Cleaning Validation of Medical Devices: What should it look like? An ASTM Guide provides Answers

In the pharmaceutical sector and in the manufacture of APIs, regulations exist regarding cleaning validation. Now, what about cleaning validation of medical devices?

Since 2016, a guideline for cleaning validation of medical devices from the American Society of Testing and Material (ASTM) has been applying. The document entitled "Standard Guide for Validating Cleaning Processes Used During the Manufacture of Medical Devices", labelled F3127-16, comprises 16 pages made of 9 chapters and three appendices. The first chapter (Scope) presents the contents of the guide. It deals with:

• The validation approach
• Equipment design
• Procedures
• Documentation
• Analytical methods
• Sampling
• The development of limits

In this first chapter, exclusion criteria are also mentioned in a subsection. Reusable medical devices are excluded although many of the principles described in this guide are also applicable to reusable medical devices, according to the guide. Cleaning of medical devices in health care establishments is also excluded. Safety aspects are also not covered.

Referenced documents are listed in Chapter 2. These comprise further ASTM guidelines, ISO standards (e.g. from the 10993 series for the biological evaluation of medical devices), tests from the American Pharmacopoeia (e.g. for the determination of endotoxins) as well as the ICH documents Q9 (quality risk management) and Q2 (R1) for the validation of analytical methods.

Chapter 3 lists definitions. Somewhat surprisingly, definitions of IQ, OQ, PQ can also be found here. More on this later. A short Chapter 4 entitled "Summary of Practice" describes the document's approach once again. The aim of cleaning validation is to demonstrate the removal of contaminations and residues introduced during production through the final cleaning process. The result is always a clean medical device. 

Chapter 5 (Significance and Use) refers to Appendix X3 (quoting cleaning validation approaches from other areas like pharmaceuticals) and states that the guide does not provide a detailed plan or road map. However, it describes considerations that can be used by a medical device manufacturer to create a detailed cleaning validation plan. Moreover, it mentions that cleaning validation, like any other validation procedures, can take many different paths to a rule-compliant, science-based, and practicable path.

Chapter 6 on the essential requirements describes that the guideline is divided into 3 different activities:

1. Understanding the "upstream" manufacturing process
2. Documenting the cleaning process
3. Establishing measuring tools which evaluate the cleaning success and which are used for the establishment of performance criteria for cleaning.

The Cleaning Validation Approach according to ASTM F3127-16

Chapter 7 starts the description of the cleaning validation approach over 4.5 pages. The criteria of a cleaning validation approach are listed in tabular form:

• Risk assessment of the cleaning process and the influence on the medical device
• Identification of contaminants (raw material, manufacturing process), machine oils that could remain on the medical device are cited as examples.
• Setting science-based impurity limits (How clean is clean?)
• Methods validation of analytical methods used to analyse impurities
• Qualification or definition of sampling techniques
• A determination that statistical requirements and related documentation are appropriate to deliver the right results.

A full-page flowchart shows the sequences of cleaning validation in a very helpful way.

For the definition of the cleaning process, criteria are specified that should be considered:

• Evaluation of the medical device
• Equipment for cleaning
• Process parameters
• Detergents
• The manufacturing material to be removed

The design and material components of the medical device have a great influence on the suitability of a cleaning process. Some examples are given like the determination of the chemical compatibility between the medical device and the cleaning agent, possibilities of penetration of a cleaning agent into gaps, etc.

In order to determine the risks of a cleaning process (also at a contract manufacturer) the ISO standard 14971 or the ICH document Q9 are mentioned as supporting documents. The risk analysis should also include activities that also have a cleaning effect, such as passivation or surface treatment. Critical in-process cleanings should also be included in the cleaning validation.

When developing a cleaning process, a process flow diagram and a list of materials used in manufacturing (e.g. polishes) and cleaning should also be provided. Material safety data sheets may also be used where possible, explicitly mentioning that their focus is on work safety. Suppliers and changes in supplies should also be considered.

The validation plan based on the process flow diagram and the risk analysis should include the following contents:

• Provision of a rationale for a product grouping
• Process definition
• A selection of the sample size
• A number of runs
• Types of analyses
• Acceptance criteria

Under the subsection "Process Qualification", further elements are addressed which should be listed in the plan:

• Studies or tests to be applied
• Evaluation criteria
• A schedule
• The responsibilities of the relevant departments and the quality assurance department
• Requirements for documentation and approval of qualification

A project plan should include criteria for evaluating changes. Now, IQ and OQ tests of the cleaning equipment and auxiliary systems are described. Factors for individual cleaning steps are listed as examples:

• Use and type of detergent
• Purity of solvents
• Presence of an acid cleaning step
• Concentration of the detergent
• Cleaning temperature
• Ultrasonic frequency
• Spray pressures etc. 

Each cleaning line should be considered individually. With the same lines and the same cleaning processes, the effort could be reduced with justification.

The PQ demonstrates that the cleaning process works on a commercial scale. To determine the process conditions in the PQ, laboratory results and pilot trials should also be included. Increases in scale should also be considered as well as comparable products and processes. If reliable data are available from the cleaning development, it is not necessary to test the entire work area in the PQ. Objective data like statistical data are strongly recommended. For example, the sample size in the PQ should be statistically justified and higher than in the later routine production. There should be at least 3 production runs to map the production variabilities.

The result of cleaning validation should flow into routine monitoring controlled by a programme. The monitoring data should be statistically trended and reviewed. Another outcome of cleaning validation should be cycles in which the need for revalidation is considered. Changes and deviations should, of course, always be evaluated with regard to potentially required revalidation.

Chapter Documentation

The subchapter Documentation details the necessary specifications in cleaning documents (19 topics addressed) and another 7 elements which should be part of a cleaning validation documentation.

In turn, a separate subchapter deals with the topic limits. In order to obtain information on criteria for limits, reference is made to Appendix X 1 of the document. Whereby in Appendix X1 no concrete values are mentioned. Instead, it is referred to the ISO standard 10993 and the USP chapters <87> and <88>. This chapter also refers to possible contaminations by the cleaning agent itself and their treatment.

Chapter Analytical Methods

Chapter 8 on analytical methods is also quite extensive with 2 pages. The text describes the significance of the Limits of Detection (LOD) and the specificity of a method. The analytical methods should be validated. The ASTM standard E2857, the USP chapter <1225> and the ICH document Q2 are mentioned as sets of rules for the validation of analytical methods. Of course, recovery rates after sampling should also be analytically considered. Recovery rates between 50 and 90% are named as example. An ASTM standard (F2459 for the determination of metal residues in medical components) requires 75% for gravimetric analyses. Special requirements apply to inspection processes that only result in a pass/fail judgement. In the following, examples of specific (GC, HPLC, etc.) and non-specific (TOC, conductivity, etc.) analytical methods are listed. Microbiological contaminations ("residual bioburden") are also addressed with reference to USP <85> and ISO standard 11737. The subchapter Sampling takes up a lot of space. Direct sampling, surface analytical techniques (e.g. photoelectron spectroscopy, PES), the swab and rinse method are described. The advantages and disadvantages of the rinse method are also explained.

Chapter Sample Size

To define the sample size (Chapter 9), the Guide requires a scientific rationale on a statistical basis. How this can be achieved is explained in Appendix X2 using various methods (k-factor test, method for attributive tests, hypothesis tests). Interestingly, there is an "opening clause" when a sample size determined on a statistical basis becomes too large. In this case, it is also possible to argue with a sample size that cannot be justified statistically. Chapter 9 finally concludes with a three-column table comprising 2.5 pages. The first column asks questions that should be completed prior to the preparation of the cleaning validation plan. Column 2 is a "Yes" column, which describes how to proceed if the question asked in column 1 can be answered with "Yes". Column 3 describes what to do if the question asked in column 1 has to be answered with "No".

Conclusion

 The ASTM Standard Guide for Validating Cleaning Processes Used During the Manufacture of Medical Devices, marked F3127-16, is relatively comprehensive and written with a high density of information, although it is not a detailed plan or road map. Yet, flowcharts, tables and appendices provide practical assistance. However, concrete acceptance limits are not mentioned.

The Standard Guide for Validating Cleaning Processes Used During the Manufacture of Medical Devices, marked F3127-16 by ASTM, can be purchased on the ASTM website.