May 1999
Today, the terms "critical" or "precision" cleaning are used interchangeably to refer to any cleaning process in which residue can cause a failure in the function of the surface being cleaned. In that regard, there is perhaps no more demanding application for cleaning than pharmaceutical manufacturing, where solids and liquids come into contact with plastic, glass, and metal piping and processing equipment, and where cross-contamination can be costly, in terms of both lost product and risk to human and animal health. Many leading drug companies, as well as firms that manufacture medical devices, are finding that aqueous cleaners provide the scrupulous cleaning required for manufacturing healthcare related products. Examples: Capsules and tablets. Some pharmaceutical ingredients resist going into solution, making tablet presses and dies difficult to clean. Even stubborn, sustained-release product residues come clean quickly with appropriate aqueous cleaners.
Suspensions. Aqueous cleaners also eliminate intensive scrubbing and human contact in cleaning large stainless steel tanks as much as 2000 gal. used in manufacturing liquid suspensions.
Intermediates. Aqueous cleaners are suitable for cleaning glass-lined chemical reactors used in processing pharmaceutical intermediates such as powders, fillers, binding agents, and other chemicals. Aqueous cleaners are synthetic detergent cleaning agents used in a water solution. The chemical and mechanical action involved includes a number of processes: Solubilization increases the solubility of a substance in a particular medium.
Wetting lowers surface and interfacial tensions so that the cleaner penetrates small spaces while getting under the soil to lift it from the substrate.
Emulsification creates an oil/water mixture by coating oil droplets with surfactant to keep them from recombining and migrating to the surface of a cleaning bath.
Deflocculation prevents agglomeration by breaking soil into fine particles and dispersing them through the cleaning medium.
Sequestration is the reaction with ions such as calcium, magnesium, or heavy metals to prevent the formation of insoluble byproducts (such as soap scum).
Saponification is the alkaline hydrolysis of fat by the reaction of fatty acids with alkalies to form water-soluble soaps. The following reviews the principal components of aqueous critical cleaners, considerations for their selection, and methods of pharmaceutical validation of their use.
Components of Aqueous Cleaners
Water, the "universal solvent," is an important basic component of aqueous cleaners because it dissolves many types of soils. Water--which may be municipal tap water, well water, deionized, or distilled water, depending on the cleaning application--also functions as a carrying medium for detergent compounds. Water is a polar solvent that is good at dissolving a wide range of polar soils. Water has a unique "V" shaped structure with two hydrogen atoms at the top of the "V" and an oxygen at the bottom. This directional shape towards the base of the "V" is called a dipole moment. Polar molecules such as water have a dipole moment. This dipole moment is important because it allows stable solutions of other dissolved polar-soil molecules to become arranged in more thermodynamically stable alternating positive and negative ends of molecules.
In addition to having a desirable dipole moment that helps dissolve other polar soils, water is capable of bonding to soils by a mechanism called hydrogen bonding. The ability of water to undergo hydrogen bonding is relatively unique among solvents. This capability gives water significant additional ability to dissolve soils as compared with other solvents. But while water is capable of dissolving many inorganic and some organic contaminants, not all soils dissolve readily in water. For this reason, aqueous detergent cleaners are complex mixtures specifically formulated to create greater chemical and mechanical cleaning action with ingredients that enhance the ability of water to hold soils. Typically these include surface-active agents (surfactants) and builders, which react with dissolved metal ions in the water to help stop them from interfering with cleaning.
It is critical that the detergent be able to clean effectively and to rinse away without leaving interfering residues and a scientifically formulated detergent will also typically include nondepositing rinse-aids. And since corrosion is the enemy of high-quality metal parts, corrosion inhibitors are often used in aqueous-cleaning formulations.
Detergent Selection
The major variables in cleaning using aqueous methods include the following:
Cleaner. The cleaner or detergent used should be matched to the desired cleaning method, and the surface and types of soils being cleaned. For instance, a low-foaming detergent should be used for spray or machine cleaning; a good anti-redeposition detergent for soak and ultrasonic cleaning; and a high emulsifying and wetting detergent for manual cleaning. The detergent, temperature, and degree of agitation should be strong enough to remove the soil to the desired level of cleanliness without harming the substrate being cleaned.
Agitation. Agitation can be none (as in soaking), or be performed manually (with a cloth, sponge, brush), ultrasonically, via flow-through clean-in-place (for pipes, tanks, and tubes), spray cleaning (clean-in-place spray balls), and high-pressure spray cleaning. In general, the more agitation, the more effective the cleaning on bulk soils. Cleaning can often be enhanced by pre-soaking, particularly if soils are dried or baked onto the part to be cleaned. It is always desirable, whenever possible, to clean prior to soils becoming dried or baked onto surfaces.
Temperature. In general, higher-temperature cleaning solutions result in better cleaning. In practice, there is typically an optimum temperature for a given combination of cleaning variables. Many soak, manual, and ultrasonic cleaning methods work best, for example, at 50-55¡C. Many spray washing techniques work best at 60-70ºC. Waxy or oily soils are more easily cleaned at somewhat higher temperatures. Particulate soils tend to be more easily cleaned at slightly lower temperatures.
Cleaning time. As a rule, the longer the cleaning time, the more thorough the cleaning. Many cleaning mechanisms-such as emulsifying, dissolving, suspending, and penetrating-are time-dependent. Up to the point where cleaning has been completed, the longer they're employed, the more cleaning is accomplished. Cleaning time can be accelerated by increased agitation, the use of more aggressive detergents, and by increasing temperature. If you cannot increase agitation, detergent, or temperature, then you must be prepared to use longer cleaning times to achieve the desired cleanliness. (There are some instances when long cleaning times may promote substrate corrosion, weakening, or swelling.)
Type of rinse. A thorough rinse will remove soils which have been cleaned from the surface and any residue from the detergent itself. Whatever contaminants are present in the rinse water can also be present after rinsing. Therefore, in pharmaceutical process equipment and medical device cleaning, high-purity rinse water is required.
Drying method. Drying can affect residues and corrosion since impurities from rinse water can be deposited during evaporation. Water, particularly high purity rinse water, can be corrosive to metal substrates during heated and air drying. The use of physical water removal drying techniques can help minimize such corrosion. It is also important to keep in mind that a cleaner's pH value can have a direct effect on cleaning effectiveness and each detergent formulation has maximum effectiveness at a specific pH value. An acidic cleaner would be effective for removing insoluble metal salts such as those used in time release coatings. Alkaline (basic) cleaners can be formulated to remove organic soils. Enzyme cleaners can be highly effective on protein soils. Alkaline cleaners work best when the soil can be hydrolyzed (typically natural oils and fats, fingerprints, natural greases, some types of pharmaceuticals, and protein residues). The cleaning process should be enclosed to avoid exposure hazards. Most cleaners are alkaline in nature since hydrolysis--and the chelation and dispersing of soils-typically occurs most effectively at alkaline pH levels. However, the higher the pH the more corrosive the cleaner.
Other Factors
It is important to select detergents for testing that are manufactured with appropriate quality-control procedures, with lot-number tracking and certificates of analysis from the manufacturer. These certificates document each lot of detergent to assure consistency and quality control from lot to lot in order to control for potential cleaning failure due to inconsistencies in manufacturing or unannounced formulation changes. It is desirable to choose a detergent from a manufacturer that maintains quality control on their raw materials and in turn keeps retained samples of each lot of detergent that is used to be able to respond to concerns about a particular batch. The detergent should be widely available and economical to use (for optimum economy, a concentrated detergent is typically used at 1:100 to 2:100 dilutions). The detergent concentrate should be diluted according to the manufacturer's instructions; typically, warm (about 50 degrees C) or hot (about 60 degrees C) water is used. Ambient temperature water may be acceptable, especially with presoaking. For difficult soils, very hot water should be used (>65 degrees C), and the recommended detergent concentration doubled.
Validation
In pharmaceutical manufacturing of human and animal health products, acceptable levels of residues must be carefully calculated. This is accomplished using a variation of the "Lilly Calculation," which involves determining a maximum dosage of the ingredient, the number of doses per volume of process equipment, and the surface area of that equipment: Maximum Residue= (maximum dose X number of doses in equipment) /surface area of equipment (Maximum dose is the highest amount to which a person can effectably be exposed--e.g., three logs below the LD50 of the compound.)
In practice, analytical methods can detect well below calculated maximum residues. The acceptable detection limits for a detergent are usually set well below, since the pharmaceutically active ingredients of a medicine will usually require much higher levels of cleanliness.
If 10 L of rinse water were used to extract the 100 L tank, then a rinse water residue of 10 ppm (100 mg/10 L) would correspond to 7 mg/square centimeter (100 mg/14,000 square centimeter). This is way below the typical calculated numbers.
There are a number of ways to analyze such residue based on the brand of detergent, including anionic surfactant analysis, direct UV/Visible determination, high performance liquid chromatography (HPLC), atomic absorption (AA) or inorganic residues, and liquid chromatography (LC), phosphate detection, protease enzyme detection, and total organic carbon (TOC). Detergent suppliers should be able to provide information on residue detection.
When rinsing with deionized water, conductivity has been used to detect conductive salts. Standard solutions of known dilution should be made up to determine the detection limits. There are two basic types of tests:
Rinse water test. Test a parameter of the rinsewater before and after rinsing the surface. No significant change in the parameter measured indicates no detected residue.
Wipe or swab test. Wipe a known area of the surface you wish to test with a clean swab or filter paper that is soaked with extraction solution such as 50/50 isopropanol/high purity water. Digest or extract the swab or filter paper and analyze for residue. Use glass fiber filter paper or swab for extraction methods. Do not use isopropanol mixtures for UV or TOC detection methods.
By choosing an appropriate cleaning method, detergent, and approach to residue detection, aqueous cleaners can be effectively used for cleaning pharmaceutical process equipment and medical devices.
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