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Cynthia A. Challener is a contributing editor to Pharmaceutical Technology.
New legislation and changes in policy at FDA are leading to better control of the API supply chain.
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In September 2011, the US Government Accounting Office (GAO) published a report on the challenges that FDA faced in assuring the safety of the API supply chain given that reliance on APIs produced by foreign manufacturers has risen dramatically and the complexity of the global pharmaceutical supply chain has increased significantly over the past two decades (1). The report found that while FDA had increased inspections of foreign API manufacturers (up 27% from 2007 to 2009, for example), its rate of inspection for foreign establishments was still far below that for domestic manufacturers. In addition, most foreign inspections were scheduled far in advance, conducted under controlled circumstances, and typically occurred during much shorter time frames. GAO also determined that FDA still lacked important information about foreign API manufacturers (1).
On a positive note, GAO recognized that FDA had begun to implement initiatives designed to improve its oversight of the drug supply chain, including increased training by overseas offices, the development of programs for control of APIs and other drug products entering the United States, and a push for risk-based inspections rather than a set schedule (1). The GAO concluded, however, that FDA needed to implement changes more rapidly to better assure the safety of drugs on the US market (1).
Since that report, new legislation has affected FDA ‘s ability to schedule and conduct inspections of API manufacturers. As a result, inspections of foreign manufacturers have increased dramatically--along with warning letters--while inspections of domestic manufacturers have decreased.
Impact of GDUFA
The most important piece of legislation affecting FDA ‘s ability to improve the safety of the pharmaceutical supply chain is the Food and Drug Administration Safety and Innovation Act (FDASIA), signed into law on July 9, 2012. The Generic Drug User Fee Amendments (GDUFA), included as part of FDASIA, instituted a Generic Drug User Fee Program that was agreed to by FDA and the generic-drug industry, specifically the Bulk Pharmaceutical Task Force (BPTF) of the Society of Chemical Manufacturers and Affiliates (SOCMA), the European Fine Chemicals Group (EFCG), and the Generic Pharmaceutical Association (GPhA).
The user fees are intended to provide additional funding for FDA ‘s drug approval and inspection efforts with the goal of increasing the safety of generic drugs and the ingredients used to produce them, increase the speed of the drug approval process, and the transparency of the industry. One of the main goals of GDUFA is to ensure that foreign facilities are inspected at a rate equal to that of domestic facilities. The fees raised through GDUFA have enabled FDA to hire approximately 1000 additional employees, making it possible for the agency to complete more inspections and speed up the approval process for abbreviated new drug applications (ANDAs) and the review of drug master files (DMFs).
Further developments with FDASIA
Several other aspects of the FDASIA legislation have also impacted the API and formulated-drug supply chain. For instance, FDASIA requires FDA to identify facilities involved in the manufacture of generic drugs and associated APIs. “Prior to FDASIA, FDA didn ‘t know how many facilities were producing formulated drugs or APIs in the US, let alone how many companies around the world were manufacturing APIs and formulated drugs and exporting them to the US,” says John DiLoreto, executive director of BPTF. Before the self-registration process began, the industry estimated that there were 1700-2000 manufacturing sites around the world. After the registration process was complete, that number was reduced to approximately 1300. DiLoreto believes that some consolidation of manufacturing plants occurred as companies looked to reduce the GDUFA fees they would have to pay by consolidating operations.
In the most recent report on foreign and domestic drug establishments issued by FDA (2), the agency identified a total of 12,949 registered drug establishments in 2014, including 9330 domestic and 3619 foreign (slightly up from 12,613 in 2013. Of those 12,949 facilities, 4383 were registered as finished drug product (FDP) establishments, and 1495 were registered as API establishments. (If a site produces both finished drug products and APIs, it is placed in the FDP category.) The remaining 7071 establishments fell into the “other” category, which includes facilities that produce, compound, or process medical gases, medicated feed, and some biologic drugs.
FDASIA also grants FDA the authority to confiscate and destroy unsafe APIs and drug products being imported into the US. With its increased ability to track the manufacturing activities and inspection histories of API and drug manufacturing sites, the agency can determine if APIs or finished drug products were produced at a facility that has not been FDA-inspected or is not in compliance. The agency has also published guidance on what conduct it considers as delaying, denying, limiting, or refusing inspection, actions that can result in determination of a drug to be adulterated. In addition, under GDUFA, all drugs produced in an unregistered facility or in a facility for which the GDUFA fees have not paid are considered “misbranded.”
“Together, these new capabilities of the agency make it possible for potentially unsafe APIs and drug products to be removed from the marketplace completely,” DiLoreto says.
FDA is also using the information on establishments to prioritize them according to the level of risk each represents. Rather than inspect facilities on a set schedule as was the case in the past-typically once every two and one-half years on average for domestic facilities and once every 10 years or more for foreign manufacturing sites-the agency now determines which facilities to inspect based on the overall level of risk they pose, which is determined using a model that takes into account inherent risk, outbreaks, recalls, adverse events, and compliance history (3). This move has led to a dramatic increase in foreign inspections and a concomitant decline in domestic inspections.
In fiscal year (FY) 2014, the total number of foreign and domestic high-risk human drug inspections by FDA was 918, which exceeded the agency ‘s target of 750 (3). In FY 2013, 443 domestic and 365 foreign high-risk establishments were inspected (total of 808); 43 GMP-based warning letters were issued as a result of those inspections (4). Overall in FY 2013, FDA conducted 967 domestic and 604 foreign GMP inspections (3). In FY 2014, those numbers were 780 and 757. FDA estimates that in both FY 2015 and 2016, there will be 591 domestic and 843 foreign inspections.
Both the agency and the industry are adjusting to the risk-based inspection approach, according to DiLoreto. “When FDA first indicated that it would be decreasing domestic inspections so significantly, BPTF was initially concerned that domestic facilities would not be receiving inspections often enough, particularly those exporting to Europe, because the European Medicines Agency (EMA) requires pharmaceutical manufacturers importing products into the European Union to have had an inspection within the previous three years,” notes DiLoreto. The agency has addressed those concerns and established an agreement with EMA. “One of the primary goals of GDUFA was to achieve inspection parity between foreign and domestic facilities, but the change to a risk-based program allows FDA to better utilize resources,” he adds.
An additional step in the right direction was made in December 2014 when FDA Commissioner Margaret Hamburg signed an agreement with Chinese officials to collaborate on inspections in China that builds on an initial agreement signed in 2007 (5). China also finally agreed to provide additional visas for more FDA inspectors, which will allow the agency to boost its number of employees from 13 to 33.
FDA is working with EMA on joint inspections and trying to establish mechanisms for sharing of inspection data, according to DiLoreto. BPTF would like to eventually see EMA and FDA inspections results considered to be equivalent. There are, however, concerns on the part of some manufacturers about how confidential business information can be adequately protected under such a scenario.
Despite the numerous advances that FDA has made in addressing concerns about APIs and formulated drugs manufactured overseas, there are still many challenges facing the agency. Some foreign governments still do not welcome the agency, and inspections of foreign facilities still suffer from many restrictions. DiLoreto does believe, however, that the situation is improving in many countries, as indicated by the recent agreement in China.
There is also the issue of the dramatic increase in warning letters issued to foreign manufacturers that has occurred along with the rise in foreign inspections. DiLoreto expects these problems to be resolved once these manufacturers have been educated about GMP requirements and become familiar with the expectations of FDA. “It is not surprising that issues are being found at facilities that are being inspected for the first time. These facilities will implement the required improvements, and the number of citations will decline as more effective quality programs are put in place,” he observes.
It is also important to remember, according to DiLoreto, that many of the FDA inspectors now on the job are still quite new. “It takes at least two years for an FDA inspector to be fully trained, because it take time for him/her to gain the practical experience needed for the job,” he says. “A large percentage of current FDA inspectors don ‘t have that two years of experience yet, and while new inspectors are on the learning curve, issues can arise,” DiLoreto continues. These difficulties, however, should also be resolved in the next few years, he notes.
1. GAO, GAO Report GAO-11-936T, “Drug Safety: FDA Faces Challenges Overseeing the Foreign Drug Manufacturing Supply Chain,” Sept. 14, 2011 (Washington, DC).
2. FDA, 2015 Annual Report on Inspections of Establishments in FY 2014, January 2015 (Rockville, MD).
3. Department of Health and Human Services, Fiscal Year 2015 Food and Drug Administration Justification of Estimates for Appropriations Committees, February 2014 (Washington, DC).
4. Department of Health and Human Services, Fiscal Year 2016 Food and Drug Administration Justification of Estimates for Appropriations Committees, Jan. 30, 2015 (Washington, DC).
5. M. Mansour et al., “United States: FDA And China Agree To Collaborate On Inspections,” Jones Day, Dec. 30, 2014.
Article DetailsPharmaceutical Technology
Vol. 39, Issue 4
When referring to this article, please cite as C. Challener, “FDA Steps Up Foreign Inspections,” Pharmaceutical Technology39(4) 2015.