Chapter 33: Cleaning, Sanitization, and Pest Control

Washing Facilities and Cleaning Procedures

“Washing and cleaning equipment should be chosen and used in order not to be a source of contamination.” This statement is a fundamental starting point for any discussion of good manufacturing practices (GMP) equipment and parts cleaning. In a pharmaceutical manufacturing environment, rooms and areas are classified based on the risk to the product. Four grades (A, B, C, and D) or classifications (ISO 100 to 100,000) of areas allow various levels of particulates or microbial challenges. These areas extend from cleanest (grade A) to less stringent requirements (grade D).

Sponges and mops used in grades A or B must be of material and design to minimize shedding of particles. Large and small GMP equipment and parts amenable to clean out of place (COP) must have facilities or a set of suites equipped with the necessary utilities (for example, water meeting World Health Organization [WHO] drinking water standards, purified water, and possibly water for injection [WFI]). Take-offs and/or hoses from the purified water and WFI loops must have mechanisms (for example, backflow preventers/check valves) or procedures that prevent back-siphonage of cleaning solutions or detergents. Flow of equipment and/or cleaning facility layout must preclude dirty equipment and parts from contaminating or mixing with clean equipment and parts. Annex 1 of the European Union (EU) GMP guidelines section on premises prohibits sinks and drains in grade A or B areas. Therefore, equipment and parts cleaning may not occur in these aseptic core suites. If equipment and parts cleaning suites exist within grade C or D areas, any floor drains should be fitted with traps or water seals to prevent backflow. Sink drains, glassware or equipment washer drains, and autoclave drains must have air breaks between the machine or sink and the drains.

GMP equipment and parts cleaning must be proceduralized to ensure consistency over time and from operator to operator. Pharmaceutical product and active pharmaceutical ingredients (APIs) can be contaminated by other pharmaceutical products or APIs, by cleaning agents, by microorganisms, or by other material (for example, airborne particles, dust, lubricants, raw materials, intermediates, auxiliaries). The cleaning process must be qualified and/or validated to demonstrate repeatability and robustness of the cleaning procedure and process. Whenever possible, the cleaning process should be automated to ensure repeatability. In cases where automation is not feasible, very strict requirements must be placed on manual cleaning methods to ensure consistency. These restrictions include identifying and controlling critical control parameters such as cleaning agent concentration, soak and/or scrub time, rinse time, temperature and volume of water, scrubbing parameters, and rinsing parameters.

Dependent on the nature of the product, process soil, and/or active ingredient, cleaning procedures may require cleaning agents and/or sanitizers. Typically, cleaning procedures and cleaning validation studies to confirm the cleaning procedure include only product-contact surface areas. Full understanding of the manufacturing process and equipment train must be attained to determine whether there are other areas in the process or equipment that are not direct product-contact surfaces that may be a source of contamination.

The intent of the cleaning validation program is to provide documented evidence of a robust and repeatable cleaning process that removes contaminates to predetermined acceptable levels. A robust cleaning validation program is established through the development and approval of a cleaning validation master plan (CVMP). The CVMP establishes the philosophy and approach for the site’s cleaning program. This document should include the requirements for development, confirmation, and sustainability of the cleaning program.

The CVMP establishes the acceptable residual limits that determine level of acceptability for the cleaning process. These limits should be achievable, verifiable, and based on the most toxic residue and/or the residue that has the highest risk to the product and/or process. These limits can be reflected in equations (for example, 10 ppm, no observable effect level [NOEL], therapeutic dose) that calculate maximum allowable carryover of residual. These limits are used during validation of the analytical methods to ensure that they are within the linear range of the method. Cleaning validation methods require full validation under International Conference on Harmonization (ICH) Q2 guidance, including limit of detection, limit of quantitation, specificity, and spike swab and coupon recovery studies. When setting acceptance limits for cleaning agents and sanitizers, the expectation is that no residual exists; ensure that the limits are appropriate. For sanitizers, residue is not acceptable on the surfaces of the equipment, and limits ensure that the cleaning procedure and analytical method can detect that the sanitizer has been removed from the product-contact surfaces.

Four elements are typical to every cleaning validation study to determine the effectiveness of a cleaning procedure and/or cycle. Each of these elements must have predetermined, defined, and approved acceptance criteria. Visual inspection is the first element and protocol test function. Once the equipment is inspected visually for any residual, the microbiological samples are collected to ensure that the surface equipment area is not contaminated by the cleaning validation sampling process. Product and process soil samples follow microbial sampling, and lastly, cleaning agent and sanitizer sampling. These sampling schemes can be adjusted based on the understanding of the cleaning process and potential product impact.

The cleaning procedure is considered robust and repeatable upon completion of three successful runs (the number of runs may be more or less dependent on the knowledge of the process), which indicate that all data met predetermined acceptance criteria, the data were reviewed, and the data were summarized in a final report and approved by the quality unit (QU).

To ensure that the cleaning process is sustainable, the CVMP must include requirements that the life cycle is maintained, including requirements on periodic monitoring to assess changes in acceptance criteria, changes in equipment, changes in product or process soil, and changes in the cleaning process. The CVMP outlines requirements for revalidation activities based on changes in the process, equipment, product mix, and acceptance criteria.

Sanitization Procedures

The United States Environmental Protection Agency (EPA) licenses chemicals for which its manufacturers claim efficacy in disinfecting inanimate objects. The EPA evaluates disinfectant efficacy chiefly by either of two methods originated by the Association of Official Analytical Chemists (AOAC):

• Use/dilution method. An organism is dried to a rod made of glass, stainless steel, polished porcelain, or other nonreactive material. The rod is submerged for 10 minutes or other claim time in a container with the disinfectant being tested (without touching the side of the container). The rod is raised and allowed to drain. A replication organism detection and counting (RODAC) plate with agar and the appropriate nutrient is placed on the rod to remove organisms for testing and incubated a set time. Zero growth permits disinfectant to pass the test.

• Spray method/ hard surface carrier test. An organism is dried to a measured surface area of a specific material. The disinfectant product is sprayed according to manufacturer’s directions, and the surface is left until sufficient contact time according to directions. The surface is scraped and applied to a RODAC plate of appropriate media, then incubated a set time. Zero growth permits disinfectant to pass the test.

Regarding the EU requirement for monitoring of disinfectant prepared at ready-to-use (RTU) dilution and in its final applicator bottle, unless the site has created and validated a production-like aseptic sterilizing filtration process and validated the sterility through expiration date along with validating the container closure of the application container, the full expectation by European Medicines Agency (EMA) is for monitoring of the solution over its shelf life. Alternatively, the supplier of prefilled, presterilized (aseptic filtered or terminally sterilized) vials must have had its validation data audited by the drug manufacturer, including container closure validation. This requirement holds true for liquid, gel-like, and moist pad antiseptics used in the sterile core. The latter, due to their exposure (sheets are pulled like tissues from a container), can not avoid the requirement for drug manufacturing site monitoring. The alternative, onerous requirement for monitoring entails sampling the disinfectant solution or wipe on a media containing a validated neutralizer against the bactericidal active ingredients.

Literature Efficacy of Various Sanitizers

Chlorhexidine has a wide spectrum of antibacterial activity against both Gram-positive and Gram-negative vegetative bacteria. A quaternary ammonium compound (QAC) has high antimicrobial activity (vegetative cells) if its carbon chain length is C8 to C18 (if aliphatic). These compounds, being positively charged, are also surfactants (that is, have detergent/cleaning properties to get inside crevices). Unfortunately, QAC are not mycobactericidal (for example, active against tuberculosis-causing organism) or effective against the Gram-negative bacteria E. coli, P. aeruginosa, and S. typhimurium. They are more active at alkaline or neutral pH than at acid pH levels.

Phenolics are effective against both Gram-positive and Gram-negative vegetative bacteria, but only slowly effective against bacterial spores. The virucidal activity of phenolics can not be generalized (that is, enveloped viruses are more susceptible than other organisms).

Glutaraldehyde (usually 2% v/v supplied alkaline but made acidic before use) possesses sporicidal activity (that is, vegetative cells), mycobacterial, and fungal spore efficacy. It is active against various types of viruses. Formaldehyde, which is a carcinogen, is widely bactericidal, sporicidal, and virucidal; it is effective against protozoa. Iodophors are surface-active agents and surfactants that can solubilize iodine to form compounds containing microbicidal activity over a wide pH range (for example, povidone-iodine solution of 10% w/v). These are sporicidal.

The most common chlorine-releasing compounds are hypochlorites and N-chloro compounds. All of these compounds are irritants and corrosive but have high antimicrobial activity, including sporicidal activity and some mycobacterial activity. These compounds are active against lipid and nonlipid viruses. Sodium hypochlorite (NaOCl) is more active at acid than at alkaline pH. Diluted RTU solutions have short shelf life and must be qualified.

Chlorine dioxide (ClO2) is an alternative to NaOCl and retains biocidal activity over a wide pH range. Oxine is a sodium chlorite solution that, when acidified, generates chloride dioxide, giving a mixture of chlorite and chlorine dioxide; it is more efficacious against pathogenic bacteria than chloride dioxide alone, and it is virucidal.

Peroxygens include hydrogen peroxide (H2O2) and peracetic acid (CH3CO3H). H2O2 is used at varying strengths (35%, 50%, and 90%) and is bactericidal and a sporicide. H2O2 can be used as a sanitizing agent and an antiseptic. Peracetic acid is available commercially as a 15% aqueous solution (35% is potentially explosive). Peracetic acid has a broad spectrum of activity, including bacteria and their spores, molds, yeasts, algae, and viruses.

Ethylene oxide (C2H4O) uses its alkylating properties on proteins (used at proper concentration, temperature, and relative humidity) to act as a potent sterilant and sporicide. Ozone (O3) is another agent that is bactericidal, virucidal, and sporicidal. Sodium hydroxide (NaOH) or lye is active against all microorganisms, including protozoa and prions.

Pest Control

Any building used in the manufacturing, processing, packaging, or storage of pharmaceutical products must be free of infestation. The pest control program requires appropriate QU oversight. Procedures must describe the use of suitable rodenticides, insecticides, fungicides, or fumigating agents. Rodenticides, insecticides, fungicides, or fumigating agents should be of the appropriate grade, approved by local regulations, and approved by the drug manufacturing site QU. Pest control records must be generated and retained, and a system must exist for the continual capture of crawling and flying pests by an entomologist or pest control expert for identification and analysis. When the latter is contracted by a manufacturing site, a quality/technical agreement must describe all the activities and responsibilities of the contract giver and the contractor. A system should be in place for the reporting/recording of pest sightings by any personnel besides the contractor.