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New program emphasizes quality, risk, and global collaboration.
After two years of planning and analysis, FDA officials are moving forward with implementation of the Program Alignment plan to better coordinate agency field inspections with product reviews from FDA research centers. The aim is to reduce redundant processes and to provide more expertise in evaluating today’s more complex and varied production systems for drugs and biologics. The growing number of pharmaceutical ingredients and finished products imported from abroad, moreover, heightens the need for risk-based oversight and increased collaboration with foreign regulatory counterparts to avoid duplicate inspections.
The reorganization of FDA’s 5000-person field force represents the most important change since the Office of Regulatory Affairs (ORA) was formed, says Melinda Plaisier, ORA chief and associate commissioner for regulatory affairs. This Program Alignment initiative, announced in September 2013 and further clarified in February 2015 (1), is dissolving ORA’s five regional offices and establishing commodity-based and vertically integrated inspection programs for drugs, biologics, medical devices, tobacco products, food, and bioresearch monitoring that will operate out of ORA’s 20 district offices.
For drugs, Plaisier explained at the PDA/FDA Joint Regulatory Conference in Washington, DC in September 2015, Alonza Cruse will be director for Pharmaceutical Quality Operations, which will have a cadre of pharmaceutical inspectors divided into four management teams. Anne Reid is acting director for Biological Operations, with two management teams, and Jan Welch heads up three teams for medical devices. Some product team directors also will head district offices.
These teams of specialized investigators will gain greater technical expertise through training, which should help them keep pace with manufacturing changes and new technology, especially those inspectors with sub-specialties in, for example, sterile drugs, compounding, APIs, or combination products. Pharmaceutical inspectorate members also will be part of the Center for Drug Evaluation and Research (CDER) product review teams so that they will fully understand development and manufacturing issues involved in a new therapy and can produce pre-approval inspection reports that reflect a common understanding of pertinent production and quality concerns.
Plaisier emphasized that the ORA overhaul is a “work in progress,” and that many final decisions and individual assignments are still to come. Questions remain about the number of field management teams for each program, where these will be located, and how to align some 2000 investigators into the different review programs, she explained. These transition activities will continue through the coming year, with the goal of starting up the new model in fiscal year 2017. ORA is looking to develop metrics to measure the impact of these changes internally, along with enhanced training programs, new work planning systems, and more centralized laboratory operations.
Clear, coherent enforcement strategies with reduced layers of review involve closer collaboration between center staff and field inspectors to eliminate duplicate case workups and to speed inspection findings to manufacturers, explained Tom Cosgrove, director of the Office of Manufacturing Quality (OMQ) in the CDER Office of Compliance (OC). These changes should accelerate re-reviews of plants looking to regain compliance status and “not leave firms in OAI (official action indicated) status for a long time,” Cosgrove commented at the PDA/FDA conference. He emphasized the importance of complete documentation of operations to demonstrate compliance with GMPs. He also noted that documentation by itself “is not enough” to demonstrate full compliance and that FDA inspectors are being trained to do a “deeper dive” into actual production practices.
FDA also seeks to halt violative imports more quickly by de-linking import alerts from warning letters. Expeditious action against noncompliant imports is important, Cosgrove pointed out, because many of these products raise data integrity issues, including data that have been deleted, back-dated, copied, and fabricated. FDA is highlighting data-integrity failures because such problems also are linked to GMP violations and other problems that represent “real risk to patients.”
OMQ also is looking hard at contract manufacturers and how well their pharma clients monitor contract operations for quality and compliance. Clients need “to get out there,” perhaps put a person in the plant, to uncover GMP and compliance problems “before we do,” Cosgrove advised. He noted that the manufacturer holding the approved license for a medical product is responsible for ensuring quality at all its production facilities-including those overseas or operated by partners and suppliers.
Amidst all these organizational changes, FDA is developing a new model for assessing plant operations based on standardized measures of a facility’s state of quality and compliance. The New Inspection Protocol Project (NIPP) will apply to pre-approval, GMP surveillance, and for-cause inspections. CDER’s Office of Pharmaceutical Quality is developing the new protocols and planning pilot NIPP inspections with ORA. The aim is to obtain quantitative scores that can help compare sites, while also reducing variability in observations by different inspectors and providing manufacturers with a clearer idea of what they need to do to maintain quality. While continuing to document observed deficiencies, inspections also will identify practices that exceed basic compliance requirements to reward positive behaviors.
Efforts at home to develop metrics for evaluating manufacturing operations and to streamline and target inspections also are being applied to foreign manufacturers producing medical products for the United States. Because FDA lacks the resources to monitor the growing global pharmaceutical market, US and European Union officials are looking for greater “mutual reliance” on each other’s inspection reports. US officials have explored such options for more than a decade, only to be stymied by legal requirements and confusing goals. Now authorities are renewing efforts to reduce the number of inspections conducted by FDA investigators in the EU, and by European inspectorates in the US, to better target resources to areas of greater risk, explained Dara Corrigan, FDA associate commissioner for global regulatory policy, at the PDA/FDA conference.
FDA conducts thousands of foreign inspections each year, many in Europe, Corrigan pointed out, and reliable information indicating that a facility meets GMPs and is a low-risk operation could help avoid unnecessary site visits. To move forward with a mutual reliance initiative, FDA investigators are observing audits of EU inspectorates, which are conducted by other EU member states as part of their own internal mutual reliance inspection program. At the same time, EU officials are auditing ORA district operations to support increased EU reliance on FDA inspection practices and reports.
Corrigan noted that FDA officials have been impressed with the high level of discussion taking place during these audits, but a number of important issues have to be addressed for the initiative to move forward. One is that US law requires FDA inspection reports to redact trade secret information before being shared with other regulatory authorities, a policy that rankles EU officials. And while the vast majority of registered European drug facilities and imported products come from six EU member states (Germany, France, Italy, United Kingdom, Spain, and Ireland), it’s not clear if a mutual reliance program could be limited to those countries. The path forward, Corrigan said, involves assessing the variability of EU inspectorates and their expertise. This is a high priority for both FDA and the EU, and, Corrigan stressed, “we want to succeed.”
1. J. Wechsler, Pharma. Techn. 39 (5) (2015).
Article DetailsBioPharm International
Vol. 28, No. 11
Citation: When referring to this article, please cite it as J. Wechsler, “FDA Overhauls Inspection Operations,” BioPharm International28 (11) 2015.