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
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.