2020-08-30T12:06:08+00:00December 20th, 2017|

A contaminated medical device may lead to serious implications and risk to the patient/user. Medical device manufacturers must ensure they have correctly identified all potential risks and contaminants and have established appropriate ‎cleaning methods, controls, and analyses to minimize contamination risks.

To comply with the QSR (21 CFR 820) and ISO 13485 regulatory requirements for cleaning of equipment, machinery and medical devices, a medical device manufacturer should establish documented evidence for cleaning methods validation.

This article focuses on a medical device glossary and FDA classification, medical device cleaning validation requirements, medical device cleaning processes, test methods and more.

Medical device cleaning validation - Bio Chem

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Medical device cleaning validation - Bio Chem
Medical device cleaning validation - Bio Chem
Medical device cleaning validation - Bio Chem
Medical device cleaning validation - Bio Chem
Medical device cleaning validation - Bio Chem
Medical device cleaning validation - Bio Chem

Medical device – FDA definition

The US Federal Food, Drug, and Cosmetic Act (FFDCA) 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 Formulary, or the United States Pharmacopoeia, or any supplement to them
  • Intended for use in the diagnosis of disease or other conditions, or in the 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 definition clearly distinguishes a medical device from other FDA-regulated products, such as drugs. Medical devices are regulated by the FDA Center for Devices and Radiological Health (CDRH).
When 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 the FDA Center for Drug Evaluation and Research (CDER).

Medical device classification by the FDA

The FFDCA requires FDA to determine the safety and effectiveness of a medical device by assessing any potential health benefits from use of the medical device compared to any potential risks of injury or illness as a result of its use.

FDA has established classifications for approximately 1,700 different generic types of medical devices, and has 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 effectiveness of the medical device.

Medical device classifications and regulatory requirements

  • Premarket Notification – The PMN or “510(k)” is a mechanism whereby manufacturers submit to notify FDA of their intent to market a medical device.
  • Class I – General Controls (Low-risk devices) for medical devices which are exempt from premarket review, unless a 510(K) is specifically required by regulation (e.g., toothbrush, thermometer, dental equipment, etc.).
  • Class II – General and special controls for medium risk devices, and require a 510(K) premarket notification, unless specifically exempted by regulation.
  • Class III – General controls and premarket approval for high risk devices require submission of a pre-market approval (PMA) application or a Humanitarian Device Exemption (HDE) application.

Medical device quality system (QS) and regulation

FDA-regulated product manufactures are required to establish an effective quality system to meet applicable requirements and specifications, and to ensure that the medical device is safe to use, effective and meets the required quality level. Manufacturing should comply to current good manufacturing practice (cGMP).

Due to the fact that the regulation covers many different types of medical devices, it does not describe in detail how a particular medical device should be manufactured. Rather, the regulation provides a framework for all manufacturers to follow and establish required procedures. An effective quality system should be established by the medical device manufacturer and ISO 13485 certification is mandatory.

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Advises, establishes, accompanies and upgrades systems of various types of quality management, executes GMP trainings and courses, assimilates the company’s GxP principles, ISO 13485, assures quality and prepares for global regulatory audits while conducting risk analysis and evaluation, equipment, systems, software, testing methods, manufacturing processes. And cleanliness until successfully audited.

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Digital healthcare consulting, software development and medical applications in accordance with 21CFR part 11 / Annex 11 / HIPAA / GDPR requirements, ISO 13485/27001/27799, CE marking, Risk Assessment, and software validation and control systems up to marketing approval.

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 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.

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 nonspecific test can be developed to quantify many different contaminants at the same time (bioburden, endotoxin, conductivity, Total Organic Carbon (TOC), total proteins, visual inspection).

There are pros and cons for both of 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, are more expensive and are usually used to detect specific active material residues, cleaning agent residues, etc.

All testing, analytical methods and microbiological analysis methods must be validated.

    לפרטים נוספים

    For further details

    Nonspecific 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 present 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.

    Biochem has been advising biomedical companies for more than 13 years.
    Contact us for medical device validation.
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