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Equipment Cleaning Validation Within a Multi-Product Manufacturing Facility
 Currently, there are multiple publications, as well as guidelines from regulatory agencies thatmake the critical process of equipment cleaning validation easier. These sources provide in-depthinformation for the validation specialist, making the development and implementation of a robustcleaning validation program possible within any particular facility developing or manufacturingparenteral, biological, or sterile ophthalmic products.Extremely important, specific, and above all, mandatory, are the requirements established byregulatory agencies such as the US Food and Drug Administration (FDA), the EuropeanMedicinal Evaluation Agency (EMEA), Australia's Therapeutic Goods Administration (TGA),etc. For example, the 2004 Code of Federal Regulations (CFR) Title 21, Volume 4, Section211.67, states:"Equipment and utensils shall be cleaned, maintained, and sanitized at appropriate intervals toprevent malfunctions or contamination that would alter the safety, identity, strength, quality orpurity of the drug product beyond the official or other established requirements."Additionally, Section 211.182 requires that cleaning procedures must be documentedappropriately, and that a cleaning and use log should be established.This article provides the reader with cleaning validation information enhanced by the author'sthirteen years of hands-on experience working in equipment cleaning validation.
SCOPE
This article focuses on manual cleaning procedures because these are considered the worst-casescenario. It applies to parenterals, ophthalmic, and biologic presentations and is intended to coverequipment validation for raw materials, contaminants, cleaning agents, as well as the control of potential microbial contaminants associated with those products.The flowchart in Figure 1 graphically shows the different aspects that should be considered whendeveloping a cleaning validation program. Understanding each aspect of the process, therelationships among these actions, and the sequence in which they should take place will makethe development of a cleaning validation program a successful experience.
PROCESS FLOW
 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 andfinal product flow. By following the flow of the product, one can identify the equipment thatcomes in contact with it, such as utensils (scoops, spatulas, funnels, pipettes, etc.), tanks, filterhousings, pressure vessels, syringes, and others. Equipment such as this is considered criticalequipment 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. Fromthe point of view of microbial load, inappropriate cleaning and sanitation of these areas maycontribute to cross-contamination. Some examples of these areas include: sampling and weighingrooms, 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. Manyactive ingredients are potent compounds, such as steroids, cortisone, antibiotics, proteins, andtherefore it is important to demonstrate their removal. But be aware that some inactiveingredients have poor solubility in water and their residues may be more difficult to remove thanthose of an active drug.Utensils used during the sampling process of raw materials require cleaning validation unlessthey are disposable. Typically, use of disposable utensils is the preferred practice for parenteraland biological products. The sampling of raw materials should be performed within a controlledenvironment (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 androom air conditions that provide an acceptable environment for raw materials sampling. Inaddition, sampling area and rooms should be cleaned with sanitizing agents. Cleaningeffectiveness on those surfaces should be challenged using microbiological tests for verificationof 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 tothe raw materials weighing process. Some ingredients will require being weighed inside a glovebox due to special environmental requirements (e.g., under nitrogen, etc.). Because glove boxesare usually shared, they too will require cleaning validation.Product Compounding: This is one of the most critical steps because the equipment used willhave direct impact on the finished product. Compounding a finished product requires equipmentwith large product contact surface areas. The handling of ingredients requires utensils with lessproduct contact surface area. This significant difference is important because the more complexthe 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 pharmaceuticalprocesses, so they do not generally require cleaning validation.Product Filling: Filling of parenteral, ophthalmic, and biologic products is usually performedwithin areas of controlled bioburden, ranging in scale from clean to aseptic rooms. Drug productsare capable of being contaminated in many ways. Contamination may occur via fillingcomponents (tips, caps, bottles, or stoppers); when coming in contact with processing equipment(tanks, manifolds, fillers, machine-syringes, pistons, and blocks); the manufacturingenvironment, or manufacturing operators.
 
 Some equipment may require cleaning revalidation if components come in contact with theproduct. Stoppers are siliconized and then are placed in a hopper during filling. Small quantitiesof silicone are accumulated in the lower part of the hopper where it can degrade over time. If thissilicone were to come in contact with the product, it would probably cause productcontamination.Requirements for aseptic processing include cleanable floors, walls, ceilings, particulate,temperature, humidity, cleaning, and disinfecting procedures. When disinfectants are used in themanufacturing area, care must be taken to prevent the product from becoming contaminated withchemical disinfectants. The selection of suitable disinfectants, verification of their effectiveness,and a surface challenge are critical in developing a cleaning and sanitization program. Writtenprocedures for cleaning, maintenance, and sanitization of manufacturing equipment andappropriate areas of the facility are required. Removal of residual disinfectants should bemonitored as a precaution against the possibility of product contamination.Know Product Ingredients and Intended Use of the Final ProductPrevious to designing the cleaning procedures, it is necessary to know all physical and chemicalcharacteristics 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. Thesecharacteristics will indicate whether solvents or detergents are needed for removal of productresidues. Avoid the use of detergents or solvents whenever possible because their use demandsadded 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 proceduressurrounding these products, because they will be intravenously administrated to patients and anyadverse reaction could cause serious damage to patient health.Developing Standard Operating Procedures (SOPs) for Cleaning ProcessesOnce we know and understand the product process flow, the product's ingredients, and theproduct's intended use, standard operating procedures associated with the cleaning processshould be established. These procedures should clearly address the specific method chosen, thecleaning 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 wherethe primary responsibility for the removal of product residues lies with the cleaning operator. Inthe 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 awell-explained SOP, personnel training, and operator commitment. With all three elementspresent, reproducibility of the results in terms of removal of product residues from equipmentsurfaces can be achieved.
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