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 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.
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:
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.