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Drug shortages and supply chain challenges bolster FDA efforts to promote modern manufacturing.
For decades, FDA officials have offered both carrots and sticks to encourage industry adoption of advanced manufacturing methods able to ensure product quality and avoid drug shortages. The goal is to shift away from outdated batch manufacturing systems that increase the risk of production problems and raise costs by offering reduced regulatory oversight to firms able to document high-quality manufacturing processes and reduced product defects and regulatory snafus. However, pharma companies have remained leery of required reporting of performance measures for fear of revealing proprietary information and damaging reports, even resisting the agency’s more recent proposal for voluntary submission of information that would support rankings of firms based on quality culture and target achievements.
Now this initiative may gain impetus from operational and supply issues created by the COVID-19 pandemic. Curbs on international trade and travel have highlighted the dangers of relying on Chinese and other foreign manufacturers for supplies of APIs as well as antibiotics and other vital medicines, especially as the halt in most on-site facility inspections further limited oversight of overseas suppliers. FDA has moved to assess regulatory compliance and product quality through past inspection reports, product defect and adverse event filings, recall information, and consumer complaints. The agency can evaluate product quality through sampling and testing in agency labs and also review social media postings citing drug adverse event reports or patient concerns about accessing a needed therapy. And inspection information from foreign regulatory authorities under existing mutual recognition agreements (MRAs) can supplement in-house information.
The situation has bolstered support for encouraging biopharma manufacturers to shift more production to the United States, a high-profile initiative of the Trump Administration. In a Sept. 10, 2020 opinion piece on CNBC.com, FDA Commissioner Stephen Hahn and Deputy Commissioner Anand Shah proposed that investment in modern manufacturing technologies can increase the efficiency and reduce costs of medical products, while also reducing the regulatory burden on companies through real-time assessments of drug quality (1).
This proposal follows an August posting on FDA’s website by Hahn and Shah that describes more fully how advanced manufacturing can relieve strain on medical product supply chains and ensure quality production of vital medicines (2). They cite a partnership between the Center for Drug Evaluation and Research (CDER) and the Biomedical Advanced Research and Development Authority to explore how continuous manufacturing techniques can improve capacity for rapid medical countermeasure production during emergencies. And FDA is supporting the development of an International Council for Harmonization (ICH) guideline on continuous manufacturing as part of its Q13 proposal.
FDA continues to devise strategies that encourage pharma companies to invest in modern manufacturing systems, primarily through submission of data documenting how resulting products meet or exceed FDA quality standards. CDER has gone through several iterations of such quality metrics initiatives and now has stepped back to learn more about how firms already collect quality data and how they utilize this information to improve product performance and reliability (3).
In 2019, CDER’s Office of Product Quality (OPQ) visited 15 manufacturing facilities that volunteered to demonstrate how they use quality metrics and other measures internally to promote quality production. Important early takeaways are that it can take years for a manufacturer to get quality metrics and quality programs up and running, reported Lucinda (Cindy) Buhse, director of OPQ’s Office of Quality Surveillance, in a presentation to the September regulatory conference sponsored by the Consumer Healthcare Products Association (CHPA) (4). She noted that quality metrics are challenging because companies need to establish consistent methods and definitions within a facility, among a company’s different facilities, and between the company and its contractors. A successful program involves integrating quality metrics throughout a company, “up to the CEO,” she commented, so that these measures become part of a firm’s strategic plan and include predictive analytics that can help a company prevent deviations and production issues.
Also at the CHPA conference, Steve Greer, Corporate Quality Assurance External Engagement Leader at Procter & Gamble, described the benefits of participating in FDA’s site visit program in 2019. FDA raised questions about how P&G defines quality metrics, how it measures quality culture, which metrics are more predictive, and which are most important in providing insight into the health of the organization, he said (4).
One immediate need, Greer and Buhse emphasized, is for manufacturers to participate in a Dun & Bradstreet Quality Benchmarking Study funded by FDA, which aims to assess data from some 2000 industry establishments on what metrics firms use to assess manufacturing performance. D&B is partnering with the University of St. Gallen in Switzerland to conduct the study with the aim of improving global understanding of which quality management practices are most effective (5).
CDER also is moving ahead with a “feedback program” that involves FDA staffers analyzing and assessing quality data from a manufacturer and then reviewing its findings with the firm on a confidential basis. Thirteen establishments are submitting quality metric data on lot acceptance and invalidated out-of-specification rates, product quality complaints, quality culture, and process performance. CDER staffers began discussing their analyses with firms in virtual
meetings that began in May 2020 with an eye to completion by the end of this year.
This information from manufacturers, both through site visits and feedback discussions, will help FDA revise and finalize draft guidance on quality metrics. Buhse noted that manufacturers have raised concerns about data validation, how FDA will address different types of companies and products, and how the agency will deal with products made at multiple sites and sites that produce multiple products.
The larger vision for FDA is that the quality metrics program will advance from basic quality management systems to more mature, proactive quality management maturity (QMM) programs that focus on outcomes affecting patients. Buhse described QMM as a “larger umbrella” for quality metrics, involving supply chain management and change management that together provide evidence that a firm can reliably provide a drug to customers.
In a report on drug shortages in 2019, CDER makes the case that manufacturers able to demonstrate high-quality drug production, as documented through a QMM system, should be able to use this achievement as a selling point with purchasers and the public that want to avoid shortages and quality problems (6). A new pilot in 2021 may offer reduced routine monitoring to firms and facilities that demonstrate QMM. And FDA anticipates important gains if staff can spend less time and effort dealing with emergency shortages and other supply chain issues.
QMM involves meeting current good manufacturing practice standards as a minimum requirement for a firm to assure the proper design, monitoring, and control of a manufacturing process and facility. Advanced change management, as outlined by the ICH Q12 guideline on streamlining postapproval changes, requires a manufacturer to demonstrate a clear understanding of process performance.
Most important for QMM is a management commitment to maintaining a quality operation. “Management sets the tone” for a company to take ownership of quality, Buhse noted. This involves a focus on performance, on outcomes that affect patients, and on efforts to reduce those quality issues that lead to complaints. A company may need to update busines processes and be willing to invest in facility improvements, in needed equipment, in staff training, and in quality systems, while also supporting analytics able to forecast supply issues and market changes.
1.S. Hahn and A. Shah, “Op-ed: The Coronavirus Pandemic Underscores the Need to Bring Drug Manufacturing Back to US,” CNBC.com, Sept. 10, 2020.
2.FDA, “Investing in Advanced Manufacturing to Support Public Health Preparedness,” FDA.gov, Aug. 3, 2020.
3.FDA, “Quality Metrics for Drug Manufacturing,” FDA.gov, accessed Sept. 10, 2020.
4.J. Ahearn, Moderator, “Creating Value Through Quality Metrics,” Conference Session at the CHPA 2020 Regulatory, Scientific, & Quality Conference, Sept. 1–3, 2020.
5.Dun & Bradstreet, “2020 Quality Benchmarking Study,” dnb.com, www.dnb.com/marketing/pharmaceutical-manufacturing-quality-study.html, accessed Sept. 10, 2020.
6.FDA, Drug Shortages: Root Causes and Potential Solutions 2019, Feb. 21, 2020.
Jill Wechsler is Pharmaceutical Technology’s Washington editor, firstname.lastname@example.org.
Volume 44, Number 10
When referring to this article, please cite it as J. Wechsler, "Will COVID-19 Pandemic Finally Establish Drug Quality Metrics?," Pharmaceutical Technology 44 (10) 2020.