The present article provides an overview of the guidance document dedicated to manufacturing information and operations in the context of premarket approval 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 applications. In particular, the document highlights the key points related to manufacturing information and operations. 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, nor are intended to introduce new rules or impose new obligations. Moreover, the authority explicitly states that an alternative approach could be applied, provided such an approach is in line with the existing legislation and has been agreed with the authority in advance. The document describes the current position of the authority regarding the matter and could be subject to changes, should such changes be reasonably necessary to reflect the amendments to the underlying regulations. 


Regulatory Background 

The present document is dedicated to the regulatory matters arising concerning the premarket approval applications (PMAs) submitted by the interested parties intended to market their products in the US. In particular, the guidance highlights the aspects related to the information about manufacturing operations the authority expects the applicant to provide. Apart from this, the document provides a brief overview of the PMA review process in general. At the same time, the authority explicitly states that the regulatory procedures conducted under the premarket notification (510(k)) framework are falling outside of the present guidance since a premarket inspection is not ordinarily conducted for this type of premarket submission. The recommendations and clarifications provided in the present guidelines are intended to assist medical device manufacturers in ensuring compliance with the applicable regulatory requirements to streamline the application review process and reduce the unneeded regulatory burden. In particular, the document addresses the following matters:

  • The sequence of events as the Office of Compliance (OC) or the Office of In Vitro Diagnostic Device Evaluation and Safety (OIVD) reviews the manufacturing section of a PMA;
  • The administrative process and projected time frames involved with each step; and 
  • How does the inspection of a manufacturing facility fit into the approval process? 

As it was mentioned before, the present guidance describes the approach the authority deems to be the least burdensome. However, the FDA also encourages medical device manufacturers and other parties involved to submit their feedback and suggestions on the way the regulatory procedures could be improved further. 

In particular, the guidance describes the approach the authority will apply when reviewing the part of information related to the Quality System (QS) regulation (21 CFR 820). At the same time, the exact scope of information to be included in the application is described in the respective guidance documents published earlier by the OC. 


Premarket Approval Applications 

First of all, the authority outlines the main types of premarket approval applications and briefly describes the applicable pathways. Hence, the applicant should consider the nature of their request to determine the particular approach to be followed. According to the document, the types of applications include:

  1. Traditional PMA, where all the elements of the application are to be submitted by an interested party. This includes, inter alia, complete scientific and technical information about the device, manufacturing information, non-clinical study information, and statistically valid and reliable data from clinical studies. All this information could be included in a single application for the authority to be able to assess the safety- and performance-related matters associated with the device and make its determination on whether the marketing approval can be granted. In this respect, the authority also refers to the guidance document named “Premarket Approval Application Filing Review” which describes the information to be included in the application. 
  2. Modular PMA – this PMA format consists of sections or modules submitted separately that together become a complete application; each module includes elements, tests, or other information that constitute a component of a complete PMA, such as manufacturing information or clinical data. 
  3. Expedited PMA (Traditional and Modular). As further explained by the FDA, some of the applications could be prioritized over others due to the aspects related to the medical devices associated thereto. 


PMA Supplements

Following the applicable regulatory requirements, in case of changes to a PMA already approved by the authority, a PMA supplement should be submitted to provide the authority with detailed information about the way the changes are expected to impact the safety and performance of the device already placed on the market. However, some of the changes are not significant and, consequently, do not require a PMA supplement to be submitted. For some of the changes, alternative submission forms could be used. In this respect, the authority mentions that the supplements with no inspections associated thereto are not covered by the scope of the present guidance. These supplements include: 

  • Real-time supplements;
  • 30-day notices;
  • 135-day supplements;
  • Special PMA Supplements – Changes Being Affected;
  • Express PMA supplements; and 
  • PMA annual reports. 

The guidance further provides a brief overview of the applicable supplements to assist medical device manufacturers in interpreting and following the regulatory requirements associated thereto. For instance, it is stated that panel-track and 180-day supplements may include information related to manufacturing processes and applications. 

In summary, the present FDA guidance describes the approach to be applied concerning PMAs and certain PMA supplements – the ones containing information about the manufacturing operations. The document provides an overview of the applicable regulatory requirements and explains the way they should be interpreted by medical device manufacturers intended to market their products in the US. 


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