The use of disinfectants in a cleanroom requires a robust supplier quality approval program for each product, knowledge of the efficacy of the chosen disinfectant, and appropriate operator training in the application method. Each of these requirements is critical to successful outcomes for contamination control.
When selecting a disinfectant for use in a cleanroom environment, an important aspect to consider is the product format, whether that is a trigger spray bottle or aerosol used to spray and wipe, pre-saturated wipes, mopping systems, pressurized spray systems or automated vapor bio-decontamination.
In many cleanroom settings, disinfectants are often delivered by either trigger sprays or aerosols, particularly for smaller surfaces. Trigger spray systems can offer significant advantages over aerosols, which is discussed in more detail later. However, there can be a significant potential drawback with some traditional trigger sprays, which are not always robust, validated closed systems.
Contaminated air can be drawn back into the bottle during use (‘suck back’), potentially compromising the sterility of the liquid.
This risk is acknowledged in the PIC/S Recommendation on the Validation of Aseptic Processes2 which states:
“9.4.1 There should be documented procedures describing the preparation and storage of disinfectants and detergents… Disinfectants and detergents used in Grade A and B areas should be sterile at the time of use. If spray bottles are used they should be sterile before being filled and have a short in-use shelf life.”
With the use of traditional trigger sprays, either those prepared and filled (and re-filled) on-site, or ready-to-use trigger sprays purchased from a third-party manufacturer, sterility assurance often cannot be maintained throughout use.
The requirement for disinfectants and detergents used in high-grade areas to be sterile, and for sterility to be maintained for the period the product is in use is outlined also in EU Annex 13 which states:
”4.35 Disinfectants and detergents used in grade A and grade B areas should be sterile before use. Disinfectants used in grades C and D may also be required to be sterile where determined in the CCS. Where the disinfectants and detergents are diluted/prepared by the sterile product manufacturer, this should be done in a manner to prevent contamination and they should be monitored for microbial contamination. Dilutions should be kept in previously cleaned containers (and sterilized where applicable) and should only be stored for the defined period.”
A key differentiating factor to reduce contamination risk in sterile disinfectant sprays is the design of the bottle and dispensing system.
Risk Reduction by Design
Common sterile disinfectant ready-to-use sprays are available in the market in either trigger spray or aerosol format.
When choosing a dispensing system, certain parameters are important to ensure the safety, efficacy, and efficiency of the disinfectant desired. The key parameters to consider are:
- Adequate coverage of surface area intended to be disinfected through variable spray patterns
- A ‘closed system’ that prevents contamination during use
- In-use expiration based on maintenance of sterility
- Validation documentation supporting the above parameters
- The ergonomic design of the bottle
- Design allowing full use of contents, negating the need for waste specialist bottle disposal where hazardous contents remain.
The SteriShield™ Delivery System (SDS) was developed for the ready-to-use sterile disinfectant products (for the Klercide™ brand) to be provided in a closed system that maintains sterility of the disinfectant during its use, in a cleanroom compatible bottle.
The system utilizes a valved trigger spray and an integral bag inside the bottle to hold the liquid. The function of the bottle is simply to enclose and protect the product within the bag throughout use.
The only point of entry into the one-piece system, i.e. the “bag in the bottle”, is the neck of the bottle which is completely sealed by the patented precision-engineered trigger head, thereby creating a closed system. This prevents any air from being drawn back into the bottle when the trigger mechanism is operated, unlike a conventional trigger spray bottle, which is designed to allow air to return into the bottle to equalize the pressure and prevent the bottle walls from distorting or collapsing as the bottle is emptied.
In the new system, the integral bag collapses as the liquid is used, ensuring that all the contents can be dispensed. As fluid is drawn out of the bottle a vacuum is created within the bottle (as no air returns to equalize the pressure). Two small holes in the base of the bottle allow the air pressure around the integral bag to equalize, thereby preventing the outer bottle from collapsing.
Validation testing was performed on the delivery system bottle for both sterility and in-use expiry.
A Validated Closed System
Simple vacuum test
Testing was performed to validate that the closed system ensured a vacuum was maintained by the trigger system. Transparent bottles were tested with both a traditional trigger system with a bag in bottle design, and the trigger system.
Colored fluid was initially added to the bottles and then both were dispensed, with 250ml of the liquid expelled. The bottles were left to stand for 24 hours and observed for a change in the fluid level. After 24 hours the traditional trigger bottle showed a significant decrease in fluid level in the bag, which indicates a loss of vacuum (bottom images). In contrast, the bottle showed no decrease in fluid level, thus no loss of a vacuum (top images). This test demonstrated that the new delivery system is an ‘air-tight’ closed system.
Media fill testing
Media fill testing was also performed using two different types of microbiological broth media, Tryptone Soya Broth (TSB) and Fluid Thioglycollate Medium (FTM).
A total of 90 bottles were filled with the media in a Grade A cleanroom environment. Bottles were then irradiated at 25 kGy within 24 hours of filling. Standard sterility and growth promotion were performed on three bottles of each medium post-irradiation, to show that the media had been successfully sterilized and that the media could still support growth, with all results passing.
The remaining bottles were transferred to a Grade D access area, and sprays were actuated five times on the jet setting (representing the largest aperture opening) every week for 24 weeks to simulate use before the bottles were returned to storage.
A set of 24 bottles with standard trigger spray systems were treated the same way as described above.
To understand and quantify the challenge the bottles were subjected to in the Grade D environment, environmental air samples (90mm settle plates) and finger dabs were taken each time the samples were actuated in the test area. The average air sample result was five cfu per plate.
The average finger dab result was one cfu per plate.
All test results for the bottles showed no growth over six months. The standard trigger system samples showed variable positive growth occurring within the same timeframe. These results support that the integrity of the delivery system is not compromised.
Validation of the SDS Using Particle Counting
In addition to the microbiological media testing, another way of showing that the system prevented air ingress and potential contamination from being brought back into the closed system during use was using cleanroom particulate monitoring.
The delivery system is a two-piece system, consisting of the bottle with an integral bag and the trigger head. This validation study explored the potential risk of contamination being brought into the system via the only point of entry: the trigger head. A test system was developed with a one-liter bottle and a remote particle counter connected by tubing (with a HEPA-filtered inlet) through the bottle fitted with and without the new delivery system.
The trigger heads under test were attached to the bottle and air was pulled through the system via the pump. The trigger was then used for approximately one minute with the same number of actuations required to remove 100ml of liquid (the number of aspirations will depend on the dispense volume of the trigger).
Controls were also run to show the particles entering a bottle with no trigger head fitted, along with background counts in the testing room. “The objective was to see what was happening to the air within the bag while the trigger system was in use, i.e. was the outside air being drawn in, thereby creating a potential chance of contamination.”1
It was clear from the results that the use of a conventional venting trigger spray head will lead to the ingress of particulate contamination and therefore potentially viable contamination inside the bottle and sterile fluid during use.
Considering that the particulate values in this study are only for the evacuation of approximately 100ml of the contents, then the risk in use is even greater. The trigger head used on the new delivery system clearly showed that no air enters the bottle, demonstrating that air is not drawn into the system when in use, therefore preserving the integrity of the contents and providing a sterile product throughout use.4,5
Lean Design and Efficiency
Utilizing a leak-tight bag in the bottle system will improve the dispensing of the full bottle contents and thus lower the risk of environmental disposal concerns.
The inner bag is sealed to the outer bottle at select locations to prevent the dip tube from being blocked by a collapsed bag, allowing for complete dispensing of the contents.
Testing was performed to evaluate the expulsion of product from each of the 222 bottles fitted with the SDS. Using a graduated cylinder, the contents of each bottle were sprayed into the collection device until no further product could be expelled. Some bottles were emptied over a set amount of time, and some bottles were emptied with a set amount of fluid repeatedly expelled over different periods.
The fluid left in each bottle was measured and recorded. The average amount of fluid that was left in the bottles that were immediately emptied was 1.89mL. The average amount of fluid left in bottles emptied multiple times over a set time was 2.67mL.
Due to the very small amounts of liquid that remain in the system after use, in most circumstances, the empty SDS trigger spray bottles can enter standard waste streams (subject to local regulations), rather than having to be treated as specialist or hazardous waste.
Aerosols Versus SteriShield™ Delivery System
A decision to choose a 70% IPA (isopropyl alcohol) trigger spray over an aerosol may be based on the desired droplet size, surface coverage, operator health and safety (exposure and potential for work-related upper limb disorders from repeated trigger actuation), and environmental impact or waste disposal.
Aerosol canisters dispense and disperse very small droplets that stay airborne longer and increase the concentration of alcohol in the air. This can increase the risk of volatile organic compound (VOC) exposure, particularly in small, contained environments (such as cleanrooms).
Trigger sprays dispense and disperse larger-sized droplets leading to a lower airborne concentration of VOC and, thus less atmospheric exposure time for operators.
The SDS trigger spray design also allows for a variation in the dispersion pattern. This variation along with the larger droplet size allows for a more consistent and adequate coverage on the application surface or material.
Aerosol canisters dispense alcohol under pressure and often do not empty fully if the propellant runs out, and thus require specific waste requirements to dispose of properly. As discussed, the SDS system can be fully emptied, potentially reducing the cost of disposal.
Summary
The SDS is a validated technology innovation for a disinfectant trigger spray system that provides added assurance for a sterile cleanroom operation to reduce the risk of microbial contamination and develop a more robust contamination control strategy.
It is critical to build control into an aseptic pharmaceutical operation by seeking and using all options currently available to minimize risk, including quality design.
The validation data demonstrates that not only does the SDS function as a “closed” trigger system which enables a recommended three-month in-use shelf life to be assigned, but it also aligns with customers’ requirements for a practical, cleanroom-compatible, trigger spray.
The SDS also enables users to employ a trigger spray dispensing system whilst remaining compliant with FDA guidelines6 for the use of sterile disinfectants in aseptic fill manufacturing areas of a facility.
References
- “Particulate validation of a new trigger spray delivery system”, J. Tucker, et al., Clean Air and Containment Review, (5) 2011, pp17-20
- Pharmaceutical Inspection Cooperation Scheme, PI 007-6, “Recommendation on the validation of aseptic processes”, Jan 2011
- European Commission, Vol 4 EU Guidelines for Good Manufacturing Practice for Medicinal Products for Human and Veterinary Use, Annex 1 Manufacturing of Sterile Medicinal Products, Aug 2022
- SteriShield™ Delivery System - Validation Pack, Ecolab, Apr 2018
- Ecolab Technical Report (TR0904R): Particulate validation of the new improved SteriShield™ delivery system, Nov 2010
- Food and Drug Administration, Guidance for Industry, “Sterile Drug Products Produced by Aseptic Processing – cGMP”, U.S. Dept. of Health and Human Services, Sep 2004
Author Details
Donald Singer and Madison Hoal- Ecolab Life Sciences
Donald Singer is Principal Global Microbiology Technical Consultant for Ecolab and a Fellow in the American Society for Quality. He was a GSK Senior Fellow and is currently a member of the European Pharmacopeia Group 1 Microbiology Committee, a Certified GMP Professional, and a Certified Specialist Microbiologist. Don is a former Chair of the USP General Chapters - Microbiology Committee of Experts and was a member for 22 years. Don is also an adjunct professor in the Biopharmaceutical Quality graduate program at the University of Maryland Baltimore County.
Madison Hoal is a Global Technical Consultant for Ecolab Life Sciences, and a pharmaceutical microbiologist with experience in the manufacture of a range of pharmaceutical formats including non-sterile liquids, topicals, and sterile injectables. In her roles, she develops and implements contamination control strategies with an aim towards compliant, safe, and efficient cleaning and disinfection programs. Her work with industry has provided her with experience leading numerous investigations into environmental monitoring non-conformities utilizing risk management principles to identify and mitigate contamination risks.
Publication Details
This article appeared in American Pharmaceutical Review: Vol. 27, No.5 July/Aug 2024Pages: 66-69
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