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Jill Wechsler is BioPharm International's Washington Editor, email@example.com.
Industry fears limited benefits as FDA readies voluntary data tracking program.
FDA plans to launch its quality metrics data initiative in January 2018 by opening an electronic portal (e-portal) to collect data on certain manufacturing processes electronically from biopharmaceutical companies. The aim is to identify and reward those firms able to demonstrate that their operations can consistently produce high-quality products and thus merit reduced regulatory oversight. Yet as the metrics program nears implementation, industry is pushing back, voicing concerns about the scope of FDA’s data requirements, the timing of the program’s launch, and what the agency will do with the resulting information.
Questions about the agency’s legal authority to require detailed reports on specific manufacturing operations prompted FDA to shift from a mandatory to a voluntary program in 2016, but that creates uncertainty about how many companies will participate and whether the results will be meaningful. Agency officials hope that many firms will submit data so that the program can better detect and prevent drug shortages and support adoption of a smarter regulatory approach by the agency.
The quality metrics program has been under development at the Center for Drug Evaluation and Research (CDER) for more than a decade, part of efforts to encourage industry adoption of advanced manufacturing systems able to produce high-quality medical products continuously and with minimal oversight. The aim is to avoid drug shortages and recalls, which largely arise from production issues, noted Lawrence Yu, deputy director of CDER’s Office of Pharmaceutical Quality (OPQ), at the Parenteral Drug Association’s (PDA) February 2017 Pharmaceutical Quality Metrics and Quality Culture Conference in Bethesda, MD. Yu added that advanced manufacturing methods based on robust quality programs are even more important with the rise of precision medicine, biosimilars, and complex combination products. And high-performing firms may be rewarded with fewer or shorter plant inspections and reduced oversight of postapproval manufacturing changes, as well as high placement on a metrics “reporters list.”
FDA’s current plan is to open the e-portal early next year for three months in which 2017 metrics data may be accepted. The agency published a technical conformance guide in 2016 with information on how to submit requested data electronically (1). A revised technical guidance will further clarify issues related to e-data transmission. FDA will announce in the Federal Register early next year when the portal is open and provide further updates on what information to submit. Manufacturers that plan to participate are collecting metrics data for 2017, even if only for six or nine months in this initial year.
FDA will evaluate the data and summarize how many firms reported which metrics and the number of products and facilities involved. A “reporters list” may identify participating firms, but not provide data on individual companies. Even so, the plan to list firms in tiers according to extent of reporting has raised concerns that this may discourage participation, especially by small companies.
This more scaled-back program reflects industry objections to FDA’s initial metrics data proposal, which was published in July 2015. A revised draft guidance issued in November 2016 makes the program voluntary, slims down data reporting, and gives manufacturers the option for reporting metrics by products or by sites (2).
These changes “reflect your voice,” Wu told industry representatives at the PDA conference, noting that the revised program seeks data only on lot acceptance rate, invalidated out-of-specification (OOS) rate, and product quality complaint rate. The agency acknowledges that it would be useful to have information on process capability, corrective actions and preventive actions (CAPA) effectiveness, or right-first-time rate, but has agreed to limit the program’s initial scope for now.
The initial program involves only drugs and biologics regulated by CDER, and not yet vaccines, blood products, and cellular and gene therapies overseen by the Center for Biologics Evaluation and Research (CBER). CBER is actively involved in the metrics program and plans to extend it to its products as the initiative matures.
FDA and industry also acknowledge the importance of a company’s quality culture in ensuring reliable drug production, but recognize the need to delay specifying metrics to measure such criteria pending further study of methods for documenting that desired state. While a strong quality culture might be reflected in visible senior management support for quality production, there’s much debate over how to achieve and report such behavior.
Many attendees at the PDA conference expressed continued reservations about the scope and timing of the metrics program and the effort involved in revising data systems and establishing complex reporting programs. Deborah Autor, head of strategic global quality and regulatory policy at Mylan, described the considerable challenge in providing metrics on more than 600 finished products and APIs, noting that reports on the three requested metrics involve mapping 11 data points from many different information systems within the company. “Slow it down,” Autor advised, proposing that FDA “phase in the program gently” and drop the reporters list until program feasibility becomes clearer.
The difficulties may be even greater for Johnson & Johnson, which is supposed to provide metrics data on hundreds of non-prescription medicinal products that fall under the program, but raise little risk of patient harm from production problems. And Barbara Allen, senior director of global quality systems at Eli Lilly, was skeptical that data on a few production indicators can really inform on risks associated with specific products or sites.
Many biotech manufacturers recognize the importance of implementing continuous improvement systems, but still may find it challenging to meet metrics requirements, said Melissa Seymour, vice-president for global quality control at Biogen, at the PDA meeting. She was optimistic that the initiative could lead to greater trust in industry and fewer inspections, but concerned that many small companies will decide that falling to the low tier of the reporters list might be worse than not being on the list at all. Hovione CEO Guy Villax agreed with “start small” proposals, predicting that participants may “game the system” to spin data to a company’s advantage.
In launching the program now, explained Ashley Boam, acting director of OPQ’s office of policy for pharmaceutical quality, FDA aims to test and improve data collection through the e-portal, to better assess which incentives encourage firms to participate, and to gain insight into how to use the resulting data to improve inspections and oversight. Data from multiple sites and firms, she noted, is key to detecting signals of possible drug shortages that often involve more than one company or operation. And FDA wants to be sure that collection of metrics data does not create barriers to manufacturers adopting new technology and continuous manufacturing systems.
FDA will continue to partner with manufacturers in defining and assessing measures of quality operations and culture. Industry organizations have sponsored multiple conferences, white papers, pilot programs, and task forces on this initiative. An International Society for Pharmaceutical Engineers (ISPE) conference in April 2017 will further discuss quality metrics and quality culture assessment, and PDA plans to publish a report on its current metrics pilot in September. Boam expects a voluntary metrics program to continue for more than a year and that it will help the agency focus resources on facilities and products that raise the highest risks to patients. FDA also intends to provide opportunities for companies to provide feedback and share knowledge from ongoing, industry-driven quality metrics programs.
1. FDA, Quality Metrics Technical Conformance Guide, Technical Specifications Document, www.fda.gov/downloads/Drugs/DevelopmentApprovalProcess/Manufacturing/UCM508464.pdf
2. FDA, Submission of Quality Metrics Data Guidance for Industry, Draft Guidance (CDER, November 2016), www.fda.gov/downloads/Drugs/Guidance ComplianceRegulatoryInformation/Guidances/UCM455957.pdf
Vol. 30, No. 4
When referring to this article, please cite it as J. Wechsler, "FDA Quality Metrics Initiative Challenges Manufacturers," BioPharm International 30 (4) 2017.