Part 1: Criteria For Drug Inspections

The global supply chain for drug products sold in the US has become increasingly more complicated in the past decades.

What was once a mostly domestic industry has become global including:

  • The sourcing of raw materials
  • APIs including their starting materials and intermediates
  • Drug product manufacture, packaging, labeling, and distribution

Moreover, each of these specific areas source materials from around the globe.

Consider also re-packagers of raw materials, APIs, intermediates and bulk drug product and this becomes a spaghetti map of confusion to trace the history of each component back to its original manufacturer for a single drug product.

The globalization of the supply chain has expanded the scope of sites FDA must routinely inspect, from those in the US to facilities worldwide.

For example, in FY2017 FDA identified just over 5,000 human pharmaceutical manufacturing sites worldwide; about 60% are located outside the US.  Similar globalization exists in the food industry and device industry. It becomes a daunting task for FDA to inspect all regulated sites with a specific frequency.

(NOTE: This is just part one of two. Download a PDF of this entire special report here.)

LI Special Report-600

Food and Drug Administration Safety and Innovation Act

Partly in response to the heparin incident of 2008, FDA made many changes and refinements to ensure that all manufacturers of products distributed in the US meet GMP regulations.

The July 2012 “Food and Drug Administration Safety, and Innovation Act  (FDASIA) amendment to the FD&C Act codifies many of these authorities and includes the following:

Section 702

Section 702 of FDASIA explicitly states that drug manufacturing sites located outside the US must register with FDA.  Occasionally, FDA issues warning letters for a firm’s failure to register.

Section 705

Section 705 of FDASIA amendments to the FD&C Act formally changed the inspection frequency for drug manufacturers from biennial (which FDA never met for all sites under their oversight) to a risk-based schedule for drug inspections of all sites registered with FDA.  

“Although FDA assigns inspections on a risk-based frequency, they must be inspected every four years.”

Although FDA assigns inspections on a risk-based frequency, they must be inspected every four years according to item ‘D’ under ‘Risk Factors’ in FDASIA legislation.

FDA implemented a risk-based approach to inspections beginning in FY2005 as a component of the “Pharmaceutical Quality for the 21st Century – A Risk-Based Approach” published in 2002. You can review the Final Report from 2004 here. FDASIA formalizes this approach in legislation.


Section 708

Section 708 of FDASIA gives FDA the authority to receive and protect information from foreign agencies, and also to exchange information with those agencies.  Health authorities had been sharing information informally, but this formalized the authority.

Section 712

Section 712 amended the FD&C Act to recognize foreign inspection outcomes.

“The new organization also expects inspectors to develop in-depth knowledge in specific area(s) rather than being expected to be a jack-of-all-trades in the areas that FDA regulates.”

Based on the authority in Section 708 and 712 above, FDA entered into a Mutual Recognition Agreement with the EU authorities who are faced with similar global supply chains and resource limitations.  Reliance on each other’s inspections permits each health authority to leverage limited inspectional resources and openly share information about manufacturing sites.

This agreement includes fifteen European health authorities with the recent addition of Portugal to the list of qualified member states.

GMP Inspection Process

FDA continues to refine the GMP inspection process. FDA made changes to the field organization and ORA in 2017 whereby a structure based on product type replaces the previous geographic structure.

The new organization also expects inspectors to develop in-depth knowledge in specific area(s) rather than being expected to be a jack-of-all-trades in the areas that FDA regulates.  

Developing inspector expertise in given areas is an aspirational goal and a work in progress, albeit a necessary one, for FDA to be able to adequately assess many of the new technologies in human medicines and devices.

Inspection Classification Database

In another welcome refinement, FDA now updates the Inspection Classification Database monthly.

Inspection Classification Database

The website, however, explicitly states that it “…does not represent a comprehensive listing of all conducted inspections.”

It also does not include inspections conducted by the States, PAI inspection and inspections that await an enforcement action decision.

A recent statement by Commissioner Gottlieb states that FDA updates the database to “support inclusion of facility status based on classification of inspection reports from recognized foreign regulatory authorities.”  I could not find any foreign inspection outcomes posted in the tabulation ending August 29, 2018, posted on the FDA website and is worth monitoring in the future.

In the next part of this series, we will look at MAPP 5014.1, reviewing transparency, risk factors, site scoring, and the application of these approaches.  You can find it here.

[NOTE: No need to click back and forth between two blog posts—download the full report instead.]

LI Special Report-600


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About the Author

Barbara W. Unger is Govzilla’s Quality Expert and Editor-in-Chief of GMP Regulatory Intelligence. She formed Unger Consulting, Inc. in December 2014 to provide GMP Quality consulting services to the pharmaceutical and biopharmaceutical industry. At Amgen, she led the segment of the Corporate GMP Audit group at Amgen focused on API manufacturers, Quality Systems and Computers. She developed, implemented and maintained the GMP Regulatory Intelligence program for 8 years at Amgen Inc. This included surveillance, analysis and communication of GMP related legislation, regulations, guidance and industry compliance enforcement trends. This was an essential service and tool within the Corporate Audit function.

Unger Consulting Inc. | | 805.217.9360

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