Cleaning validation for medical devices
Contamination of a medical device may lead to serious implications and risk to patients or other users. Medical device manufacturers must ensure they have correctly identified all potential contaminants and have established appropriate controls to minimize risk of contamination.
FDA requirements for medical device cleaning validation
FDA captures cleaning validation requirements within the Quality System Regulations (QSR, 21 CFR 820), stating that each manufacturer shall:
- Establish and maintain the required procedures to prevent contamination of equipment or product by substances, materials or foreign matter that could reasonably be expected to have an adverse effect on product quality and patient/user safety.
- Establish and maintain procedures for the use and removal of such materials to ensure that it they are removed or significantly reduced to the allowable limit which does not adversely affect patient and user safety and device quality.
ISO 13485 requirements for medical device cleaning validation
The ISO 13485:2016 standard includes requirements for medical device manufacturers to establish documented evidence (validation) of product cleanliness when:
- the medical device/product is cleaned prior to sterilization and/or its use, or
- product is supplied non-sterile and is to be subjected to a cleaning process prior to terminal sterilization and/or its use, or
- product is supplied to be used non-sterile and its cleanliness is of significance and to be verified prior usage, or
- process materials and cleaning agents are to be removed from the medical device/product during the manufacturing process.
Therefore, in order to comply with the QSR and ISO 13485 requirements, a medical device manufacturer must establish documented evidence for cleanliness as part of cleaning validation.
Hazard information about manufacturing materials, disinfectants and cleaning agent residuals can be obtained from Material Safety Data Sheets (MSDS).
An MSDS should be available for all materials used in the medical device manufacturing, cleaning and sanitization processes.
Medical device risk analysis and material identification
For risk analysis, the impact of contaminants must be analyzed and evaluated, from the perspective of potential hazards and of intended functionality.
Useful tools for identifying which contaminants are of high concern are Hazard Analysis and Failure Mode and Effects Analysis (FMEA). These may be employed to evaluate potential contamination effects on the final product and patient. By ranking the risks of severity and likelihood, the risk level can be determined. After the risk level is defined, the ability to detect the risk can be assessed and the risk prioritization determined. Based on risk prioritization, the required mitigation activities, if any, are carried out to reduce risk to an acceptable risk level.
Toxic contaminants in medical devices and medicinal products
TI (tolerable intake) is the daily amount of a chemical that has been assessed as safe for humans.
For toxic contaminants where there are well-known toxicity data, ISO 10993-17 is a very useful tool. It describes a method to determine the allowable limits for leachable substances from a medical device using the No Observed Adverse Effect Level (NOAEL). The NOAEL is the highest concentration of a material that causes no significant adverse effects in the exposed population. The standard takes this value and uses it to calculate the tolerable intake (TI) for a specific leachable substance. This approach can be used to calculate limits for pre-identified materials being used in a manufacturing process.
However, in many instances, the NOAEL is unknown, and so the medical device manufacturer must use LD50 values to determine acceptable limits.
LD50 is the median lethal dose of a specific material. In other words, it is the amount of a particular toxin that will kill 50% of a population over a specified time duration. LD50 values can be readily obtained from the MSDS. LD50 values are then used to calculate the Acceptable Daily Intake (ADI), using the following equation:
ADI = LD50 x mB/CF
LD50 = Median lethal dose
mB = Body mass of the patient population (generally defaulted to 70kg)
CF = conversion factor
UF (uncertainty factor) is a number (equal or greater than 1) used to divide NOAEL or LOAEL values, derived from measurements in animals or small groups of humans, to estimate a NOAEL or LOAEL value for the whole human population; also called margin-of-safety.
The conversion factor (CF) is typically a number between 100 and a 1000 which is derived to incorporate uncertainty factors (UF) such as:
- Extrapolation from animal to human tolerances (typically a default factor of 10)
- Inter-human variability (typically a default factor of 10)
Additional UFs can be based on the type of medical device (i.e., medical device class) and the duration of exposure. The weighting of each UF should be documented and justified. The UFs are then used to calculate the CF:
CF = UF1 x UF2 x UF3
Using this approach, a cleanliness limit can be calculated for each specific toxin that was identified during the risk analysis.
Obviously, this approach only identifies a cleanliness limit for known toxins. It is not suitable for calculating the cleanliness limit where there is a lack of toxicological data available or the contaminants have no associated toxicity but will impact the proper functioning of the device.
Spiking studies before cleaning validation
For potential toxins where there is no readily available toxicological data, a series of spiking studies can be completed. This is where the medical device is artificially contaminated with known amounts of the potential toxin.
Viruses are infectious impurities. When a process which contains cells (microorganisms/plant/human cells) is infected by even one viral impurity, the entire process may be compromised. For that reason, special measures must be taken to consider and determine the appropriate removal or inactivation method.
A spiking study is a study done to determine the possible methods of viral removal or inactivation.
In other words, instead of finding the failure point, the medical device is spiked with a known amount of the contaminant that is above the level expected to be observed after cleaning. If this higher level is established as safe for the patient, it can be defined as the cleanliness limit to be tested as part of the cleaning validation.
Spiking studies can also be useful in cases where the risk analysis has identified a potential cumulative effect of various contaminants. In other words, if each contaminant is treated independently of each other, a cleanliness limit may be established that does not take into account a potential cumulative effect. In this instance, the patient may be exposed to unacceptable risk.