Health Canada, the country’s regulating authority in the sphere of healthcare products, has published a notice and guidance for implementation dedicated to significant changes to medical devices already placed on the market. The document is intended to assist medical device manufacturers and other parties involved in interpreting and applying provisions of current legislation related to change control for medical devices already placed on the market.
First, the document describes how changes to a medical device should be assessed in order to determine whether they are “significant” enough to trigger additional regulatory requirements. For this purpose, the guidance provides three tools to be used by the manufacturers, namely:
- A generalized discussion of the broad principles that can be used to determine if a change would affect the safety and effectiveness of a medical device;
- The set of flowcharts which details specific questions and answers to assist manufacturers in determining if a change is considered to be significant;
- A list of examples of significant and non-significant changes, grouped in accordance with the change types.
The aforementioned flowcharts provide additional clarifications regarding the most common types of changes and cover such aspects as manufacturing processes, quality control procedures, design, sterilization, software, materials (for general and in vitro diagnostic devices separately), and labeling. The authority also mentions that the examples the third tool provides are not exhaustive and should be used only for general reference purposes.
Significant Changes: Regulatory Approach
According to the document, a “significant change” is a change that significantly impacts the safety or effectiveness of the product. For instance, a significant change usually:
- Results in risks to the patient not previously identified;
- Increases the probability of existing hazards occurring;
- Alerts the presentation of existing or new risks to the user (this can involve labelling changes or new indications for use); and/or
- Changes the performance, safety or effectiveness of the device.
In the case of changes falling within the categories listed above, the manufacturer shall conduct a rigorous assessment of the potential impact such changes will have on the overall safety and performance of the device. If there are several changes to a medical device implemented together, the manufacturer should assess both the collective impact of all the changes and the impact caused by each of them separately.
If a new medical device is similar to one already placed on the market in terms of design, materials, and construction and differs only in size (due to the size range), this should not be treated as a significant change. However, the manufacturer would still have to demonstrate that such change has no impact on the safety and performance of the medical device in question. At the same time, in the case of additional changes to the design, such changes should be subject to separate assessments.
Changes to Manufacturing Processes
The first flowchart provided by the authority is dedicated to changes to manufacturing processes, facilities, or equipment. Since these factors have a significant impact on the safety and performance of a medical device, they should be treated as “significant changes” and require amendments accordingly. For instance, if the manufacturer adds a new production site, it should be covered by the Quality Management System (QMS) certification. However, if such a change occurs, it will be sufficient for the manufacturer to apply for an amended license. It is not required to provide evidence demonstrating compliance with the applicable regulatory requirements. The authority emphasizes that the changes to the sterilization processes in most cases are significant ones. In this regard, the authority refers to the appropriate section of the guidance.
Changes to the Manufacturing Quality Control Procedures
According to the guidance, changing or adding a new test acceptance criteria or test method to provide equivalent or better assurances of reliability is not considered to be a significant change, while removal of test acceptance criteria, in-process inspections, or final inspections without replacement of these activities is considered significant.
Moreover, changes to the methods and procedures applied to control the quality of the materials used to manufacture medical devices are considered significant, provided they impact specifications, so the manufacturer will have to submit a license amendment application. The same approach applies to changes to the criteria used by the manufacturer to check the materials used in the manufacturing process.
Changes in Design
According to the guidance, any and all changes to the design of the device should be subject to a rigorous assessment in order to evaluate the actual effect these changes have on the safety and performance of the medical device. The final determination regarding whether such changes are significant or not should be based on the results of such an assessment. For instance, changes to control mechanisms would be considered significant in most cases. The same approach applies in the case of changes to operating principles. In the case of changes to the design specifications or software, the manufacturer will also have to assess the impact caused by such changes to the indications for use.
Changes to Sterilization
Health Canada states that in order to comply with the applicable regulatory requirements, the manufacturer shall demonstrate the appropriate sterility assurance level (SAL). Moreover, the sterilization process implemented by the manufacturer should be subject to verification and validation in order to ensure continuous compliance and effectiveness. Thus, any and all changes made to the sterilization process should be duly documented. The changes which require special attention include those related to the process itself or equipment used, the quality control verification, and also to the design and material of the device, provided such changes impact the sterilization process. The same approach should be applied in the case of any changes to the packaging of medical devices intended to be supplied sterile as the packaging of such devices should ensure the device remains sterile when being transported and stored in accordance with the recommendations communicated by the manufacturer, and for the whole period of shelf life. At the same time, a simplified approach could be applied if such changes to packaging have already been reviewed in the context of another medical device.
Changes to Software
As stated in the guidance, most of the changes to software would be considered significant and trigger the obligation of the manufacturer to apply for a license amendment. For instance, significant changes to the software includes those that:
- Impact the control of the medical device in question;
- Impact the way the data is read or interpreted by the person using the device;
- Add a new feature impacting the functioning of the device in terms of diagnosis or therapy.
In summary, the present Health Canada guidance describes in detail the main types of changes to medical devices and how they should be assessed by the manufacturer in order to determine the impact they can cause to the safety and performance of the device. The document outlines the main criteria to be applied when considering the changes as significant and thus requiring an application for a license amendment to be submitted.
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