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Drug manufacturers face added pressure and incentives for meeting new FDA compliance policies and priorities.
The globalization of drug production has prompted FDA to overhaul its strategies for ensuring the safety and quality of drugs and biologics coming into the United States, as well as those produced at home. Recent legislation enhancing FDA inspection authority supports stiffer enforcement of manufacturing standards, along with added incentives for establishing high quality operations. Increased FDA reliance on information submitted by manufacturers about their operations and products also means more focus on data integrity and voluntary compliance with the rules.
Former FDA commissioner Margaret Hamburg emphasized how the rise in international biopharmaceutical production has affected the agency in a series of speeches marking her recent exit from FDA. She highlighted the importance of collaboration with the European Medicines Agency (EMA), particularly in sharing reports from each other’s inspection programs, at a meeting in London to mark the 20th anniversary of EMA. And in a farewell speech at the National Press Club in Washington, DC, Hamburg reiterated how globalization has required FDA to change how it does business, most visibly by establishing outposts around the world to support overseas field operations.
At the same time, Howard Sklamberg, deputy commissioner for global regulatory operations and policy, traveled to India with Cynthia Schnedar, director of the Center for Drug Evaluation and Research’s (CDER) Office of Compliance, to discuss the importance of tackling drug safety and regulatory challenges with local authorities and drug manufacturers. Their visit reflected efforts by FDA to ensure the quality of the vast array of drugs imported to the United States from that country; CDER has sponsored workshops to help Indian drug manufacturers understand and meet US standards and avoid curbs on imports.
New inspection approaches
During the trip, Sklamberg and Schnedar also explained that Indian manufacturers may qualify for less frequent inspections and reduced oversight by achieving high quality ratings from plant inspections and quality metrics under development (1). FDA sought to offset complaints that it’s singling out India for stricter enforcement by emphasizing increased cooperation, as seen in joint inspections with local officials.
FDA’s broader aim, Sklamberg and Schnedar noted, is to standardize inspection methods in all regions, including the US, so that “quality will be understood and aspired to by manufacturers--no matter where they are in the world.” A new inspection questionnaire is being developed to harvest uniform data in all regions to support accurate measures of quality.
These efforts fit the FDA Program Alignment (PA) initiative, which is restructuring FDA’s Office of Regulatory Affairs (ORA) to shift from a geography-based operation to one with specialized cadres of inspectors for pharmaceuticals and for other regulated products, Sklamberg explained at the IBC Pharmaceutical Compliance Congress in March 2015. ORA’s pharmaceutical inspectorate will work closely with CDER’s Office of Pharmaceutical Quality as part of a team approach for reviewing applications and maintaining post-market surveillance of manufacturers, incorporating a risk-informed process for setting inspection priorities based on improved data on firm operations and compliance histories.
An FDA pilot is testing the PA program for domestic and foreign inspections of human and animal drugs (overseen by FDA’s Center for Veterinary Medicine) to see if it reduces duplicative work and minimizes disagreement between FDA centers and the field over inspection findings. The team approach will involve pre-inspection briefings, real-time communication of inspection findings to ORA and CDER, joint development of recommendations, and enhanced communication of inspection findings.
The aim is to transition by late 2015 to multi-year, risk-based inspection planning based on staff resources, performance-based metrics, and compliance outcomes. FDA centers will establish enforcement strategies and compliance policies, and they will collaborate with ORA on modernizing enforcement standards and determining the underlying reasons for quality failures found during inspections.
In addition to citing problems, inspections will document where a firm’s quality management system exceeds requirements and thus open the door to reduced oversight. The payoff for quality achievement could be less frequent inspection of that facility and regulatory flexibility related to post-approval manufacturing changes where risk of manufacturing problems in a facility is minimal. FDA officials also propose to reduce oversight of high quality operations on occasion by requesting documents and posing questions online, instead of actually visiting the site.
It is not surprising, however, if drug manufacturers are skeptical about real reductions in FDA oversight. Agency officials have been talking for years about relief in submitting post-approval changes for low-risk activities, but so far have failed to make significant modifications in documentation and preapproval requirements for most changes in production systems, ingredients, and sites.
While offering regulatory “carrots” to compliant manufacturers, FDA officials also predict strong action against those that violate the rules. Federal enforcement agents are targeting drug companies that submit inaccurate data to the agency--an issue that has led to serious repercussions for a number of Indian generic-drug makers. Federal prosecutors are looking hard at cases involving manufacturers “doctoring their data” and anticipate more charges related to fraudulent reports, particularly from small companies.
These efforts are supported by the FDA Safety and Innovation Act (FDASIA) of 2012, which provides added resources through generic-drug user fees for the agency to expand inspections of overseas producers. The legislation also proposes stiffer penalties on firms that refuse access to their manufacturing facilities or fail to provide full and complete documentation on their products.
FDA issued a final guidance in 2014 that spells out how it will interpret industry actions it regards as “delaying, denying, limiting, or refusing” a drug inspection. Such behavior could be grounds for declaring products from that facility as “adulterated” (2).
In response, a legal group is questioning FDA’s interpretation and implementation of the inspection policy, stating that it goes beyond the agency’s statutory authority. A legal backgrounder by attorneys with Hyman, Phelps & McNamara for the Washington Legal Foundation (WLF) claims that FDA’s approach could have “draconian effects” on companies that, for any reason, are not aware of specific FDA inspection requirements and fail, even inadvertently, to meet its demands (3).
A key point of dispute is whether FDA inspectors have the right to take photographs as part of an inspection, a practice that industry lawyers have long challenged. Because FDA is asserting authority not specifically provided by statute, the attorneys advise manufacturers to challenge demands from agency inspectors to review records kept in another facility, to photograph any and all operations, or to question any company employee, especially those not trained to deal with regulatory authorities. A manufacturer could have legitimate reasons for requesting a different date for a plant inspection or to direct questions to certain specialists, without fear that its operations will be shut down and products taken off the market, the lawyers advise.
Much of the debate hinges on how FDA interprets what is “reasonable” and “timely” for inspectors to request, or for a manufacturer to challenge. The need to clarify FDA’s expanded inspection authority will be debated further as Congress continues to weigh a broad range of proposals for refining FDA programs and policies in upcoming legislation.
1. H. Sklamberg and C. Schnedar, “From New Jersey to New Delhi, a Global Focus on Quality,” FDAVoice, FDA.gov, March 24, 2015.
2. FDA, Guidance for Industry, Circumstances that Constitute Delaying, Denying, Limiting, or Refusing a Drug Inspection (CDER, October 2014).
3. FDA Law Blog,“HP&M-Authored WLF Legal Backgrounder Provides ‘Warning Letter’ to Industry Regarding FDA’s Inspection Practices,” FDALawBlog.net, March 16, 2015.
Vol. 28, No. 5
Citation: When referring to this article, please cite it as J. Wechsler, “FDA Revises Field Inspections to Reflect Global Market and Quality Initiatives,” BioPharm International 28 (5) 2015.