The new article describes in detail the scope of information the authority expects to receive concerning the changes to the manufacturing site.
The Food and Drug Administration (FDA or the Agency), the US regulating authority in the sphere of healthcare products, has published a guidance document dedicated to the manufacturing site changes supplements. In particular, the document describes the regulatory framework for changes to the manufacturing sites. The guidance highlights the key points for submissions required in case of changes to the manufacturing facilities involved in the processes. Also, it explains the approach to be applied when determining whether an additional inspection is required. The document is intended to provide additional clarifications regarding the applicable regulatory requirements, as well as recommendations to be considered to ensure compliance thereto. At the same time, provisions of the guidance are non-binding and are not intended to introduce new rules or impose new obligations. Moreover, an alternative approach could be applied, provided such an approach is in line with the applicable legislation and has been agreed with the authority in advance. The FDA also reserves the right to make changes to the recommendations provided in the guidance, should it be reasonably necessary to reflect the respective changes to the underlying regulations.
Site Change Supplement: Submission Content
According to the applicable regulation, namely, 21 CFR 814.39(c), the PMA supplement must contain information needed to support the use of a different facility or establishment to manufacture, process, or package the device. The authority further states that to approve a site change supplement, the information submitted must show that, for the different sites, the methods used in, and the facilities or controls used for, the manufacture, processing, and when relevant, packaging and installation of the device conform to the requirements of the QS regulation, 21 CFR Part 820.
As described in the guidance, a site change supplement should contain, inter alia, the following information:
- A detailed description of the product manufactured and its intended use, as well as the details regarding the intended site change and particular processes to be performed at the new facility.
- A diagram was describing the new site.
- A detailed step-by-step description of the manufacturing processes to be undertaken at the new facility (should be provided as a flow diagram).
- Details about the processes to be performed and equipment to be used.
- A list of standards to be applied.
- Details about the validation process.
- Information about the processes that are not subject to validation, but would still be assessed and inspected.
- Details about the process validation or revalidation procedures (respective protocols and reports, especially in case a prior inspection are to be conducted by the FDA before approval is not required).
- The procedures for environmental and contamination controls, when applicable. In the case of a significant number of such procedures, the one most relevant will suffice.
- If different from the original PMA, any procedures that explain how the inspection, measuring, and testing equipment are routinely calibrated, inspected, checked, and maintained (21 CFR 820.72).
- Should the changes to the manufacturing site result in changes to the supplier used, additional details should be provided as well? The aspects to be addressed include, inter alia, the quality controls implemented, communication methods used, and change control mechanisms adopted to ensure adequate control over design and process-related changes. Apart from this, the authority would also expect to receive information about the record-keeping procedures related to suppliers. The applicant would also have to provide documentation related to a specific supplier, vendor, or contract manufacturer it works with.
- Details about the incoming acceptance procedures and processes (should they remain the same as under the additional PMA, the appropriate reference could be provided).
- Details about the final acceptance procedures employed at the manufacturing site in question, in case these procedures are different from the ones under the initial PMA.
Pre Approval Inspections: Key Points
As it was mentioned before, the guidance also describes the approach to be applied when determining whether an additional pre approval inspection is required. According to the guidance, such an inspection for a site change supplement may be necessary for FDA to find that the methods used in, or the facilities or controls used for, the manufacture, processing, packaging, storage, or installation of the device conform to the requirements of the QS regulation, 21 CFR Part 820. Hence, an inspection could be required to ensure that any applicable regulatory requirements are followed to a letter and that the proposed manufacturing site change would not adversely impact the overall quality, safety, and performance of the medical devices manufactured.
The FDA further explains that the determination of whether a preapproval inspection is needed would be based on the assessment of such factors as:
- The dates of the last inspections of the current site and the new site;
- The classification of the last inspection of the current site and the new site;
- The relevance of the last QS regulation inspection to the moved manufacturing, processing, or packaging activities (e.g., whether similar products or processes were inspected);
- A review of relevant recalls and adverse events, associated with manufacturing processes for devices manufactured, processed, or packaged at this site; and
- The risk to the safety or effectiveness of the device is associated with the manufacturing activities performed at the new site.
The abovementioned factors would be taken into consideration when determining the need for a preapproval inspection. At the same time, the applicants themselves are also allowed to contact the authority to discuss the inspection-related matters in advance.
Apart from the recommendations described hereinabove, the guidance also provides references to the additional resources that could be useful for medical device manufacturers who are intended to make changes to the manufacturing sites. In particular, the document contains references to other guidance documents issued by the FDA and dedicated to related matters.
In summary, the present FDA guidance clarifies the expected content of the manufacturing site change supplement and outlines the scope of information to be provided by the applicant. The document also describes the criteria to be used when determining the need for a preapproval inspection.
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