto the floor and then disperse the concentrate with a water-dampened mop rather than to diluting and applying the disinfectant following SOP instructions.
The best way to prevent microbial problems from occurring is with proper facility design and well-developed training programs which address personal accountability as well as technical training.
This was done with no consideration for current good manufacturing practice (cGMP) compliance or worker safety, and is an example of deliberate nonconformance. Not all personnel management issues are so extreme, but this type of attitude by a management-level person generally leads to nonconformance from others in the area.
There are many other examples of non-deliberate behavior, such as operators removing goggles in order to see better, scratching their heads under their hoods, etc. I recently observed an operator in an ISO Class 7 fermentation suite place an operations manual onto the floor to review instructions in proximity to the bioreactor. After he had completed his adjustments, he placed the manual back onto a worktable.
I also recently observed an operator in an ISO Class 5 filling room raise her goggles while inside the filling area due to fogging. In these examples, the operators were not thinking about the contamination aspects of their behavior. Regardless of whether the behavior is deliberate or not, contamination control problems may be the unintentional result.
One thing to keep in mind is that within manufacturing areas we are trying to control particles that are largely non-visible (0.5 micron), including microorganisms. Therefore, there may not be visual indicators of problems, such as heavily soiled floors and walls. Since we can't see the skin flakes being shed or the myriad of other human contaminants we may be introducing, much less the actual microorganisms that we are trying to control, adherence to good procedures is paramount to maintaining control. Adherence to procedures is also a cGMP requirement.
Training on basic microbiology and chemistry should convey an understanding of the diverse nature of organisms and the variety of chemical means by which they can be safely controlled.
Over the years, I have noted an increasing trend among middle management and frontline supervisors. All too often, instead of supervising or managing, these critical employees are attending meetings, conducting non-compliance-related investigations and taking part in the paper chase that is considered an anathema, yet a significant requirement for this industry.
In the face of reduced supervision, effective training is more important than ever in ensuring compliance. This training should include job-related SOPs, basic microbiology, basic chemistry and cGMPs. Because reading comprehension varies tremendously from one individual to another, whenever possible, SOP training should include three elements:
Read It: Review the document and ask clarifying questions of an experienced operator or supervisor.
See It: Observe an experienced operator executing the SOP.
Do It: Execute the SOP under the observation of an experienced operator or supervisor.
Basic microbiology and chemistry training should be designed to convey an understanding of the diverse nature of microorganisms, their sources, and the means by which they may be remediated. Appropriate chemical hygiene and safety in preparation and handling of disinfectant use dilutions should also be addressed.
Not ready for prime time
Often in the face of effective training, supervision and cleaning techniques, contamination control problems persist due to the poor conditions or design limitations of the manufacturing facility. I have toured several facilities that were simply not designed for the manufacturing taking place inside.
For example, several years ago I toured a sterile IV solutions manufacturing site that was approximately 50 years old. The building had undergone many additions and a new filling room had been added onto an original outside wall. There was a door in this wall that had originally served as the exit to the outside area. This door was left in place after the expansion, even though it was not to be used for traffic.
While I was standing in the hall talking with the area supervisor about current microbial control problems, someone walked up to the door, which was posted with a “Do Not Open” sign, and opened the door to say something to the operator working over at the ISO Class 5 filling area inside this ISO Class 7 room. The casual manner in which this was done indicated that this type of behavior occurred quite frequently.
If the operator were better trained and supervised this would never have happened. One could also argue that if the unnecessary door was not available to open, this would not have happened—both are certainly valid points. Systems that rely on proper human behavior are difficult to control; therefore, whenever possible, human traffic should be engineered to avoid contamination of critical areas.
It's all in the design
While there are several ways to address microbial problems once they are identified, the best way is to prevent them from occurring with proper design. Proper design includes traffic control measures that don't allow for multidirectional traffic in critical manufacturing areas.
I have toured facilities which, due to design constraints, have one entry to the manufacturing area used as both a gowning area and a pass-thru, greatly increasing the likelihood of cross-contamination. I have also seen facilities in which significant rust and surface damage is present.
Damaged surfaces are difficult to decontaminate; in some cases, the only solution is to replace the surfaces, such as floors and biosafety hoods. Additionally, facilities must have adequate HVAC and HEPA filtration.
I recently toured a facility that must use supplementary dehumidifiers during the summer months due to design limitations. In this situation, by the time the dehumidifiers were brought online, mold excursions had already occurred. I have also seen facilities that don't monitor or review pressure readings and humidity and temperature spikes. This is important data that can provide valuable insight into the root causes of excursions, and should be reviewed as part of the investigation.
Many facilities do address personnel management problems and design problems by increasing cleaning frequency. Cleaning frequency may be increased as a way to improve these issues; however, it is not a magic bullet. There should be a plan to address the “root causes” of the contamination control problems rather than merely establishing an over-dependence upon a chemical solution. An over-dependence on the chemical solution may lead to other problems, such as corrosion and residue.
Develop a plan to address “root causes” by reviewing data in the context of activities. In this way, a cause and effect relationship may be isolated, which leads to a sound strategy and better contamination control. Establishment of cause and effect relationships is easy to suggest, but may be challenging to implement because the cause may be hidden from observation.
For example, damage behind walls and in interstitial spaces may lead to endemic mold problems, but is difficult to detect. However, as this document demonstrates, there are many obvious causes of contamination control failures, such as cleaning and facility deficiencies and personnel behavior problems that occur everyday by both well-meaning and well-trained personnel.
Commence the balancing act
The key to success in combating these problems is to first understand them. Observation, documentation, retraining and facility upgrades will subsequently lead to better compliance and fewer microbial excursions.
Effective contamination control is a balancing act. It requires a thorough understanding of both the key contributors and the key barriers to contamination: cleaning/sanitization programs, facilities design/condition and personnel management. Failure to address these key issues both from a tactical and a strategic standpoint leads to the time and expense invested in investigating excursions, and potentially in rejected product.
Elaine Kopis Sartain is director of technical services with Steris Corp. and a member of the CleanRooms Editorial Advisory Board. She can be contacted at [email protected].