Medical Device Definition according to the FDA
The Federal US Food, Drug, and Cosmetic Act (FD&C Act) defines a medical device as an ”instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
- Recognized in the official National Repertory, or the United States Pharmacopoeia, or any supplement of them.
- Intended for use in the diagnosis of disease or other conditions, or in cure, mitigation, treatment, or prevention of disease, in humans or animals.
- Intended to affect the structure or any function of the body of humans or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body and which is not dependent upon being metabolized for the achievement of any of its primary intended purposes.”
This FDA definition provides a clear distinction between a medical device and other FDA regulated products such as drugs. In cases where the primary intended use of the product is achieved through chemical action or by being metabolized by the body, the product is usually defined as a drug. Human drugs are regulated by FDA’s Center for Drug Evaluation and Research (CDER).
Medical Devices Classification according to the FDA
The act requires the FDA to determine the safety and effectiveness of a medical device by assessing any potential health benefit from the medical device use against any potential risk of injury or illness as result of using it.
The Food and Drug Administration (FDA) has established classifications for approximately 1,700 different generic types of medical devices and grouped them into 16 medical specialties referred to as panels.
Each of these generic types of medical devices is assigned to one of three regulatory classes based on the level of control necessary to assure the safety and efficacy the medical device.
Medical Device Classification and regulatory requirements
- Premarket Notification – PMN or 510(k) is a form that manufacturers must submit in order to notify FDA of their intent to market a medical device.
- Class I – General Controls (Low-risk devices)
Exempt from premarket review, unless 510(K) is specifically required by regulation (toothbrush, thermometer, dentist equipment, band etc).
- Class II – General Controls and Special Controls (Medium risk devices) requires a 510(K), unless specifically exempted by regulation.
- Class III – General Controls and Premarket Approval (High risk devices) requires a Pre market approval (PMA) or a Humanitarian Device Exemption (HDE).
Medical Device Quality System (QS) and Regulation
FDA-regulated products manufactures are required to establish an effective quality system in order to meet applicable requirements and specifications and to ensure the medical device is safe for usage, effective and meet the required quality level. The manufacturing standards should comply current good manufacturing practices (cGMP).
Due to the fact that the regulation should cover many different types of medical devices, it does not prescribe in detail how a medical device should be manufactured. Rather, the regulation provides the framework that all manufacturers should follow and establish the required procedures. An effective quality system should be established by the medical device manufacturer and in addition, ISO 13485 certification is mandatory.
Cleaning Validation for Medical Devices
Contamination of a medical device may lead to serious implications and risk the patients/users. Medical device manufacturers must ensure they have correctly identified all potential contaminants and have established the appropriate controls in order to minimize the risk of contamination.
Medical Devices Cleaning Validation Requirements according to the FDA
The United States Food and Drug Administration capture the cleaning validation requirement within the Quality System Regulations (QSR) by stating that each manufacturer shall:
- Establish and maintain the required procedures in order to prevent contamination of equipment or product by substances, materials, foreign matters 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 is removed or were reduced significantly to the limited allowable amount that does not adversely affect patients and user safety and device’s quality.
Medical Devices Cleaning Validation Requirements according to ISO 13485
Based on the International Organization for Standardization (ISO) 13485:2016 requirements, the medical device manufacturer will establish a documented evidence for cleanliness (validation) of product in case :
- The medical device/product is cleaned prior to sterilization and/or its use, or
- Product is supplied non-sterile and 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 to be verified prior usage, or
- Process material 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 regulatory requirements a medical device manufacturer must establish documented evidence for cleanliness as part of cleaning validation.
Hazardous information of manufacturing materials, disinfection materials and cleaning agents residuals can be obtained from the Material Safety Data Sheet (MSDS). The MSDS should be available for all the manufacturing materials used in the medical device manufacturing, cleaning, and sanitization processes.
Risk Analysis of Medical Device and Identification of Materials
For the risk analysis, the impact of the contaminants from a hazardous perspective and from an intended functionality perspective must be analyzed and evaluated.
A useful tool for identifying which contaminants are representing high concerns is to use a hazard analysis or Failure Mode and Effects Analysis (FMEA) and to evaluate the contamination effects on the final product and the patient. By ranking the risk of Severity and Likelihood we can determine the risk level. After risk level was defined, the ability to detect the risk will be assessed and as a result, the risk prioritization will be determined. Based on risk prioritization, the required mitigation activities, if any, will be proposed in order to reduce risk level to the acceptable risk level.
Toxic Contaminants in Medical Device 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 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 the pre-identified materials being used as part of the manufacturing process.
However, in many instances, the NOAEL is not known, and so the medical device manufacturer must use the LD50 values. LD50 is the median lethal dose of specific material. In other words, the amount of a particular toxin that will kill 50% of the population over a specified time duration. These LD50 values can be readily obtained from the MSDS.
The 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 factors – A number (equal or greater than 1) used to divide NOAEL or LOAEL values derived from measurements in animals or small groups of humans, in order to estimate a NOAEL or LOAEL value for the whole human population; also called margin-of-safety.
The conversion Factor (CF) is typically a factor between 100 and a 1000 and is derived to incorporate uncertainty factors (UF) such as:
- Extrapolation from animal to human tolerances (typically defaulted to a factor of 10)
- Inter-human variability (typically defaulted to a 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 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 the reason that special measures must be taken to determine the appropriate removal or inactivation method must be considered.
A spiking study is a study done in order 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.
Medical Devices Cleaning Test Methods
After understanding the limitations of contamination control, the cleaning testing and analysis methods should be developed.
- A specific analytical test can be developed to quantify a contaminant (Spectroscopy, HPLC, GLPC etc.)
- A non-specific test can be developed to quantify many different contaminants at the same time (Bioburden, Endotoxin, Conductivity, Total Organic Carbon, total proteins, Visual inspection).
There are pros and cons for both these approaches.
With a specific analytical test method, an accurate measurement of a particular residue/contaminant can be evaluated. This can be very important when this residue has been identified as being highly hazardous.
Specific methods are more difficult to implement and are more expensive and usually being used to detect specific active materials residuals, cleaning agents residuals etc.
All testing methods, analytical methods and microbiology analysis methods must be validated.
Non-specific methods are commonly used as part of cleaning validation of production lines. They are less expensive and easier to develop. Generally, this can be sufficient where the requirement is to demonstrate a certain level of overall cleanliness and there is no need to detect a specific material and/or contaminant.
When developing any test method, the following factors should be considered:
- Detection Limit; for example, the test method must be sensitive enough to detect relevant levels of the contaminants existing and the acceptance criteria.
- Percentage recovery; the amount of contaminants that can be recovered from the device must be determined and proved
- Reproducibility and Repeatability
Once the test methods have been developed, they must be qualified/validated prior to being used in a cleaning process validation. The test method validation must demonstrate that the analytical method and the extraction and/or sampling method are repeatable.