Progress Report on Risk-Based Inspections

Is the US Food and Drug and Administration achieving parity in inspections of foreign and domestic manufacturers? A recent report by the US Department of Health and Human Services’ Office of the Inspector General (IOG) examined the FDA’s progress and the role of risk-based inspection models.

The IOG report examined the data for inspections and registered manufacturers of generic drugs to determine the number and types of inspections to see whether the FDA is progressing toward goals of achieving parity in domestic and foreign inspections and improving the efficiency for inspections. So what is the verdict? DCAT Value Chain Insights (VCI) examines the findings.

Key findings and background
The OIG study was prompted by a Congressional request expressing concerns about the safety and quality of generic drugs produced by foreign manufacturers and requesting that the OIG evaluate whether the FDA is achieving parity in inspections of foreign and domestic manufacturers. For the study, the OIG analyzed FDA data for inspections and registered manufacturers of generic drugs for 2011-2013 to determine the number and types of inspections. It also analyzed FDA data to determine whether manufacturers listed on approved applications had registered with the FDA as required. The IOG also analyzed FDA records and interviewed FDA staff to determine the extent to which it is progressing toward achieving parity in domestic and foreign inspections and more efficient processes for inspections.

The study found that FDA increased its preapproval inspections of manufacturers of generic drugs by 60% between 2011 and 2013. However, it did not conduct all of the preapproval inspections requested by its own generic drug application reviewers during this time. Preapproval inspections occur prior to the FDA approving an abbreviated new drug application (ANDA) in the case of generic drugs and a new drug application in the case of a new molecular entity. The FDA’s Center for Drug Evaluation and Research (CDER) established the criteria for determining whether the manufacturers listed on ANDAs need preapproval inspections. If FDA has never inspected the facility before, the agency will conduct a preapproval inspection. In most cases, FDA will also conduct a surveillance inspection by which the FDA inspects manufacturers to monitor compliance with cGMPs, laws, and regulations. These inspections cover their facilities and procedures for producing drugs. Once a year, FDA uses a risk-based model to create a list of prioritized manufacturers, both those of generic drugs and those of brand-name drugs, for surveillance inspections. This list includes production, testing, and packaging facilities both for active pharmaceutical ingredients and finished pharmaceuticals. The FDA gives the highest priority to manufacturers without prior inspections. FDA may also conduct a surveillance inspection of a manufacturer on a for-cause basis to investigate a specific problem.

In 2013, the FDA conducted surveillance inspections of all generic manufacturers that it had identified as high risk. FDA also reported progress toward achieving parity in inspections of foreign and domestic manufacturers of generic drugs and ensuring compliance with generic manufacturer registration. The study found that FDA had created some policies and procedures to request manufacturer records in lieu or in advance of an inspection, but has not yet used these procedures to request records.

The OIG study recommended that the FDA should conduct outstanding preapproval inspections of manufacturer s of generic drugs, where appropriate, which could lead to more timely approval of these drugs. It also highlighted the importance of the requirements for manufacturers of generic drugs to register with FDA to provide a complete and up-to-date registration database that would facilitate the implementation of the agency’s plans for conducting inspections. The study also said that the FDA should use its authority to request records in lieu or in advance of an inspection. Such requests could increase FDA’s capacity for inspections, and review of the records could be completed in advance, which could free up staff time during the onsite portion of the inspection. IOG said that the FDA concurred with all three recommendations.

Tracking progress
The Food and Drug Safety and Innovation Act of 2012 (FDASIA) increased the FDA’s resources for generic drug oversight and strengthened the agency’s authority over manufacturers of generic drugs. FDASIA authorized the FDA to request records from manufacturers in advance of or in lieu of inspections, such as those related to drug testing, drug manufacturing, facility maintenance, and administration. The Generic Drug User Fee Act (GDUFA) requires manufacturers of generic drugs to identify themselves to the FDA. This requirement includes manufacturers of final-dosage forms and manufacturers of active pharmaceutical ingredients. The FDA created a database that has been availa ble for registration since the start of fiscal year (FY) 2013. The FDA maintained no such list ofmanufacturers of generic drugs prior to FY 2013. Since FY 2013, the FDA has had the authority to collect user fees from manufacturers of generic drugs. These fees are intended to speed ANDA review times and increase FDA’s resources for inspecting facilities where gene ric drugs are manufactured. The FDA committed to achieving parity in surveillance inspections of foreign and domestic drug manufacturers by FY 2017. Section 705 of FDASIA requires a risk-based approach for inspecting drug manufacturers, whether domestic or foreign.

The study found that the FDA increased its preapproval inspections of manufacturers of generic drugs by 60% from 2011 to 2013. The FDA increased preapproval inspections every year from 2011 through 2013. The GDUFA was implemented in FY 2013, increasing FDA’s resources for conducting inspections; the agency collected nearly $300 million in user fees in FY 2013. The FDA used these additional resources for, among other thing, hiring and training staff to conduct additional inspections of manufacturers of generic drugs. For this period, FDA conducted the majority of preapproval inspections in conjunction with surveillance inspections. In 2013, it conducted 243 combined preapproval and survelliance inspections, up from 211 in 2012 and 149 in 2010.

Furthermore, FDA conducted more preapproval inspections of foreign manufacturers from 2011 to 2013 than in previous years. The FDA performed 101 ANDA preapproval inspections of foreign manufacturers (compared to 68 of domestic manufacturers) in 2011 and 142 such inspections of foreign manufacturers in 2013 (compared to 129 inspections of domestic manufacturers). However, the proportion of ANDA preapproval inspections conducted at foreign manufacturers as a share of all ANDA preapproval inspections decreased from 60% in 2011 to about 50% in 2012 and 2013.

In the first year of risk-based inspections–FY 2013–FDA prioritized at least 283 manufacturers of generic drugs for routine surveillance inspections and conducted inspections at all of them. The FDA’s current risk-based model incorporates the outcomes of previous surveillance inspections, the type of establishment, and the type of product manufactured, among other factors. Of the 283 generic manufacturers that the FDA prioritized for inspection in FY 2013, 185 (65%) were foreign.

On the basis of these high-priority inspections, the FDA required corrective action for 11 generic manufacturers, two of which are foreign. FDA took enforcement action against nine of the 11 manufacturers with classifications of Official Action Indicated. These actions included four Warning Letters, one of which applied to two manufacturer, and four regulatory meetings. The two manufacturers against which the FDA did not take enforcement action are both located in the United States.

In FY 2013, the FDA conducted additional surveillance inspections beyond those of prioritized manufacturers of generic drugs. In FY 2013, FDA conducted a total of 589 surveillance inspections of generic drug manufacturers, 337 (57%) of which were inspections of foreign manufacturers. Most of these inspections were routine surveillance inspections, which are periodic inspections to ensure manufacturers’ compliance with cGMPs.

These 589 inspections also included 20 surveillance inspections that FDA performed as followups (i.e., following up on an enforcement action or a previous inspection with a final classification of Official Action Indicated) and six inspections performed as a result of consumer complaints. The FDA required corrective action for 26 surveillance inspections conducted in FY 2013. The FDA took action against 20 of the 26 manufacturers with inspection results of Official Action Indicated. Of these 20, 7 are domestic and 13 are foreign. The actions that FDA took included 13 warning letters, 7 import alerts, 4 regulatory meetings, and 1 untitled letter. Of the 20 manufacturers against which the FDA took action, there were 4 against which it took multiple enforcement actions. All four are located in India: (1) Sentiss Pharma, the FDA issued an import alert and a warning letter; (2) RPG Life Sciences Limited FDA issued a warning letter and an import alert that applied to two separate manufacturers owned by this company; (3) Hospira Healthcare India, the FDA issued one import alert and a warning letter; and (4) Wockhardt Limited, the FDA issued two warning letters to two different manufacturers owned by this company, as well as two import alerts. All were related to cGMP violations for finished pharmaceuticals.

In seeking to achieve parity of inspections between foreign and domestic manufacturers, the FDA defines “parity” as equal frequency of foreign and domestic inspections plus or minus 20%with both kinds of inspections conducted with “comparable depth and rigor.” In its FY 2013 GDUFA performance report, the FDA reported achieving parity in inspection frequency on the basis of this definition, an assertion supported by the IOG report. The report showed that of 589 surveillance inspections that FDA conducted in FY 2013, 337 (57%) were of foreign manufacturers. In FY 2013, 1,514 manufacturers of generic drugs registered with the FDA, 1,111 (73% of which are foreign. Of these, foreign manufacturers, 624 are located in Asia and 396 are located in Europe. Although FDA documented a similar frequency of domestic and foreign inspections in FY 2013, its FY 2013 GDUFA performance report did not fully address the commitment to achieve parity based on risk. To reach that goal, FDA is using a risk-based model to select manufacturers for surveillance inspections without distinguishing between whether the manufacturers are foreign or domestic. The FDA planned to report, in FY 2014 and future years, on steps it was taking to schedule and conduct inspections of both domestic and foreign manufacturers according to identical risk factors. The FDA did not report on progress for the second metric of parity, i.e., conducting inspections with comparable depth and rigor. FDA planned to present information addressing this metric in its FY 2014 performance report on GDUFA.

FDA has encouraged generic manufacturers to register through industry outreach, by releasing draft guidance on registration, and by announcing registration reporting periods in the Federal Register. For known generic manufacturers that failed to register in FY 2013, FDA sent letters as reminders to register in the FY 2014 registration period. The FDA has issued two warning letters to manufacturers for failing to register in FY 2013. According to FDA, warning letters were sent only to manufacturers that are in the GDUFA Facility Arrears List for failure to pay required annual fees. As of December 31, 2013, not all known generic drug manufacturers had registered accurately with FDA, despite the agency’s efforts. Of the 432 generic drug manufacturers listed on ANDAs approved in 2013, 45 (10%) did not match entries in FDA’s registry of generic manufacturers as of that date. Furthermore, 62% (28 of 45) of the manufacturers that IOG was unable to locate in the registry are foreign.


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