Currently, there are multiple publications, as well as guidelines from regulatory agencies that make the critical process of equipment cleaning validation easier. These sources provide in-depth information for the validation specialist, making the development and implementation of a robust cleaning validation program possible within any particular facility developing or manufacturing parenteral, biological, or sterile ophthalmic products.
Extremely important, specific, and above all, mandatory, are the requirements established by regulatory agencies such as the US Food and Drug Administration (FDA), the European Medicinal Evaluation Agency (EMEA), Australia’s Therapeutic Goods Administration (TGA), etc. For example, the 2004 Code of Federal Regulations (CFR) Title 21, Volume 4, Section 211.67, states:
“Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals to prevent malfunctions or contamination that would alter the safety, identity, strength, quality or purity of the drug product beyond the official or other established requirements.”
Additionally, Section 211.182 requires that cleaning procedures must be documented appropriately, and that a cleaning and use log should be established.
This article provides the reader with cleaning validation information enhanced by the author’s thirteen years of hands-on experience working in equipment cleaning validation.
This article focuses on manual cleaning procedures because these are considered the worst-case scenario. It applies to parenterals, ophthalmic, and biologic presentations and is intended to cover equipment validation for raw materials, contaminants, cleaning agents, as well as the control of potential microbial contaminants associated with those products.
Figure 1. Depiction of Different Aspects for Consideration When Developing a Cleaning Validation Program
The flowchart in Figure 1 graphically shows the different aspects that should be considered when developing a cleaning validation program. Understanding each aspect of the process, the relationships among these actions, and the sequence in which they should take place will make the development of a cleaning validation program a successful experience.
After all applicable cleaning information sources and regulatory guidelines have been consulted, the first item to consider when establishing a cleaning validation program is the raw material and final product flow. By following the flow of the product, one can identify the equipment that comes in contact with it, such as utensils (scoops, spatulas, funnels, pipettes, etc.), tanks, filter housings, pressure vessels, syringes, and others. Equipment such as this is considered critical equipment because it comes in direct contact with the product.
Other areas where raw materials or products are processed, which might be considered non-critical because they are not in direct contact with the product, should also be considered. From the point of view of microbial load, inappropriate cleaning and sanitation of these areas may contribute to cross-contamination. Some examples of these areas include: sampling and weighing rooms, as well as formulation and filling rooms.
Typical steps to follow in process flow are as follows:
Raw Materials Sampling: Raw materials include both active and inactive ingredients. Many active ingredients are potent compounds, such as steroids, cortisone, antibiotics, proteins, and therefore it is important to demonstrate their removal. But be aware that some inactive ingredients have poor solubility in water and their residues may be more difficult to remove than those of an active drug.
Utensils used during the sampling process of raw materials require cleaning validation unless they are disposable. Typically, use of disposable utensils is the preferred practice for parenteral and biological products. The sampling of raw materials should be performed within a controlled environment (classified as 1,000, 10,000, 100,000, etc.,) in order to reduce the introduction of non-intrinsic contamination to the process.
Some firms use extraction hoods equipped with high efficiency particulate air (HEPA) filters and room air conditions that provide an acceptable environment for raw materials sampling. In addition, sampling area and rooms should be cleaned with sanitizing agents. Cleaning effectiveness on those surfaces should be challenged using microbiological tests for verification of bioburden reduction of non-sterilized parts, such as tables, walls, ceiling, fillers, etc.
Weighing of Raw Materials: Some rules followed during raw materials sampling also apply to the raw materials weighing process. Some ingredients will require being weighed inside a glove box due to special environmental requirements (e.g., under nitrogen, etc.). Because glove boxes are usually shared, they too will require cleaning validation.
Product Compounding: This is one of the most critical steps because the equipment used will have direct impact on the finished product. Compounding a finished product requires equipment with large product contact surface areas. The handling of ingredients requires utensils with less product contact surface area. This significant difference is important because the more complex the equipment, the more samples must be taken to demonstrate effective cleaning.
Product formulations involve the use of tanks and ancillary equipment, such as gaskets, pipes, hoses, mixers, and filter housings. Gaskets and hoses are disposable in many pharmaceutical processes, so they do not generally require cleaning validation.
Product Filling: Filling of parenteral, ophthalmic, and biologic products is usually performed within areas of controlled bioburden, ranging in scale from clean to aseptic rooms. Drug products are capable of being contaminated in many ways. Contamination may occur via filling components (tips, caps, bottles, or stoppers); when coming in contact with processing equipment (tanks, manifolds, fillers, machine-syringes, pistons, and blocks); the manufacturing environment, or manufacturing operators.
Some equipment may require cleaning revalidation if components come in contact with the product. Stoppers are siliconized and then are placed in a hopper during filling. Small quantities of silicone are accumulated in the lower part of the hopper where it can degrade over time. If this silicone were to come in contact with the product, it would probably cause product contamination.
Requirements for aseptic processing include cleanable floors, walls, ceilings, particulate, temperature, humidity, cleaning, and disinfecting procedures. When disinfectants are used in the manufacturing area, care must be taken to prevent the product from becoming contaminated with chemical disinfectants. The selection of suitable disinfectants, verification of their effectiveness, and a surface challenge are critical in developing a cleaning and sanitization program. Written procedures for cleaning, maintenance, and sanitization of manufacturing equipment and appropriate areas of the facility are required. Removal of residual disinfectants should be monitored as a precaution against the possibility of product contamination.
Know Product Ingredients and Intended Use of the Final Product
Previous to designing the cleaning procedures, it is necessary to know all physical and chemical characteristics of the product ingredients. Characteristics such as appearance, solubility, potency, and toxicity play an important part in the design strategy of a cleaning validation program. These characteristics will indicate whether solvents or detergents are needed for removal of product residues. Avoid the use of detergents or solvents whenever possible because their use demands added controls.
Regarding the intended use of the product, cleaning procedures related to the production of parenterals are the most critical. Great precautions should be taken with the cleaning procedures surrounding these products, because they will be intravenously administrated to patients and any adverse reaction could cause serious damage to patient health.
Developing Standard Operating Procedures (SOPs) for Cleaning Processes
Once we know and understand the product process flow, the product’s ingredients, and the product’s intended use, standard operating procedures associated with the cleaning process should be established. These procedures should clearly address the specific method chosen, the cleaning process itself, any detergents, and the allotted cleaning time.
There are three types of cleaning procedures for process equipment: automated Clean in Place (CIP), Clean out of Place (COP), and the manual process. However, the major concern of regulatory agencies has targeted pieces of equipment that will be cleaned manually, and where the primary responsibility for the removal of product residues lies with the cleaning operator. In the case of manual cleaning methods, the effectiveness of cleaning depends upon the design of the procedure and the commitment of the operators to follow that procedure. This requires a well-explained SOP, personnel training, and operator commitment. With all three elements present, reproducibility of the results in terms of removal of product residues from equipment surfaces can be achieved.