The new article describes in detail certain additional aspects to be considered by medical device manufacturers applying for marketing approval concerning the manufacturing information to be included in such applications. 

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 review and inspection of premarket approval (PMA) applications in terms of manufacturing information and operations. The document outlines the scope of information the authority expects the applicant to provide and also highlights the key points to be considered. The guidance is non-binding and is 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 considered to ensure compliance thereto. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with underlying legislation and has been agreed with the authority in advance. The document describes the authority’s current position, and thus could be subject to changes, should such changes be necessary to reflect the corresponding changes to the applicable regulations. 


Inspection Timelines 

According to the guidance, a domestic inspection should be carried out within 45 days from the date the respective request has been received by the authorized department of the FDA. In case of foreign inspections, the timeline will be slightly extended — to 60 days — due to additional time needed for traveling. 

Upon completion of an inspection, the staff involved in it will have additional 30 calendar days to prepare the respective report. The timeline for preparing an inspection report is the same for both domestic and foreign inspections. 

As further explained by the FDA, an inspection could have one of the following outcomes: 

  • Should no objections be raised in the course of an inspection, approval for the manufacturing section of the PMA will be granted, provided no regulatory actions are needed. 
  • In case there are certain objectionable conditions, but they do not prevent from moving forward and do not require administrative actions (i.e., minor issues), the authority will notify the applicant accordingly and provide recommendations regarding the actions to be taken to address these issues. It is also important to mention that the authority will later conduct an additional inspection to ensure these issues are duly addressed. 
  • In case the issues identified during an inspection create a basis for regulatory or administrative sanctions, the following outcomes are possible:
    • In case the issues in question are related to the PMA product which is currently under review, the authority will issue a deficiency letter within 30 calendar days for a non-expedited PMA and within 20 days for an expedited PMA;
    • At the same time, in case the issue identified potentially impacts even other products already placed on the market, the authority may issue a Warning Letter or Untitled Letter. In such a letter, the authority will notify the applicant that the approval cannot be granted as long as the issue exists. The appropriate notice will be also added to the database. It is also important to mention that such a letter stops the review clock for the PMA. In case such a letter is received, the applicant shall provide its response within the respective time frame indicated by the authority in its request. The authority acknowledges that sometimes a few rounds of correspondence may be required to address the issue. Once the issues are corrected, a new inspection will be scheduled by the general procedure. 

Manufacturing Section: General Review Cycle and Delays 

According to the guidance, the authority expects that the whole cycle including the review of manufacturing information provided by the applicant, subsequent inspection, and finalizing of the report should take around 140 days for a non-expedited PMA, and 120 days for an expedited PMA. As it is stated in the guidance, the inspection assignment phase and manufacturing review phase are concurrent. 

The authority further outlines the most common factors that may result in a delay. These factors include, inter alia, the following ones:

  • When OC or OIVD issues a manufacturing section deficiency letter to a PMA applicant, a timely and thorough response facilitates the review process. Until OC or OIVD receives the requested information, the review of the manufacturing section remains on hold and no inspection will be scheduled.
  • When a timely response is not received to real-time questions during the manufacturing section review and the milestone is exceeded, FDA may issue a manufacturing section deficiency letter and/or an approvable pending GMP letter. 
  • The manufacturing process should be in operation as soon as possible after PMA submission. As noted, all process validations should be completed and the design successfully transferred into production. Rescheduling a PMA inspection may result in further delays in the FDA review of the PMA’s manufacturing section and operations and result in an approvable pending GMP letter.

The document also contains a flowchart that provides a general overview of the process and indicates the main steps and milestones. 

In summary, the present FDA guidance describes in detail the approach the authority applies when reviewing the manufacturing section of a PMA application. The document outlines the scope of details the authority expects to be included and also explains the way compliance with the respective requirements will be verified. As explained by the FDA, efficient cooperation between the authority and the applicant is vitally important to facilitate the process and avoid delays. 



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