CLEANING AND DISINFECTION - A RISK BASED VS AN ARBITRAY APPROACH - PART II
Lifecycle Approach to Confirm the Disinfectant Rotation ProgrammesDisinfectant use is unlikely to lead to microbial resistance development13. Sutton concludes that "the probable scenario for selection of a development of resistant variant would require exposure of an extremely large number of cells (in excess of 1,000,000 CFU) to a low level of the toxic chemical."13. Such circumstances should not arise in a typical clean-room. Also, Sutton states that "selection of mutants that are resistant to in-use levels of disinfectants has not been shown to happen in cleanroom settings. Literature reports of resistance to in-use levels are restricted to descriptions of survival of specific microorganisms in contaminated solutions". Therefore, the dilution, the filtration, and the storage must be performed effectively to avoid microbial contamination of the disinfectant solution. Finally, the open container stability (use shelf life), the bioburden or the sterility (if used in grade A/B or ISO5) should be monitored during a predefined period of use to confirm the absence of microbial contamination15. To date, there have been no conclusive data showing resistance by microorganisms to these chemicals14. The idea behind disinfectant rotation is to cover the largest microbial spectrum. The disinfectant rotation frequency should be based on the historical EM data trending over time and the disinfectants' efficacy profile. Based on this, the sole routine use of a sporicide with proven microbial efficacy against facility flora can be implemented without rotation14,16. However, since a sporicidal agent has an inherent corrosive nature, it is typically not recommended for daily use17. Therefore, if one broad-spectrum disinfectant along with a periodic use of a sporicidal agent covers the largest microbial spectrum and is effective to control microbial contamination, adding another broad-spectrum disinfectant may not add value. The rotation of two disinfectants with the same microbial efficacy profile is baseless practice. Rotation of two disinfectants should only occur with two different types of chemistries, or similar chemistries with two distinct microbial efficacy profiles, due to other aspects of the formulations. The complementary microbial actions should ensure that the alert level is not reached. An effective disinfectant rotation programme should take into consideration the following steps14,17,21:
1. Routine disinfectants should be used daily for cleaning and disinfection of non-product contact equipment to effectively kill vegetative microorganisms and remove soils, while minimizing the risk to personnel and cleanroom surfaces. The use of a detergent (for the cleaning step) should be defined based on the soil level of cleanrooms surfaces, the composition and effectiveness of the disinfectants, e.g., a surfactant in the composition will help to clean and disinfect.
2. A sporicidal agent should be used periodically to achieve kill of spore-forming bacteria (e.g., Bacillus species). The frequency of use should be based on the MRA results, area classifications and historical EM data.
Note that the frequency of use of a sporicidal agent might be higher inside a restricted access barrier or isolator (ISO 5 or grade A area) than in a lowest grade classification. This situation is justified based on the area classification, microbial specification and the cleanness of the non-product contact surfaces inside an ISO 5 or grade A/B area. As a consequence, it justifies a reduction in the use of routine disinfectants.
3. Disinfectant and sporicidal agent residue should be periodically rinsed using 70% Isopropanol (IPA) or Water For Injection (WFI) or purified water. The rinse frequency should be set based on a visual inspection and tactile observations of the surfaces in the cleanroom. There are certainly some cases where residues become such an issue that a cleaner is needed (e.g., sticky, tacky, or slippery floors or doors) and then the cleaner residue is rinsed using purified water or WFI dictated by the area classification. Note that the periodic rinse could be integrated into the cleaning step when a detergent is used prior disinfection.
The number of disinfectants, their rotation, and programme frequency should be justified based on the microbial risk assessment results, disinfectant and sporicide microbial efficacy profiles, area classification, and review of the historical EM data. However, for a new or entirely revamped facility, the justification should be based on the MRA results, disinfectants and sporicides microbial efficacy profiles and the classification area. The environmental control programme, including EM programme, cleaning and disinfection programme, qualification and periodic re-testing of the disinfectants should be looked at as a lifecycle approach (feedback loop). As a matter of fact, the historical EM data review, Figure 1, is one of the triggers to adapt or improve the cleaning and disinfection programme and confirm that the disinfectant and sporicide microbial efficacy profile and spectrum is adequate. Finally, periodic historical EM data review and analysis must be performed to:
- Confirm the absence of the increase in excursions from the previous historical EM data analysis.
- Identify the specific re-occurrence of trend or adverse events (e.g., the recurring deviation with the same microorganism or recurring excursion on the same sampling position).
- Identify specific worst-case microorganism.
- Categorize the source of isolate and contamination factors.
- Confirm the absence of a high occurrence of microorganisms of concern or microorganisms considered as objectionable or those under official scrutiny, e.g., Burkholderia cepacia18.
Based on Figure 1, conclusion and actions cannot be drawn based only on historical EM data review and analysis. The conclusion and actions could only be confirmed if supported by an audit of the cleaning and disinfection procedure. The goal of the audit is to demonstrate that the personnel and the microbial contamination control practices are compliant with the defined procedures. Moreover, the audit aims to confirm the absence of improper practices in the manufacturing area, e.g., ineffective chemistry is applied (e.g., use of alcohol against spore-forming microorganism), suboptimal concentrations, errors in dilution, wet contact times not in line with the disinfectant qualification data report or presence of visible residue (e.g., dust) affecting the efficacy of the disinfectant. Finally, based on the historical EM data analysis and the audit results, the team can confirm if the cleaning and disinfection programme should be adapted or improved, if a disinfectant or sporicide should be replaced or added or if the contact time or frequency should be reviewed. The approach mentioned above corresponds more to a lifecycle risk-based approach rather than arbitrary approach.
Depending on the regulatory guidelines, it is expected that at least one disinfectant be used to control routine vegetative microbial flora. Also, a periodic use of a sporicidal agent is justified if the historical environmental monitoring data confirms the presence of spore former microorganisms.
Today, most (bio)pharmaceutical firms use a programme where a disinfectant is used routinely, such as daily, and is complemented by the use of a sporicide to more efficiently reduce the bioburden levels14. Finally, the use of a disinfectant with a sporicide is considered superior or is encouraged over the rotation of multiple disinfectants14,16.
Effective risk management principles must be integrated into the product lifecycle to minimize microbial contamination and ensure the safety, quality, and efficacy of the product. Consequently, the manufacturer should incorporate the environmental monitoring programme including the cleaning and disinfection programme into the risk management strategy used and the product lifecycle to confirm product and patient safety. Therefore, the goal of cleaning and disinfection programme should be beyond elementary regulatory compliance. The disinfectant rotation and rotation frequency must be based on the results of the microbial risk assessment, the chemical agent microbial efficacy profile, periodic audit and the historical environmental monitoring data. Finally, compliance will be reached if the cleaning and disinfection programme is capable of controlling the bioburden level in the clean rooms to acceptable levels.
Walid El Azab
... is a Technical Services Manager for STERIS Life Science. He currently provides technical support related to cleaning chemistries, disinfectants and sterility assurance products and their application and validation. Walid is an Industrial Pharmacist and is Secretary of the Belgium Qualified Person association.
13 Sutton, S. "Disinfectant Rotation a Microbiologists View" Cleanrooms, 2005, access on May 25, 2017 at: https://www.cemag.us/article/2005/07/disinfectantrotation-microbiologists-view
14 PDA Technical Report Number 70: Fundamentals of Cleaning and Disinfection Programs for Aseptic Manufacturing Facilities (2015)
15 European Commission, Good Manufacturing Practice Medicinal Products for Human and Veterinary Use - Annex 1, Manufacture of Sterile Medicinal Products
16 United States Pharmacopeia 38 (USP) <1072> - Disinfectants and Antiseptics. The United States Pharmacopeia Convention/National Formulary, Rockville, MD.
17 Sartain K.E., Disinfectants rotation, access on July 1, 2017 at: https://www.cemag.us/article/2005/03/disinfectant-rotation
18 FDA advises drug manufacturers that Burkholderia cepacia complex poses a contamination risk in non-sterile, water-based drug products, access on May 25, 2017 at: https://www.fda.gov/Drugs/DrugSafety/ucm559508.htm?source=govdelivery&utm_medium=email&utm_source=govdelivery
19 United States Department of Health and Human Services Food and Drug Administration, Guidance for Industry Sterile Drug Products Produced by Aseptic Processing - Current Good Manufacturing Practice, 2004.
20 Regulatory Science of Pharmaceuticals and Medical Devices from Ministry of Health, Labour and Welfare of Japan, Guidance on the Manufacture of Sterile Pharmaceutical Products by Aseptic Processing, 2006.
21 Rogers M. and Polarine J., Rinsing Strategy, access on August 25, 2017 at: http://www.ivtnetwork.com/article/jim-polarine-and-marc-rogers-rinsing-strategy