Selecting suitable cleaning agents and determining justifiable cleaning process parameters are critical prerequisites for cleaning validation. Proper selection of cleaning agents and parameters could simplify cleaning validation efforts immensely.
Process cleaners may range from a single component, such as an organic solvent, to multi-component formulations that use multiple cleaning mechanisms such as solvency, solubilization, emulsification, wetting, chelation, dispersion, hydrolysis, and oxidation. Although the most important cleaning parameters are cleaning time, impingement-level, cleaning solution concentration, and temperature, other factors that influence cleaning performance include nature of the substrate, surface finish, soil conditions, soil levels before cleaning, level of mixing, water quality, and rinsing. Proper selection of cleaning agents and parameters can be achieved through laboratory evaluation followed by field confirmation, and requires an understanding of substrate and design constraints, residue limits, desired cleaning objectives, cleaning chemistry and the contribution of various parameters to performance.
Introduction Cleaning processes must be validated according to current GMPs. Since validation is time-consuming for a multi-product facility, there is often an urgency to embark on executing the cleaning validation process. Selecting suitable cleaning agents and determining appropriate cleaning parameters are, however, critical prerequisites for cleaning validation. Proper selection of these agents and parameters could help in developing a system that is more easily validatable, thus simplifying cleaning validation efforts immensely. Also, since these cleaning agents and parameters are difficult to change once they are validated, and can have an important influence on the operating procedures and therefore on the cost of manufacture, it is important to understand and evaluate the various available options at an early stage.
This paper provides a broad perspective and an overview, based on laboratory and field experience, of the various options and factors that need to be considered in selecting cleaning agents and parameters. Various cleaning mechanisms, types of cleaning agents, cleaning parameters and factors affecting performance, laboratory screening and evaluation processes, and an overall strategy for selection of cleaning agents and parameters are presented.
Cleaning Mechanisms Depending on the type of cleaning agent selected, one or more of the following mechanisms are involved in the removal of the soil (product contaminant) from the surface. These mechanisms have been discussed in literatures and only a brief summary is presented here.
Solubility The solubility of one substance in another is commonly defined and reported as the maximum amount that can be dissolved (uniformly dispersed at the molecular or ionic level) at a given temperature and pressure. Solvents are either polar (e.g., water, alcohol) or non-polar (e.g., hexane). From basic chemistry, like dissolves like. Solubility provides useful information on the capacity of the solvent for dissolving the solute, but does not address the issue of the required dynamics or time taken for that solute to be removed from a product contact surface. The dissolution process works fast when the soil is broken down into small fragments, thus increasing the interracial surface area. Pharmaceutical product soils can, however, be attached to surfaces by a combination of van der Waal's forces, electrostatic effects and mechanical adhesion making cleaning a more complex process.
Solubilization This is a term used for the process of converting a normally insoluble material to a soluble one. Solubilization is usually achieved with the use of surfactants in detergent formulations, but a simple change in the pH may aid the process.
Emulsification Emulsification, as applicable to process cleaning, is the process of suspending a water insoluble liquid material, such as an oil, in an aqueous solution and preventing its redeposition. The lipophilic, or "oil-loving" end of surfactants, could attach to the soil, leaving the hydrophilic or "water-loving" end exposed to the water, thus completely covering the surface of the soil and converting it into a "micelle," or an easily removable droplet. In cases where the soil is not soluble in an aqueous solution, emulsification could be an easier and faster way to remove the soil out of the system without redeposition.
Wetting When cleaning a surface the interracial energy, as well as the surface energy of both the substrate and the liquid, are important. These factors determine how well the cleaning solution will wet and spread into the soil and surface irregularities. This, in turn, determines the solution's ability to displace particles and penetrate the soil, providing a larger surface area which allows for an increased rate of other mechanisms such as solubilization and diffusion. Wetting agents in formulated detergent systems lower the surface energy of the solution very significantly.
Chelation Complexing agents, or chelants, are used in formulations to improve the cleaning effectiveness for inorganic soils. Chelants "grab" metal ions to form strong complex bonds preventing these ions from other adverse influences. Chelants are also used for iron oxide removal in derouging and passivating agents.
Dispersion Dispersants are used in formulated cleaning agents to prevent particulates from clumping, and thus helping to ease their transport by the cleaning solution flow. This mechanism can be useful also in preventing hard water scale from depositing on the surface while rinsing alkaline cleaning solutions.
Hydrolysis This is the process of using acids or bases to "lyse" or break chemical bonds, thus creating smaller molecules that are more easily solvated. When this mechanism is employed, it is important for analytical methods to be able to target and account for such breakdown products.
Oxidation Oxidants such as sodium hypochlorite break down proteins and other organic compounds that cannot be cleaned by other means. Since these aggressive agents can also act on the substrate, they are used for process cleaning applications only when other mechanisms are inadequate.
Physical Mechanisms such as diffusion and convection help transport soil molecules away from the surface while allowing fresh cleaning solution to interact with the soil. Unfortunately, the active components are usually relatively large molecules with low diffusivities, thus requiring convective flow to transport them.
Cleaning Agent Options Broadly, three categories of cleaning agents are used for cGMP processes. These are organic solvents, commodity acids and alkalis, and formulated detergents.
Organic Solvents Organic solvents are used mainly in the bulk pharmaceutical manufacturing industry. They rely primarily on solubility for residue removal. There are some advantages of using organic solvents. If the solvent is the same as the process solvent that is used in the manufacture of the next batch, there is no external contaminant introduced. The solvent being usually a single-component cleaning agent, analytical methods are simplified. Unlike aqueous cleaning agents, solvents also have some, although limited, cleaning action when vaporized and refluxed. Safety, environmental and disposal issues, and cost are the main disadvantages and reasons why manufacturers prefer aqueous cleaning agents whenever possible.
Commodity Alkalis and Acids Aqueous solutions of commodity alkalis (such as sodium hydroxide or potassium hydroxide) and acids (such as phosphoric acid or citric acid) are commonly used for process cleaning. The advantages of these agents are that they are widely available, relatively inexpensive, and are simple, single-component cleaning systems. They utilize cleaning mechanisms such as solvation and hydrolysis, but do not exploit the other mechanisms described above, particularly wetting, emulsification, and dispersion. For these reasons sodium hydroxide alone, which is a very commonly used cleaning agent, has drawbacks such as precipitation due to water hardness, limited soil suspending ability, and insufficient penetration into soil due to low wetting characteristics. The commodity alkalis are generally difficult to rinse and often require follow up with acid rinsing.
Formulated Detergents Formulated detergents take advantage of several of the above cleaning mechanisms. Surfactants in these formulations may provide better wetting, surface action, and emulsification, depending on the chemistry and concentrations used. Multiple mechanisms could provide faster and more effective cleaning of a broader spectrum of soils. This is important because pharmaceutical product residues may be complex formulations of different chemistries that comprise the actives and the excipients. Over a period of time there could also be other contaminants from the water (e.g. scale), or from the substrate (iron oxides), that could build up. Addressing a broad spectrum of soils with a single cleaning agent can also help in using product grouping strategies, thus simplifying validation efforts. The disadvantages of using formulated detergents are that they are often proprietary formulations, there are a limited number of sources, and their selection process and mechanism of action are not always well understood.
Cleaning Parameters For a given cleaning agent and soil, the most important parameters that determine cleaning performance are the cleaning time, the action or impingement on the surface, the concentration of the cleaning agent and the temperature of the cleaning solution. These parameters - time, action, concentration, and temperature - are closely related. It is therefore possible to compensate one for the other and obtain the same cleaning performance. This will be discussed later in more detail.
Time It is well known that the cleaning performance improves with cleaning time, provided all other parameters are at their desired level. To help design and understand a cleaning process, the total cleaning time should be divided into its components, such as effective wash time, soak time, rinse time, or other lost time. The implications of those times on the overall cleaning performance should be assessed. The following examples illustrate the point.
For a half hour manual scrubbing of a tank with a brush, the time for which the brush moves across any specific surface area would be a very small fraction (typically a few seconds) of the total time taken to clean the tank. The time taken between scrubbing and final rinsing could be different for different areas of the tank and would depend on the cleaning procedure. In the case of rotating spray devices, the impingement acts on any given surface for only a certain fraction of the total time, due to the rotating nature of the spraying device. When cleaning complex vessels using spray devices that do not give complete direct coverage, a certain spray time may elapse before wetting of difficult-to-reach areas begins. This could be a result of design constraints. In such a situation, although a half hour wash cycle may clean the soil through a gradual wetting process, a short rinse cycle (for say three to four minutes) that follows may not provide adequate time to contact and wet those shadowed areas and rinse away even a freely rinsable cleaning agent.
Action Action or impingement refers to the shear force acting on the surface. This is unfortunately the least-monitored and -understood parameter and is often the cause for inadequate cleaning. In a process train, if the action or impingement varies from one area to another due to design or flow constraints, the lowest level of action (corresponding to worst case locations) should be identified. The other cleaning parameters should then be chosen at levels high enough to compensate for the low levels of action, and at levels which meet the acceptance criteria even at those worst case locations. An optimized cleaning process will try to establish similar levels of action across the entire system.
Concentration In general, the higher the concentration of an aqueous cleaning agent, the better the cleaning. Higher concentrations could increase reaction rates, increase solubilization, and reduce surface tension - up to a limit. Concentrations above a critical level are required for formation of emulsions. Substrate compatibility and safety may limit the use of high concentrations.
Temperature Increasing temperature has a strong positive effect on cleaning performance since several mechanisms such as solubility, diffusion, activity of certain surfactants, and reactions like hydrolysis and oxidation are temperature dependent. In the case of certain proteins, however, denaturation can cause a decrease in cleaning effectiveness beyond a certain temperature.
Note: This ends Part 1 of our two-part look at cleaning agents for cGMP processes. Go to Part 2
For more information: George Verghese, Senior Applications Engineer, STERIS Corp., P.O. Box 147, St. Louis, MO 63166. Tel: 314-535-3390.
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