During my time at my former company, we came across the challenge of demonstrating compliance to the 21 CFR Part 4 requirements.  The background to this was that some products in the US are considered ‘combination products’ even if registered as drug products.  We found that two of the products fell into this category one being a drug delivery type product and the other being a Transdermal patch.


I was tasked with ensuring that the company could demonstrate compliance to the Part 4 requirements in the event of potential inspections or questions from the FDA.  We set up a project charter and obtained endorsement from key stakeholders within the company and proceeded to kick off building a compliance strategy.


The FDA provides a good overview of what is required and also allow companies to take different approaches based on their processes and systems in place already.  At my former company we already had both a relatively mature GMP quality system adherent to CFR 210/211 and a young Medical Devices QMS which was under my ownership.   Thus, after assessing the best strategy I recommended to take the approach below in order to demonstrate compliance: 














As the company already had an established QMS to the FDA’s 21 CFR 211, the approach we took was to ‘add on’ the unique device requirements.  Here most established Pharma companies will find that they may already be compliant to the many of device requirements, however, most likely not the ‘Design Controls’ requirements.


There were two key facets to implement in order to demonstrate compliance:


  1. Overall QMS set up and compliance of relevant stakeholders within the supply chain

  2. Design History File (DHF)


For point 1, an analysis of the product supply chain was made and identification as to whether the Part 4 requirements also impacted our suppliers.  In the cases where they did, we liaised with our suppliers to ensure they were compliant (obtaining written confirmation) and updated relevant quality agreements to reflect these requirements.  An overarching document was created to provide this holistic overview and easily demonstrate compliance in case of inspections.


For point 2, dependant on how you have developed your combination product, some companies may already have a lot of information required as per the FDA 820 requirements for design controls.  The key point here is to have a process in place for Design Controls and use that as a reference and perform a gap analysis of your current documentation vs the design control requirements.  Here you will find potential gaps are really product dependant and should be taken on a case by case basis, decisions made via a team consensus and a pragmatic approach if needing to rebuild or update documentation to have a compliant DHF.


For my former company the two products varied in terms of what documentation was available for the DHF, we used our internal Design Control processes and procedures as a reference point and built the DHF accordingly.  Building the DHF was headed by the device technical leads with a project team of relevant stakeholders supporting to provide the final living DHF.


Demonstrating compliance to the 21 CFR Part 4