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Madison Hoal is global technical consultant at Ecolab Life Sciences.
Donald Singer is senior microbiology technical consultant at Ecolab Life Sciences.
Consider how to assess risks and understand possible sources of disinfectant residues in pharmaceutical manufacturing.
In aseptic manufacturing, the application of cleaning and disinfection agents reduces contamination to an acceptable level for the grade of cleanroom and prevents cross-contamination from surfaces that are part of or adjacent to good manufacturing practice (GMP) manufacturing operations.
There is systemic complacency within the industry regarding the cleaning and disinfection products used and the associated program. A common response within industry when asked about the rationale for a given cleaning regime is: “We have always done it that way.” When a review of the associated environmental monitoring trends demonstrates a degree of control, everyone is satisfied.
Historically, cleaning has been the “residual contaminant” removal step and disinfection has followed, often at times leaving the disinfectant on the surfaces indefinitely. Legacy cleanroom environments were often following the old adage that “visible disinfectant residues on the surface are a preventative measure.” But this rationale may be changing. The authors have seen a prolonged and increased concern from regulators over residues left from disinfectants post-application.
Current industry thinking, along with recent compliance mandates (1), is that any residual chemical is a potential chemical or particulate contaminant to a process and possibly to product. This renewed focus has led a change from legacy thinking to a consideration of how to assess and address disinfectant residues, including an evaluation of what properties other than efficacy, such as residue profile, should be considered for cleaning and disinfectant products.
Product quality risk. The presence of a disinfectant residue represents a risk to product quality as either a physical or chemical contamination risk, which is why products such as alcohols are commonly used in close proximity to open product, as they leave little or no residues. For aseptically produced and low-bioburden products, contamination control is intertwined within the quality system, facility design, and process validation. The US Pharmacopeial Convention (USP) says (2):
“The removal of residual disinfectants should be monitored for effectiveness as a precaution against the possibility of product contamination.”
Cleanrooms are typically designed to facilitate contamination control for pharmaceutical products at the point in the manufacturing process where internal controls are most important. The highest risk products, sterile injectables, require product contact surfaces to be contamination-free and are commonly subjected to validated sterilization processes. Adjacent surfaces on production machinery and containment equipment (e.g., isolators or restricted access barriers) can be decontaminated, with the assurance that residual agents are removed, to prevent possible cross-contamination during the filling process where product is minimally exposed.
Biopharmaceutical cleanrooms can range in use from bulk manufacturing, containing large tanks/vessels and complex purification equipment, to fill/finish operations for sterile injectables. The concern with residual disinfectant cross-contamination into product processing is a moderate risk in bulk manufacturing areas, unless product processes are directly adjacent to a decontaminated surface, such as a fermentation tank with any size hatch that can open. Filling operations are similar in high risk to the sterile injectable.
Cleanrooms used for cell therapy manufacturing may have more containment features to protect the live cells and inherently short manufacturing times, yet there are still many surfaces that need to be part of the contamination control strategy. These surfaces are disinfected routinely with expectations that no residue exists that can be carried by operators (on their gloves or gowns) or mobile equipment from one activity to another in the manufacturing suite(s). Appropriate choice of disinfectants is also crucial when using single-use bags containing live cells throughout the life cycle of a cell therapy.
Despite the expectation that no disinfectant residue exists in these critical and adjacent manufacturing areas of any type of pharmaceutical operation, broad-spectrum disinfectants and sporicidal agents used in these same areas often leave residue, which may or may not be visibly apparent.
The new draft of Annex 1 contains a specific regulatory guidance statement about disinfectants, which highlights that cleaning programs should be effective at removing disinfectant residues. This expectation is in line with the developing expectations of industry and with historical regulatory observations. Annex 1, section 4.36 says (1):
“The disinfection of cleanrooms is particularly important. They should be cleaned and disinfected thoroughly in accordance with a written programme. For disinfection to be effective, prior cleaning to remove surface contamination should be performed … Cleaning programs should effectively remove disinfectant residues.”
Regulatory risk. Regulatory compliance is always a business expectation because of its impact on final products and the patients who are the primary customers. Regulatory inspections follow the legal requirements stated in practical terms as current good manufacturing practices (CGMPs). Inspectors have authority to interpret CGMPs when they evaluate a manufacturing operation.
Evaluation of cleaning and disinfection practices are part of the CGMP inspection. Most evaluations of the cleaning and disinfection program are based on visual observation. Inspectors will not only indicate and question visual observation of residues from product, but they also will note disinfectant-type residues. Since cleaning validation usually relates to product contact surfaces, most non-product contact surfaces do not have a quantitative analysis of residues. Thus, the visual observation of residue by an inspector is often generalized and unqualified as to its identification as a residue from manufacturing products (actives or excipients), cleaning, or disinfection. Notation of color and location is often the extent of an observation, which leaves the identification of the residue and the subsequent corrective action with the manufacturer. In most situations, residue of any kind becomes an observation/finding from the inspection with a requirement to identify and mitigate/prevent future occurrence.
Health and safety risks. Another aspect to consider is the health and safety risk disinfectants may have on cleanroom operators and cleaning technicians. All disinfectants are by their very nature toxic to living organisms; however, these chemicals are an effective and safe tool when handled appropriately with adequate safety measures in place. Training on proper storage, mixing, handling, and application procedures is essential.
The interaction between some disinfectants can lead to undesirable risks to cleanroom operations. If the cleaning and disinfection program does not address disinfectant residues prior to applying different chemistries, there is a potential for chemical interactions between the chemistries in use (3). For example, a chlorine-based disinfectant applied after a phenolic-based disinfectant may result in the release of toxic chlorine gas. Additionally, these chemical reactions may also interfere with the disinfectant’s efficacy. The presence of disinfectant residues may also reduce the biocidal activity of disinfectants subsequently applied to the surface. This may result in frequent environmental excursions or increased recovery of microorganisms that the cleaning and disinfection regime should have been effective at managing throughout the facility.
Disinfectant residues can also interact with one another, causing sticky or slippery floors. Both outcomes pose a risk of slips, trips, and falls to cleanroom operators. In addition, the presence of sticky floors may also lead to the accumulation of debris on the surfaces, posing a gross contamination risk. It is imperative that pharmaceutical manufacturers review their cleaning and disinfection program to ensure that a residue removal step is incorporated when changing or rotating between different disinfectants, such as prior to sporicides.
Facility risk. Cleanroom operators are sure to have seen evidence of disinfectant residues, such as an oily sheen on stainless steel or the chalky white powder on the floor coving. Other effects from the use of disinfectants on cleanroom surfaces can be rouging on stainless steel or the reduction of the epoxy floor sheen.
In cleanrooms, disinfectant residues are often monitored, or measured, visually. These residues, if not managed preventatively, can cause degradation to the facility over time, which can lead to costly reconstruction or require deep cleaning measures.
A significant source of facility degradation tends to be rotational sporicides. Due to effective use levels of sporicidal formulations, these chemicals tend to be corrosive in nature and can quickly age a facility if not appropriately managed. It is crucial that the residues of these types of chemicals are removed from the surface after the appropriate contact time to avoid degradation over time. However, it should be noted that residue should not only be removed from cleanroom surfaces where the residue is visibly apparent, such as on stainless steel and glass, but also on surfaces where the residue may not be visibly apparent, such as non-reflective surfaces.
Consumption of time and resources. The disinfection residue removal process is likely to require additional time and resources in the form of increased cost of labor and supplies to remove residues, which in turn leads to reduced production time and productivity.
Disinfectant residues need to be removed from the cleanroom environment, but most disinfectants have some degree of residues. It begs the question: How can cleanroom operations meet the regulatory requirements without impacting their production schedule and targets?
Several aspects of the cleaning and disinfection program can be reviewed to reduce the impact and/or risk posed by disinfectant residues, such as introducing a residue removal regime, reviewing application techniques, and choosing low-residue formulations.
Insufficient or non-existent residue removal. All disinfectants, with the exception of some isopropanol and hydrogen peroxide formulations, leave some amount of residue on the surface, which will require routine residue removal.
Cleanroom disinfectants are typically aqueous-based formulations and are therefore readily dissolvable in water. Thus, the best solvent to remove disinfectant residues is water. Normally, this is water for injection or purified grade water, depending on the location and risk to the cleanroom. However, water poses another risk to the cleanroom: origin or potential for microbiological growth. To address this concern, 70% alcohols are commonly used in critical environments. While 70% alcohols are disinfectants, they are also used to reduce the build-up of other disinfectant residues.
The effectiveness of the residue removal step should be assessed for each disinfectant used in the site’s cleaning and disinfection program. The frequency of the residue removal will depend on the means of application and the disinfectant formulation.
Over-application. When applying disinfectant to cleanroom surfaces, the end-user should be cautious of oversaturating a surface. Over-application can be the result of many common challenges within the cleanroom. One challenge is achieving the validated contact time. A heavy application of disinfectant may seem like a way to achieve the validated contact time. However, by oversaturating a surface, more disinfectant is being applied, resulting in more disinfectant residues building-up over time.
Another common challenge is improper use of the cleaning and disinfectant tools. The user should seek cleaning and disinfecting tools that apply the disinfectant in a controlled manner, such as an effective wringer and a defined saturation level for wipes. If controls are not in place, variability in application can result among operators, which in turn can impact effectiveness of the cleaning and disinfection program. Over application can also impact the frequency of the residue removal program.
Manufacturing sites should also ensure that their cleaning and disinfection personnel are adequately trained to apply disinfectants in a cleanroom setting. This includes training on the saturation level of mops and wipes, as well as how controlled application is important on surfaces. Multiple coatings and overlapping the same surface do not only serve as a potential cross-contamination issue, but also contribute to disinfectant residue build-up.
Disinfectant formulation. It is important to be aware of and understand the formulation of a disinfectant when applied to a particular surface for consideration about potential residues. Good practice utilizes high quality pharmaceutical-grade water (e.g., water for injection) for dilution of disinfectant concentrate. Following a manufacturer’s label for the volume of water to use when diluting disinfectant concentrate is critical, and any variation can influence the occurrence of residue and performance. Disinfectant stability may be related to incorporated inactive ingredients in the formulation, yet also may influence residue occurrence. Compatibility of the disinfectant on a particular surface is another parameter.
Consider the intended purpose that the disinfectant was formulated to serve. Some cleaning and disinfection products intended for GMP environments may have been originally formulated for clinical or hospital settings that are more commonly highly soiled environments. Although these products are available for use within a cleanroom environment, these products will be formulated to address greater soiling and contamination than would be anticipated in the average pharmaceutical cleanroom. Therefore, it is likely that these types of disinfectants will contain a higher degree of surfactants and actives than are necessary to control and maintain a classified cleanroom; all contribute to the residue profile of the product.
Disinfectant residues pose various risks to the cleanroom environment, which is why the industry and regulatory groups have a renewed focus on the effective removal of their residues. End-users can combat disinfectant residues in many ways, such as implementing a routine residue removal program, instituting "low-residue" disinfectant formulations, and focusing on operator training to control application.
1. EC, EudraLex, Volume 4, EU Guidelines to Good Manufacturing Practice Medicinal Products for Human and Veterinary Use, Annex 1, Manufacture of Sterile Medicinal Products, Draft (2020).
2. USP, USP General Chapter <1072>, “Disinfectants and Antiseptics,” USP 42–NF 37 Rockville, MD (2019).
3. The CDC Handbook: A Guide to Cleaning and Disinfecting Cleanrooms, T. Sandle Ed. (Grosvenor House Publishing Ltd, London, England, 2012).
Madison Hoal is global technical consultant, and Donald Singer is senior microbiology technical consultant, both at Ecolab Life Sciences.
Vol. 44, No. 6
Pages: 28–31, 60
When referring to this article, please cite it as M. Hoal and D. Singer, "Why Do Disinfectant Residues Matter?" Pharmaceutical Technology 44 (6) 2020.