Validating the Cleaning Process

Validating the cleaning process to internal standards, customer standards, and industry standards is important; validation tests may be conducted based on discussions with regulatory personnel. Validating the cleaning process can involve the process, the process chemicals, and the product or component surfaces. Certain analytical techniques are commonly used.

Examples include total organic carbon (TOC), gravimetric determination, particulate counts, extraction with a non-polar organic solvent such as hexa-ne or heptane, or with a chlorinated solvent such as meth-ylene chloride. In addition to the extraction chemical and the extraction technique, specifics of even relatively straightforward techniques vary. Some companies attempt gravi-metric determination of residue on devices by weighing the component itself before and after cleaning; because of the high ratio of component to soil typical of critical applications, this approach shows high variability, tends to be inaccurate, and is not recommended.

Aqueous extraction of the component cleaned by the proposed process followed by in vitro testing can provide a good, overall indication of potential toxicity of the residue or lack thereof. The levels of tolerable residue are sometimes extrapolated using historical data from devices that have performed acceptably.

In addition, an indication of total viable contamination can be achieved by bioburden testing of an aqueous extract of the non-sterile component or finished device that has been subjected to the selected cleaning process. Data may be used to verify acceptable levels of viable contamination since sterilization validation may be based on bioburden levels (e.g., radiation sterilization).

Also, an indication of total endotoxin (lipopolysac-charide found in bacteria and a structural component in the bacteria that is released mainly when bacteria are lysed) can be achieved by endotoxin testing of an aqueous extract of sterilized finished device (products that directly or indirectly contact the cardiovascular system, lymphatic system, or cerebrospinal fluid).

If any aspect of a validated cleaning process is significantly modified, the modified process should be validated. The key phrase is “significantly modified.” It is important to consider the cleaning chemistries and the cleaning process, including temperature, time, cleaning action, and pressure if airless or vacuum cleaning systems are used. One prudent way to check for significant changes is to monitor process performance and process parameters. Complex assemblies with multiple assembly steps are particularly susceptible to unexpected changes. Fabrication steps, including perhaps undocumented cleaning steps, are conducted by specialized contract facilities.

In addition, formulations for cleaning chemistries can change; this is a particular issue with aqueous cleaning agents that may contain organic and inorganic additives. The formulations may be modified in response to environmental regulatory or safety requirements. Other process materials, such as lubricants and polishing materials, can also impact cleaning performance and those formulations may be modified as well. Therefore, in addition to requiring process consistency, it is prudent to assign responsibility for documenting and monitoring any process changes and requests for changes. This means that, ideally, suppliers of cleaning agents and process fluids must not change the formulation — ever. Unfortunately, change is inevitable.

Therefore, whatever group is responsible for monitoring process quality must be notified by the supplier if changes are anticipated. Particularly with medical devices, even minor changes in formulation chemicals that are present below 1% (and, therefore, would not appear on the MSDS) may impact performance and toxicity of the residue might have to be considered. Therefore, to have an adequately documented process, you should obtain the entire formulation of each process chemistry; doing so may require confidentiality agreements and negotiation with the suppliers.

There is another aspect to cleaning process validation and that relates to process continuity between the prototype and the marketed product. This means that the cleaning process should not be added on and validated right at the start of full production; rather, the cleaning process should be developed in parallel with the development of the device. The adage “the proof of the pudding is in the eating” is especially true for complex devices. Given the variables and subtleties involved in cleanliness and surface characteristics, it is safe to hypothesize that no cleaning process validation is completely foolproof. Using fully developed cleaning processes during clinical validation helps assure a historically validated product right from the start.