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Volume 32, Issue 2
Policies emphasize the importance of ensuring data integrity in the United States and abroad.
With drug shortages on the rise-driving up prices of scarce medicines in the process-and data integrity transgressions increasingly visible in inspection reports, FDA officials are highlighting the importance of strategies for ensuring a reliable supply of critical pharmaceuticals that meet regulatory standards. The agency is issuing new guidance, cracking down on violative products, and emphasizing the need for greater vigilance and innovation to advance quality drug manufacturing.
The recall of hundreds of batches of valsartan blood pressure medicines made with APIs from China containing a suspected carcinogen set off alarms in 2018 about tainted drugs and inadequate quality controls. As the crisis expanded, leading generics makers recalled multiple products, creating shortages and evidently leading to price increases by producers of untainted valsartan-containing therapies able to document quality.
Such failings in production have prompted FDA Commissioner Scott Gottlieb and other agency officials to highlight the importance of industry efforts to maintain standards. FDA aims to foster “a culture of compliance” where companies follow best practices and requirements of the law not just to avoid liability, but to support a “shared commitment to serve as good stewards of the public health,” Gottlieb commented at the December 2018 Enforcement, Litigation and Compliance conference sponsored by the Food and Drug Law Institute (FDLI) (1).
The commissioner highlighted the importance of high-quality data in submissions and manufacturing systems, noting that inaccurate information on manufacturing often masks production problems and failures. At the conference, Gottlieb announced an updated FDA guidance on data integrity and good manufacturing practices (GMPs) to prevent lapses in this area and help firms create “a quality culture” where employees understand the importance of ensuring that accurate information is developed and submitted to the agency (2). While inaccurate data and information may arise from deceptive practices, Gottlieb noted that more often such errors reflect inadequate processes and systems. The new advisory updates a draft from 2016 and provides advice to help manufacturers identify data integrity lapses, implement best practices, and ensure commitment to standards. Data integrity failures are cited in three-fourths of FDA warning letters, a trend that agency officials hope to address in the latest guidance.
The emphasis on ensuring quality data has become a global issue. The Pharmaceutical Inspection Cooperation Scheme (PIC/S) released a draft guidance outlining recommended GMP inspection practices, with an emphasis on defining and detecting data integrity vulnerabilities and strategies to harmonize inspection practices (3).
Donald Ashley, director of the Office of Compliance in FDA’s Center for Drug Evaluation and Research (CDER), reported at the FDLI conference a rise in warning letters involving cGMP issues. One factor, Ashley explained, is linking that trend to an increase in inspections of never-visited facilities, particularly firms producing over-the-counter products. FDA has updated its site-selection model to focus inspections on higher-risk facilities, part of the agency’s Program Alignment plan that aims to bring greater expertise and consistency to field operations. Warning letters continued to increase in 2018 for firms in India, China, and other nations.
FDA also seeks to improve production methods and standards for sterile injectable products by launching the first New Inspection Protocol Project (NIPP) in this area. A pilot program aims to collect data in a structured manner to improve the consistency and efficiency of inspections for these products, with an eye to better detecting and preventing lapses in an area where quality manufacturing issues have led to shortages and closures (4).
In addition to more targeted and efficient inspections, FDA aims to reduce duplicative site visits that waste resources and impose a burden on industry by fully implementing a Mutual Reliance Agreement (MRA) with the European Union. This program allows FDA to rely on information from drug inspections conducted within each other’s borders and thus avoid visiting operations that show strong compliance histories. FDA has completed assessments that enable it to recognize the inspection capabilities of 20 EU member states and aims to complete the task by July 2019. The parties also plan to extend the agreement to veterinary medicines this year and to certain vaccines by 2022.
International collaboration also has been extended to GMP inspections of plants producing APIs to similarly avoid duplicative inspections. The program was useful in allowing information sharing regarding planned inspections of valsartan API facilities in order to target oversight to uninspected plants.
Added resources, moreover, have enhanced FDA’s ability to expand its capacity to block the import of violative medical products. The agency has increased the number of inspectors at international mail facilities and plans to expand the number of packages it can review to better detect dangerous or counterfeit drugs.
While FDA wants to assist industry in avoiding regulatory violations, Gottlieb emphasized that the agency will take action when it sees “willful disregard for the rights or even the safety of people” affected by substandard or adulterated products (1). He expressed optimism that these initiatives in FDA’s inspection program will better target oversight to products and processes that pose a greater risk to public health.
1. FDA, “Remarks by Dr. Gottlieb to the FDLI Enforcement, Litigation, and Compliance Conference,” FDA.gov, Dec. 12, 2018.
2. FDA, Data Integrity and Compliance with Drug CGMP, Questions and Answers, Guidance for Industry (CDER, December 2018).
3. PIC/S, Guidance on Classification of GMP Deficiencies (PIC/S, January 2019).
4. FDA, “Statement from FDA Commissioner Scott Gottlieb, M.D., on New Steps to Strengthen and Modernize Agency’s Oversight and Reporting of Inspections for Sterile Injectable Drugs,” Nov. 9, 2018.
Vol. 32, No. 2
When referring to this article, please cite it as J. Wechsler, “FDA Promotes Quality Standards to Reduce Shortages," BioPharm International 32 (2) 2019.