Guest Column | September 27, 2018

What Risk Factors Does The FDA Consider In Scheduling Drug GMP Inspections?

By Barbara Unger, Unger Consulting Inc.

The global supply chain for drug products sold in the U.S. 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 sources materials from around the globe.  Considering re-packagers of raw materials, APIs, intermediates, and bulk drug product as well, tracing the history of each component back to its original manufacturer for a single drug product becomes a spaghetti map of confusion.

The globalization of the supply chain has expanded the scope of sites the FDA must routinely inspect from those in the U.S. to facilities worldwide.  For example, in FY2017 the FDA identified just over 5,000 human pharmaceutical manufacturing sites worldwide, about 60 percent of which are located outside the U.S.  Similar globalization exists in the food and device industries, and it has become a daunting task for the FDA to inspect all regulated sites with a specific frequency.  Partly in response to the heparin incident of 2008, the FDA made many changes and refinements to ensure that all manufacturers of products distributed in the U.S. meet GMP regulations. The July 2012 Food and Drug Administration Safety and Innovation Act  (FDASIA) amendment to the Food, Drug, and Cosmetic Act codifies many of these authorities, including the following:

  • Section 702 of FDASIA explicitly states that drug manufacturing sites located outside the U.S. must register with the FDA.Occasionally, the FDA issues for a firm’s failure to register.
  • Section 705 of FDASIA formally changed the inspection frequency for drug manufacturers from biennial (which the FDA never met for all sites under its ) to a schedule for drug inspections of all sites registered with the FDA.Although the FDA assigns inspections on must be inspected every four years according to item ‘Risk Factors The FDA implemented a risk-based approach to inspections beginning in FY2005 as a component of “Pharmaceutical Quality for the 21st Century – A Risk-Based Approach,” published in 2002.The Final Report from 2004 is . FDASIA formalizes this approach in legislation.
  • Section 708 of gives the FDA the to receive and protect information from foreign agencies and to exchange information with those agencies.Health authorities had been sharing information informally, but this formalized the authority.
  • Section 712 amended the FD&C Act to recognize foreign inspection outcomes.
  • Based on the authority in Section 708 and 712 above, the FDA entered into a with the EU authorities that are faced with similar global supply chains and resource limitations. permits each health authority to leverage limited inspectional resources and openly share information about manufacturing sites. This agreement includes 15 European health authorities with the recent addition of Portugal to the list of qualified member states.

The FDA continues to refine the GMP inspection process.  The FDA made changes to its 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 jacks-of-all-trades in the areas that the FDA regulates.  Developing inspector expertise in given areas is an aspirational goal and a work in progress, albeit a necessary one, for the FDA to be able to adequately assess many of the new technologies in human medicines and devices.

Expanded FDA Transparency

In another welcome refinement, the FDA now updates the Inspection Classification Database monthly.   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, pre-approval inspections, and inspections that await an enforcement action decision.  A recent statement by Commissioner Gottlieb states that the 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 Aug. 29, 2018, posted on the FDA website. This is worth monitoring in the future. 

As well as more frequent updates of the inspection database, the FDA is committed to communicating inspection classification information to the inspected facility within 90 days of the close of a surveillance inspection as part of the Generic Drug User Fee Amendments II (GDUFA II) legislation. The FDA is applying this across the board to all drug manufacturers and not limiting it to generic drug facilities. Note this does not necessarily include communication of outcomes of pre-approval inspections or for-cause inspections within this same time frame.  “Integration of FDA Facility Evaluation and Inspection program for Human Drugs:  A Concept of Operations” provides a full description of this effort.  The FDA appreciates the impact that an official action indicated (OAI) decision may have for a generic firm seeking approval of a product that is currently in shortage and is working to effectively communicate the information so firms can quickly make necessary remediations.

The FDA’s most recent efforts at transparency in the drug GMP inspection planning process is found in Manual of Policies and Procedures (MAPP) 5014.1, “Understanding CDER’s Risk-Based Site Selection Model,” used to prioritize sites for routine surveillance GMP inspections.  The MAPP is effective Sept. 26, 2018.  This MAPP addresses inspections of sites that manufacture commercial drug product, in process material, and active pharmaceutical ingredient used in the manufacture of human drugs. The FDA excludes the following types of sites from the scope of this MAPP:  compounding sites registered under section 503B of the FD&C Act, medical gas sites, excipients, and investigational drug manufacturing sites. The latter two types of sites can be inspected if necessary, generally for-cause. The FDA states that the model is under continuous improvement with “statistical analyses …used to assess the correlation between certain outcomes and current prospective risk factors.”  More on this later.

The risk factors identified on page 3 of the MAPP are those taken from FDASIA section 705, as identified above, supplemented with additional risk factors. These additional risk factors include:

  • Site type (manufacturer, packager, control lab)
  • Time since the last inspection
  • FDA compliance history
  • Inspection history from qualified foreign regulatory authority which currently includes a collection of countries within the EMA group
  • Patient exposure
  • Hazard signals, including but not limited to field alert reports (FARs), biological product deviation reports (BPDRs), MedWatch reports, recalls
  • Inherent product risk, including dosage form, route of administration, sterile non-sterile dosage forms, API load, biologic product, therapeutic class, narrow therapeutic index drugs, emergency use drugs

The MAPP states that the site selection model is used to generate a score for each site.  Some of the scores are based on empirical evidence; others are based on subject matter experts’ judgment. It is difficult to find fault with any of the risk factors identified and considered during development of the score development process.  It does, however, raise some important questions.

What factors are used to establish “FDA compliance history”?  I see this factor as a composite of hazard signals as defined above and previous inspection outcomes.  In the interest of transparency, it would be helpful to understand what is considered in this risk factor and whether it is based on empirical data or expert judgment.

More important, and challenging, is the weighting applied to each of the identified risk factors as a site score is assigned.  I worked for a firm that developed an algorithm to determine time intervals between corporate GMP audits based on a selection of risk factors similar to those in the FDA MAPP.  The challenge with such programs comes in assigning the number of risk categories so that weighting of each leads to a meaningful result. Using too many risk factors, each with an assigned weighting, can obscure important information and fails to distinguish among sites with important differences as an experienced auditor would judge them. The FDA states that it performs an annual review of the model.  I would like to see the data generated for this review.  Some of theis data is undoubtedly proprietary and not able to be publicly released, but other information should be releasable.  One relevant analysis might be the number, or percentage, of sites that were the subject of import alerts, warning letters, or recalls and whether those sites had higher risk scores than others that were not the subject of such enforcement actions in that year.  For FY2018, it would be interesting to know whether the manufacturer(s) of the valsartan API that was contaminated by a carcinogenic impurity had a risk score that suggested potential problems. Perhaps this is true because this API site was subject to inspections in both 2016, 2017, and 2018. This problem has already resulted in recalls by many valsartan drug product manufacturers.  I encourage the FDA to publish its annual review results, appropriately redacted, so the industry can have ongoing confidence in the process. 

The new MAPP is a welcome addition to the FDA’s ongoing efforts at transparency in the GMP inspection process.  The risk factors identified are not novel and largely reflect those identified in FDASIA, including reliance on qualified foreign inspections.  While this MAPP does not appear to include novel approaches or requirements, it is an important communication from the agency, allowing sites to better understand the inspection planning process.  The process itself is remarkably similar to processes that pharmaceutical firms use to determine inspection frequency for their suppliers, CMOs, and company-owned manufacturing sites, so it should come as no surprise to the regulated industry.

About The Author:

Barbara Unger formed Unger Consulting, Inc. in December 2014 to provide GMP auditing and regulatory intelligence services to the pharmaceutical industry, including auditing and remediation in GMP areas including data management and data integrity. Her auditing experience includes leadership of the Amgen corporate GMP audit group for APIs and quality systems. She also developed, implemented, and maintained the GMP regulatory intelligence program for eight years at Amgen. This included surveillance, analysis, and communication of GMP-related legislation, regulations, guidance, and industry compliance enforcement trends. Unger was the first chairperson of the Rx-360 Monitoring and Reporting work group (2009 to 2014) that summarized and published relevant GMP- and supply chain-related laws, regulations, and guidance. She also served as the chairperson of the Midwest Discussion Group GMP-Intelligence sub-group from 2010 to 2014. She is currently the co-lead of the Rx-360 Data Integrity Working Group.

Unger received a bachelor's degree in chemistry from the University of Illinois at Urbana-Champaign. You can contact her at