The new article describes in detail the regulatory approach to be applied in case of changes to the manufacturing site, and also provides additional clarifications regarding the reporting requirements. 

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 modifications to devices subject to premarket approval (PMA). In particular, the document describes the aspects related to the PMA supplement decision-making process and explains the factors to be considered when determining a particular submission type to be used depending on the changes in question. It is also important to mention that FDA guidance documents are non-binding in their legal nature, and are not intended to introduce new rules or impose new obligations, but rather to provide additional clarifications regarding the existing regulatory requirements as well as recommendations to be taken into consideration by medical device manufacturers and other parties involved in order to ensure compliance thereto. 

As it was mentioned before, the guidance describes in detail the main pathways to be followed when making changes to a medical device already placed on the market under the PMA framework. The submission types described in the guidance include, inter alia, the following ones: 

  • Traditional PMA,
  • Panel-Track Supplement,
  • 180-Day Supplement,
  • Real-Time Supplement,
  • Special PMA Supplement (changes being effected),
  • 30-Day Notice, and 
  • Manufacturing Site Change Supplement. 

The purpose of the guidance is to assist medical device manufacturers in determining the proper type of supplement to be submitted when applying for changes to the products they are responsible for. The document highlights the key aspects to be considered when making such a determination and also provides clarifications regarding the interpretation of the underlying legislation. 


Manufacturing Site Change Supplement: Key Points 

Under the general rule, after approval of a PMA, an applicant shall submit a PMA supplement for review and approval by FDA before making a change that affects the safety or effectiveness of the device, including a change that uses a different facility or establishment to manufacture, process, or package the device. In case of such changes, a party responsible for a medical device already allowed for marketing and use in the US would have to submit a “manufacturing site change supplement”. 

As further explained by the FDA, the supplements of this type are actually 180-day supplements regulated under 21 CFR 814.39(c) and 814.40. Depending on the nature of changes in question and the impact they can potentially cause on the safety and effectiveness of the device manufacturers, some of the changes covered by the scope of such supplements could require pre-approval inspection to be undertaken by the authority in order to ensure compliance with the applicable regulatory requirements. In this respect, the authority mentions that a separate guidance document will be issued to address the aspects related to pre-approval inspections and the approach to be applied when determining whether they are required or not in a specific case. Hence, these matters are not covered by the present guidance, so the medical device manufacturers who are intended to make changes to the manufacturing site (e.g., to move to another manufacturing facility) are encouraged to contact the authority for further guidance. 

It is also important to mention that the previous regulatory framework contained a concept of “express supplements” used in the context of changes to the manufacturing site that do not require a pre-approval inspection. Nowadays the said term is no longer used to distinguish such submissions as a separate category. However, in case a pre-approval inspection is not required, the whole process of obtaining the approval to be granted by the authority will be shorter. 


Periodic Reports 

The applicable regulation also provides that the medical device manufacturer could be obliged to submit periodic reports – this could be used as a condition for the authority’s approval. As it is stated in the document, in most cases, after the PMA is approved, the PMA applicant is required to submit reports to FDA annually unless a different time frame is specified in the approval order. Hence, when speaking about periodic reports, the authority usually refers to the annual reports. 

As further explained by the FDA, if the changes are falling beyond the threshold requiring a traditional PMA or a PMA supplement to be submitted, the information about such changes should be included in the annual report. At the same time, it should be noted that simple changes related to the device documentation or manufacturing process documentation, such as rewording or expanding for clarification, translating from one language to another, correcting typographical errors, and moving component characteristics from an engineering drawing note to a different document (e.g., standard operating procedure), do not need to be reported in the annual report. 

In order to assist medical device manufacturers in interpreting and following the regulatory requirements described hereinabove, the document also provides several examples of changes different in their nature and explains the approach to be applied. All these changes are not expected to impact the safety and effectiveness of the product in question, hence, the information about such changes could be included in the annual report, without the need in submitting a separate supplement and obtaining approval from the FDA in order to be allowed to implement them. 

In summary, the present FDA guidance provides an in-depth overview of the existing regulatory requirements related to the changes to medical devices placed on the market under the PMA framework. By the virtue of guidance, the authority describes the approach to be applied by medical device manufacturers intended to make changes to the products they are responsible for when determining the regulatory nature of such changes and obtaining approval from the authority if necessary. 


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