10/31/2018 Validation of a Cleaning Process for Medical Devices | IVT - Cleaning Validation

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Validation of a Cleaning Process for Medical Devices | IVT

By Sebastian Clerkin, Ph.D. Dec 15, 2013 12:10 pm PST

Peer Reviewed: Cleaning Validation

Abstract

Many medical device manufacturers find it a considerable challenge to plan and conduct a cleaning
validation. The main challenges are an establishment of the cleanliness limits and an identification of
the challenge conditions to be assessed during the process validation. This paper describes a logical
risk-based approach to overcome these challenges.

It begins with assessing the complete manufacturing process and identifying the manufacturing
agents. It discusses risk tools to determine which manufacturing agents need to have cleanliness
limits. It describes the manufacturing conditions to be considered when conducting the cleaning
validation.

The concepts described within this paper can be utilized by a medical device manufacturer to
establish a cleaning process that will consistently provide clean medical devices and comply with the
relevant regulations.

Introduction

Contamination of a medical device can have serious implications. Medical device manufacturers must
ensure they have correctly identified all potential contaminants and have established controls.

The United States Food and Drug Administration captures this requirement within the Quality System
Regulations (QSR) by stating that each manufacturer shall (1, 2):

Establish and maintain procedures to prevent contamination of product by substances that could be
expected to have an adverse effect on product quality

Establish and maintain procedures for the use and removal of manufacturing materials to ensure that
it is removed or limited to an amount that does not adversely affect the device’s quality (2).

International Organization for Standardization (ISO) 13485 requires that a medical device
manufacturer establish documented requirements for the cleanliness of a medical device in the
following circumstances (3):

Product is cleaned by the organization prior to sterilization and/or its use, or

Product is supplied non-sterile to be subjected to a cleaning process prior to sterilization and/or
its use, or
Product is supplied to be used non-sterile and its cleanliness is of significance in use, or
Process agents are to be removed from product during manufacture.

Therefore, to comply with the QSR and ISO 13485, a medical device manufacturer must establish
documented cleanliness requirements.

However, these regulations do not explicitly state that a cleaning process validation must be
completed. The Global Harmonization Task Force (GHTF) Study Group 3 does provide guidance on
the requirement for a cleaning process validation. Their process validation guidance (4); which was
written by regulators in the US, Europe, Japan, Australia and Canada; states a cleaning process may
be validated or may be satisfactorily covered by verification. ISO 14696, which provides guidance on
the application of ISO 13485, states that a cleaning process needs consideration of use and the
controls in place to determine whether some or all of the elements of validation are required (5).
Therefore, a decision to conduct a cleaning process validation is dependent on the outputs of the
cleaning process and the controls in place. For example, Figure 1 shows a manufacturing process
flow that has an intermediate cleaning step. The sole output of this intermediate clean step may be
that the parts are visibly clean. In this instance, verification may be sufficient with no requirement for
process validation. On the other hand, the manufacturer taking a risk-based approach has specified a
level of acceptable residues after intermediate cleaning. In this instance, verification would not be
sufficient and process validation would be necessary.

Figure 1: Example of a Manufacturing Process Flow.

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In the above manufacturing process flow (Figure 1), the final cleaning step is the more critical
cleaning step of the two, as this is the last step in the process to make sure that the medical devices
are sufficiently clean prior to packaging. The cleaning validation approach described within this paper
is more applicable to this final clean step. It consists of a number of logical steps from identifying the
risks to establishing limits and from validation to process monitoring.

Review Process Flow and Identify the Manufacturing Materials

In order to determine the cleanliness limits for manufacturing agents after the final cleaning process, it
is imperative to first evaluate the complete manufacturing process. An overall process flowchart
should be created to demonstrate that the process has been adequately assessed, and it should
contain information on the manufacturing materials that come in contact with the product at each
process step. Examples of manufacturing materials that must be considered include: lubricants,
detergents, wipes used during inspection, and polishing agents. This manufacturing material maybe
attributable to one of the following groups:

An organic residual; these are mostly insoluble in water and include greases and oils
An inorganic residual; these are water soluble, and examples include metal ions
Particulate; an example would be metallic particles left over from a cutting process.

Hazardous components of manufacturing materials can be obtained from the Material Safety Data
Sheet (MSDS). The MSDS should be available for all the manufacturing materials used in the
process.

It must be noted, however, that the MSDS generally only lists the main components that are present
in a mixture. For example, the United States Department of Occupational Safety and Health
Administration (OSHA) only requires that hazardous constituents in excess of 1% be disclosed on a
MSDS (6). For carcinogens it is 0.1%. This is due to the fact that MSDS are designed to protect the
workers, not identify potential hazardous contaminants on a medical device.

There is also a risk that multiple constituents below the 1% disclosure threshold could have a
cumulative effect on the intended use of the device.

Even though the MSDS does have these shortcomings, it is still a very useful initial tool in identifying
potentially hazardous manufacturing agents.

When dealing with complex manufacturing materials such as cutting fluids, it is a considerable
challenge to identify the individual components as they contain many different chemicals. These
chemicals may not be identified by the supplier or may be considered proprietary. In these instances,
it is imperative to liaise directly with the manufacturing material supplier to identify any potential
contaminants that could impact the intended use of the device.

In addition, any process steps completed by an external supplier must also be evaluated. For
example, manufacturing material may be present on a supplied component. These must be
considered. This is why it is crucial that the medical device manufacturer has a written agreement in
place with their supplier that no changes are made to their manufacturing materials without prior
agreement.

Only after the overall process flow has been completely reviewed and all the potential contaminants
on the device identified can the manufacturer start to consider their impact. Their impact is assessed
by conducting a risk analysis.

Risk Analysis and Identification of Materials of Concern

For the risk analysis, the impact of the contaminants from a hazardous perspective and from an
intended functionality perspective must be considered.

A useful tool in identifying which contaminants are of the most concern is to use a hazard analysis
and to ask the following questions:

Will too much of this contaminant be harmful to the patient?

Will too much of this contaminant impact the proper functioning of the device?

An example of a hazard analysis is shown in Table I; the process steps, manufacturing material and
particular agents are listed, and then the risk is considered. The mitigation from the hazard analysis
can be used to establish a particular cleaning limit or use of an alternative manufacturing material.

Table I: Hazard Analysis. Severity (S) is scored1 to 5, 5 being the most severe; Likelihood is scored
1 to 5, 5 being the most likely; Risk index (R) is calculated by multiplying the Severity score by the
Likelihood score.

Process Manufacturing Potential Potential

Potential Cause S L R Mitigation S L R
Step Material Hazards Effect
Passivation Passivation Sodium Carcinogen; 5 2 10 Use a passivation 5 1 5
solution dichromate Irritant; solution that
Residual Sodium
(CAS#: 7789- Mutagen contains no
12-0) dichromate present Sodium
dichromate

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on the finished
device

Third body Establish a

Metallic particulates
Metallic wear of particulate
Grinding Grinding wheel present on finished 4 2 8 4 1 4
particulates bearing specification for
device
surface finished device

Establishing Cleaning Limits

Now that the potential hazardous contaminants have been identified, the acceptable level of
contamination on the medical device must be determined. These levels or limits must be documented
and scientifically justified by the medical device manufacturer.

For toxic contaminants where there is known toxicity data, ISO 10993-17 is very useful. It describes a
method to determine the acceptable levels of leachable material from a medical device using the No
Observed Adverse Effect Level (NOAEL) (7). 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 manufacturing materials.

However, in many instances, the NOAEL is not known, and so the manufacturer must rely on using
the LD50 values. LD50 is the median lethal dose. In other words, the amount of a particular toxin that
will kill 50% of the population over 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

Where:

LD50 = median lethal dose

mB= is the body mass of the patient population and is generally defaulted to 70kg
CF= conversion factor

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 (8). The UFs are then used to
calculate CF:

CF = UF1 x UF2 x UF3

In most cases, a conversion factor between 100 and 1,000 is sufficient; however, there may be
instances where significant risks have been identified and a CF as high as 10,000 may be appropriate
(9). Refer to Kramer et al.for further information on conversion factors (10).

Consider a real world example of the above approach using an alkaline cleaner:

The CF has been established as 1,000 to account for no human toxicity data (factor of 10), inter-
human variability (factor of 10), and a short exposure time of the device (factor of 10).
The LD50of the alkaline cleaner is 365 mg/kgrat.

The average human body weight is 70 kg.

This would give:

ADI/device = 365 mg/kg x 70 kg/1000 =25.55 mg/device

Therefore, the cleanliness limit for this chemical would be 25.55 mg per device.

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.

For potential toxins where there is no readily available toxicological data, a series of spiking studies
can be completed. This is where the device is artificially contaminated with known amounts of the
potential toxin. Biocompatible studies can then be completed to determine the point of failure. The
suite of ISO-10993 standards provide a wealth of information that can be used to define the
biocompatibility studies needed in establishing the failure point. Cytotoxicity, sensitization, systemic
toxicity, and genotoxicity studies are examples of biocompatibility studies that could be considered.
The established failure point can then be used to derive the cleanliness limit.

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Another approach to spiking studies is to approach the issue from the opposite end. In other words,
instead of finding the failure point, the 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.

Spiking studies can also be useful if 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.

Spiking studies should also be considered for contaminants where the LD50 value is known but the
manufacturer has identified additional risks. For example, if a carcinogen has been identified as a
potential contaminant, a spiking study may be instigated with a genotoxicity and/or carcinogenicity
study as the endpoint.

Working out the cleanliness limits for non-toxic contaminants, which have the potential to interfere
with the proper functioning of the device, needs to be established by reviewing historical data or by
spiking experiments. The spiking study is conducted in a similar manner as above, but instead of a
biocompatibility study being the endpoint, the levels of contamination are now evaluated against a
specific functional requirement for the device. For example, for a device that has a bearing surface
and device failure attributed to particulate contamination, a spiking study may be developed to
determine the level of particulate that will induce the failure.

Establishing Cleaning Test Method

Now that the cleaning limits have been identified for specific manufacturing agents, the next step is to
decide on a method to quantify the levels. There are two types of tests that can be developed:

A specific analytical test can be developed to quantify a contaminant (refer to Table II for
examples).
A non-specific test can be developed to quantify many different contaminants at the same time
(refer to Table II for examples).

There are pros and cons for both these approaches. With respect to a specific test method, an
accurate measurement of a particular residue can be evaluated. This can be very important when this
residue has been identified as being highly hazardous. However, these specific methods are more
difficult to implement and are more expensive; therefore, they are really only used when a specific
risk has been identified during the risk analysis.

Non-specific methods are more commonly used in validating cleaning lines; they are less expensive
and easier to develop. However, due to their non-specific nature, they do not give an accurate
quantification of any individual contamination, only a total level of a group of contaminants. Generally,
this can be sufficient where the requirement is to demonstrate a certain level of overall cleanliness.

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.
Percentage recovery; the amount of contaminants that can be recovered from the device must
be determined.
Reproducibility and Repeatability
Linearity
Specificity.

Table II: List of Test Methods. Each could potentially be used to assess outputs of a cleaning
process.

Specific/Non-
Test Method Description
Specific
A spectroscopic technique. Useful to identify and quantify specific
Specific Infrared Spectroscopy
molecules

Gas Liquid Partition Useful for quantifying a specific contaminant that can be vaporized
Specific Chromatography (GLPC) without composition

High-Performance Liquid A method that separates a mixture allowing individual components to

Specific
Chromatography (HPLC) be quantified
Non-Specific Conductivity Measure of ionic compounds
Quantitative measure of carbon contained within an organic compound.
Non-Specific Total Organic Carbon (TOC)
A very good method of showing overall cleanliness.
Non-Specific Visual Visual Assessment of cleanliness
Non-Specific Gravimetric Analysis Quantitative measure of mass of a solid within a solution

Once the test methods have been developed, they must be qualified 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 is repeatable. With respect to the extraction method, it must be
demonstrated that the contaminant can be consistently recovered from the medical device. There is
no point in having a repeatable analytical method if the contaminant of interest cannot be consistently
extracted off the device.

Cleaning Equipment Qualification (IQ)

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The cleaning equipment must be qualified prior to commencing the process validation. This will
demonstrate that the equipment is installed correctly and functions as intended.

Operational Qualification (OQ)—Challenge Conditions

As part of the OQ phase, the critical process inputs should be identified. It must be established how
these process inputs impact the cleanliness outputs. Brainstorming and tools such as fishbone
diagrams can be very useful in identifying the critical process inputs. Some examples of potential
process inputs that could be considered during a brainstorming are listed in Table III.

Table III: Cleaning Process Inputs.

Cleaning
Process Comment
Inputs
Tank
Higher temperatures are generally more effective while lower temperatures are less effective.
Temperature
Cleaning Time Longer times are generally more effective while lower times are less effective.
Usually the higher the concentration of cleaning agent the better; however, at higher concentrations
Concentration
there may be higher level of cleaning residual present on the parts post-cleaning.
As parts are processed through the cleaning solution, it will become contaminated. There is a risk
Cleaning
that as the cleaning tank becomes dirtier, its cleaning effectivity will decrease. To assess this, the
Solution
change-out frequency of the tank, the level of contamination on the parts, and the number of parts
Contamination
processed between change-outs must be considered.
Flow Rate of
Cleaning Higher flow rates are generally more effective while lower flow rates are less effective.
Agent
Agitation Agitation should improve the cleaning effectiveness.
Ultrasonic Ultrasonic should improve the cleaning effectiveness.
Load A higher number of parts or dirtier parts may represent a greater challenge to the cleaning process.
Rinse Rinse times, temperatures and volume are important in removing the cleaning agent from the
Parameters product.
Time, temperature and airflow are critical parameters that can impact the dryness of the parts. The
Drying geometry of some parts, such as the internal diameter of a narrow tube, may make them difficult to
Parameters dry. Another consideration is the temperature used for drying. Too high a temperature could have an
impact on the material properties of the product.

To adequately challenge a cleaning process during OQ, the worst-case product should be used. For
medical device manufacturers that clean multiple different devices, identification of the worst-case
product can be a challenge. To aid in this identification, a worst-case product matrix can be used to
help determine the worst-case product. Each product is scored according to predefined criteria.
These predefined criteria would have a potential impact on the cleaning ability of the process.
Examples include the following:

Device geometry; more complex geometry is potentially more difficult to clean

Surface area; greater surface area could be a greater cleaning challenge.
Up-stream process flow; this could have an impact on the cleanliness levels of the parts pre-
cleaning. A greater level of contamination on the parts pre-clean would obviously be a greater
challenge to the process.

The scores against these criteria can then be tabulated in the form of a matrix and used to calculate a
total risk score. See Table IV for an example.

Table IV: Worst-Case Product Matrix. The product is scored between 1 and 10 for each criterion.
These values are then multiplied together to give the total risk score. The product with the highest risk
score is then considered the worse case product.

Worse Case Product Matrix

Product Number Surface Area Device Geometry Up-Stream Process Flow Total Risk Score
1001 10 10 5 500
1002 7 5 10 350

Once one has established the critical process inputs, these should be challenged within the OQ to
prove that product can be cleaned that meets the pre-determined cleaning specifications under all
anticipated manufacturing conditions.

Performance Qualification

PQ means establishing by objective evidence that the process, under anticipated conditions,
consistently produces a product that meets all predetermined requirements (11). To establish this, the
medical device manufacturer must demonstrate that the process in anticipated manufacturing
conditions is stable and can consistently produce product to the predefined cleaning specifications.
The manufacturer can use tools such as control charts to demonstrate that the process is stable as
well as capability analysis to show that the process is consistent.

With respect to identifying the anticipated conditions of a cleaning process, factors that could be
considered are the following:

Material lots, for example, batches of cleaning agents

Environmental conditions
Multiple Shifts
Operators
Process operating windows defined in the OQ; for examples, see above.

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Process Monitoring

After the cleaning process is validated, it is desirable to implement process monitoring of key process
parameters and product outputs to maintain a state of control. The action levels can be established
during the process validation.

ISO 14969 specifically states that the process parameters used for cleaning should be routinely
monitored in accordance with documented procedures (12). Examples of critical process inputs that
could be monitored would be conductivity on a rinse tank or concentration of cleaning agent in a
cleaning tank.

The product outputs that would be monitored are risk-based and would relate to the cleaning
specifications established previously. For example, the medical device manufacturer may consider
monitoring the TOC of the product on a regular basis to maintain confidence that the cleaning
process is still in control. For newly developed cleaning processes, this monitoring can initially be at a
higher frequency and reduced as the manufacturer gains more confidence in their process.

Revalidation

Obviously, changes to the cleaning system and process should be assessed for their impact to the
validation. In addition, any changes to the manufacturing materials used in the up-stream
manufacturing processes may have an impact on the cleaning validation. This includes manufacturing
steps completed by an external vendor. If the change is deemed to have an impact, the cleaning
validation should be either repeated in part or in full. Again, this needs to be a risk-based decision.

The addition of new products to the clean line should be assessed to determine if they are a new
worst-case. If they are considered a new worst-case product, the cleaning validation should be
repeated. A recommended approach to determining if revalidation is required with a new product is to
update the worst-case product matrix described earlier with the new product. If the new addition
scores higher than the original worst-case, then the cleaning validation must be repeated.

Conclusion

The main steps in conducting a cleaning validation is to assess the manufacturing material for each
manufacturing process step, establish cleanliness limits, and then validate the cleanliness test
methods and the cleaning process itself (Figure 2).

Figure 2: Overall Process Flow to a Cleaning Validation.

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Cleaning validation does not need to be difficult. If medical device manufacturers take a methodical
approach and base each decision on sound scientific rational, they will be able to establish a cleaning
process that will consistently provide clean medical devices to the market.

References
1. Code of Federal Regulations, Title 21, Quality System Regulations, Part 820.70(e), 2013
2. Code of Federal Regulations, Title 21, Quality System Regulations, Part 820.70(h), 2013
3. ISO 13485:2003, Medical devices -- Quality management systems -- Requirements for
regulatory purposes, section 7.5.1.2.1.
4. Global Harmonisation Task Force Study Group 3, Quality Management Systems Process
Validation Guidance, January 2004
5. ISO 14969:2004, Medical devices -- Quality management systems -- Guidance on the
application of ISO 13485: 2003, section 7.5.2.1.1.5.
6. Code of Federal Regulations, Title 29, Part 1910 - Occupational Safety and Health Standards,
Subpart Z Toxic and Hazardous Substances, 2013.
7. ISO 10993-17:2009, Biological evaluation of medical devices -- Part 17: Establishment of
allowable limits for leachable substances.
8. ISO 10993-17:2009, Biological evaluation of medical devices -- Part 17: Establishment of
allowable limits for leachable substances.
9. ISO 10993-17:2009, Biological evaluation of medical devices -- Part 17: Establishment of
allowable limits for leachable substances.
10. H.J. Kramer, W.A Van Den Ham, W. Slob, and M.N. Pieters, “Conversion Factors Estimating
Indicative Chronic No-Observed-Adverse-Effect Levels from Short-Term Toxicity Data,”
Regulatory Toxicology Pharmacology 23, 249-255, 1996.
11. Global Harmonisation Task Force, Quality Management Systems - Process Validation
Guidance Edition 2, January 2004
12. ISO 14969:2004, Medical devices -- Quality management systems -- Guidance on the
application of ISO 13485: 2003, Section 7.5.2.1.1.6.

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