Modern Manufacturing Systems Key to FDA Quality Initiative

Published on: 
BioPharm International, BioPharm International-04-01-2015, Volume 28, Issue 4
Pages: 40–45

More reliable operations would accelerate product development and prevent drug shortages.


To ensure patient access to high quality, safe, and effective medicines, FDA spends considerable time and resources enforcing GMPs, inspecting production facilities, and overseeing a growing volume of imported pharmaceutical ingredients. Agency officials have urged biopharmaceutical manufacturers for more than a decade to adopt more reliable and efficient advanced manufacturing technologies capable of ensuring consistent high-quality production that meets standards and public expectations. Such approaches, the authorities predict, could reduce waste, prevent drug shortages, and avoid the scale-up and production challenges that can delay final approval of innovative breakthrough therapies.

To support real change, FDA’s Center for Drug Evaluation and Research (CDER) has launched a full-court press to convince industry of the value of adopting modern drug manufacturing systems. The agency seeks clearer standards and policies that provide more predictability and reduced oversight of firms that invest in more efficient production methods. At the same time, more transparent company reports on quality operations, market pressures to cut costs, and public demands for reliable patient access to critical therapies are combining to support a shift away from outdated, unreliable production methods. 

CDER’s new Office of Pharmaceutical Quality (OPQ), led by CDER director Janet Woodcock, is establishing systems to identify high-risk, problematic facilities and products--and those operations that reliably achieve quality standards--to be able to detect and respond to quality issues before they disrupt production and lead to plant closures. Woodcock has repeatedly called for industry investment in advanced manufacturing systems as part of her vision for shifting from rule-based to risk-based regulation, offering less oversight of operations and products that demonstrate a capacity to ensure quality and reduce risk. She reiterated this approach at the February 2015 annual meeting of the Generic Pharmaceutical Association, urging development of continuous manufacturing operations that can achieve consistent product quality. 

Quality data key

Science-based standards for application review and plant inspection support this approach by communicating clear expectations for industry. Such standards will aim to capture critical product attributes that can indicate quality problems, needed corrective actions, and justify enforcement decisions. OPQ’s Office of Policy for Pharmaceutical Quality (OPPQ) is examining current policies and areas where risk-based regulation and guidance would encourage continuous quality improvement by industry throughout drug development and production. OPPQ further coordinates FDA quality-related policies with other regulatory authorities and with independent standards-setting organizations. 

This approach will be supported by a new quality metrics reporting initiative that requires biopharma companies to submit data on operations key to consistent quality production. FDA has been working closely with industry for more than a year to devise a set of metrics that will indicate the ability of a firm and its facilities to produce high-quality therapies on a continual, error-free basis. Likely measures include right-first-time rate, quality-related complaints, invalidated out-of-specification results, recalls, and stability failures.

Agreement on metrics has been tricky, though, as seen in delays in publishing draft guidance on which production measures may be most accessible and useful. Discussion has been most intense on devising a set of metrics that indicate the “quality culture” at a company (1). 

Industry metrics will be part of a comprehensive information system that will manage the “inventory” of CDER-regulated manufacturing sites and products. This information technology system is being developed by OPQ’s Office of Surveillance to track the state of quality for all regulated sites based on data from applications, inspections, and quality metrics reports. A risk-ranking process for all locations will drive CDER inspection planning and site visits, with an eye to focusing on more serious problems. Metrics may inform inspection frequency, help FDA set inspection priorities, and identify products and processes to target (or omit) during a site visit.

Ideally, the program will identify and reward firms that  “go above and beyond” meeting basic standards, preferably by investing in modern, continuous manufacturing systems and high-tech processes that ensure quality production. “Quality scorecards” devised by OPQ would inform companies confidentially on how they compare to industry performance. While CDER does not plan to publish specific company ratings at this time, a manufacturer could choose to promote high quality reports to payers, patients, and health professionals. 

Biopharma companies that take steps to enhance manufacturing quality should be better positioned to expedite development and production of innovative therapies promising important benefits for patients with critical illnesses. OPQ’s lifecycle review initiative and its team approach for integrating quality review and compliance aim to support accelerated review of a growing cadre of breakthrough drugs. 


Changes in OPQ’s Office of Biotechnology Products (OBP), for example, aim to enhance its capacity for assessing the quality and safety of a broader range of biotech therapies in development or under review by the agency, including orphan drugs and biosimilars that raise new analytical challenges. OBP now has four Divisions of Biotechnology Product Review & Research, each with a cadre of reviewers and scientists capable of assessing a spectrum of biotech therapies. This structure replaces specific divisions for monoclonal antibodies and for other proteins staffed by more specialized reviewers. The change should help OBP manage its workload more effectively as biotech product development continues to expand, OBP chief Steve Kozlowski explained at the January 2015 WCBP symposium in Washington, D.C. (2). 

Reducing shortages

More information on the ability of a production facility to consistently produce high quality products also can help FDA identify potential problems early on that could cause manufacturing disruptions or failures in product quality. Such situations often result in critical drug shortages, particularly for low-cost sterile injectable products made by a limited number of generic-drug companies. FDA has been able to prevent and mitigate drug shortages more often in the past two years by obtaining earlier reports from manufacturers of potential production problems or ingredient shortages (3). But a more long-term solution lies in industry investment in advanced manufacturing systems and adoption of a quality culture in their operating units that encourage employee creativity and proactive risk management. 

Such an approach is described in a new technical report from the Parenteral Drug Association (PDA) on how manufacturers should establish a risk-based approach for preventing and managing drug shortages (4). The report outlines a model for companies to assess the factors likely to lead to a shortage and its potential impact on patients. For certain high-risk situations, a manufacturer should consider adding manufacturing sites or lines, engaging additional raw material suppliers, and installing new equipment and technology.

The prospect of more transparency in company quality performance may drive such change, as will pressure on manufacturers to achieve more efficient and economical production systems to cut costs in response to squeezed revenues from more price-sensitive customers. Regulatory carrots and sticks have provided some incentives for industry to replace outdated facilities, but the market shift from blockbuster drugs for chronic conditions to “precision” medicines for small patient populations should do much to further investment in more flexible and cost-effective operations. 


1. J. Wechsler, “The Quest for Quality Metrics Continues,”, Jan. 20, 2015,

2. J. Wechsler, “CDER and Biotech Quality Assessment,”, Feb. 11, 2015,

3. J. Wechsler, “Manufacturers Weigh Strategies to Prevent Drug Shortages,, Feb. 24, 2015,

4. PDA, Technical Report No. 68, Risk-Based Approach for Prevention and Management of Drug Shortages (PDA, 2014). 

Article Details BioPharm International
Vol. 28, Issue 4
Pages: 14-15
Citation: When referring to this article, please cite it as J. Wechsler, "Modern Manufacturing Systems Key to FDA Quality Initiative," BioPharm International 28 (4) 2015.