The global supply chain for drug products sold in the US has become increasingly more complicated in the past few decades, and as such this globalization has expanded the scope of sites FDA must routinely inspect, from those in the US to facilities worldwide.
If you missed the first part of this series, we reviewed FDASIA amendments to the FD&C Act (Sections 702, 705, 708, and 712), changes to field organization and ORA, and updates to the Inspection Classification Database. You can find that article here.
We continue the discussion here by covering aspects of GDUFA II and MAPP 5014.1, featuring timely communication, transparency, risk factors, and site scoring, closing with an overview of the application of these aspects.
(NOTE: No need to click back and forth between two blog posts—download the full report instead.)
Communicating Inspection Classification Information
As well as more frequent updates of the inspection database, 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 GDUFA II legislation.
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 timeframe. “Integration of FDA Facility Evaluation and Inspection program for Human Drugs: A Concept of Operations” provides a full description of this effort.
“FDA is committed to communicating inspection classification information to the inspected facility within 90 days.”
FDA appreciates the impact that an 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 that firms may quickly make necessary remediations.
MAPP 5014.1 and Transparency
FDA’s most recent efforts at transparency in the drug GMP inspection planning process is found in MAPP 5014.1, “Understanding CDER’s Risk-Based Site Selection Model” used to prioritize sites for routine surveillance GMP inspections.
The MAPP is effective as of September 26, 2018. This MAPP addresses inspections of sites that manufacture:
- Commercial drug product
- In-process material
- Active pharmaceutical ingredient used in the manufacture of human drugs
FDA excludes the following type of sites from the scope of this MAPP:
- Compounding sites registered under 503B of the FD&C Act
- Medical gas sites
- Investigational drug manufacturing sites
The latter two types of sites can be inspected if necessary, generally for-cause.
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 in the article.
The risk factors identified on page three of the MAPP are those taken from FDASIA section 705 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 FARs, BPDR, MedWatch Reports, recalls
- Inherent product risk including dosage form, route of administration, sterile vs. non-sterile dosage forms, API load, biologic product, therapeutic class, narrow therapeutic index drugs, and 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 expert’s 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.
“Some of the scores are based on empirical evidence, others are based on subject matter expert’s judgment.”
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.
“Using too many risk factors, each with an assigned weighting, can obscure important information.”
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.
FDA states that they perform an annual review of the model. I would like to see the data generated for this review. Some of these data are 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 who 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 FDA to publish their annual review results, appropriately redacted, so that the industry could have ongoing confidence in the process.
The new MAPP is a welcome addition to 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 legislation from 2012 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 so that sites may 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.
[Download this entire report here.]
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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. | www.ungerconsulting.net | 805.217.9360