The US Food and Drug Administration (FDA) Office of Pharmaceutical Quality (OPQ) of the Center for Drug Evaluation and Research (CDER) recently published a White Paper laying out a framework to evaluate the Quality Management Maturity (QMM) of pharmaceutical manufacturing sites. The White Paper supports CDER’s long-held vision for pharmaceutical quality in the 21st century, described as a “maximally efficient, agile, flexible manufacturing sector” that is able to reliably produce high-quality drug products without extensive regulatory oversight.[1] The Agency is hosting a two-day workshop on May 24 and 25 for stakeholders to provide feedback on the proposed QMM, which may be a welcome shift towards a more holistic, metric-based review of manufacturers with mature quality systems.
Current State: Product Quality is High, Supply Chain Resilience is Low, Drug Shortages Persist
Citing a 2019 report “Drug Shortages: Root Causes and Potential Solutions” issued by the multi-agency Federal Drug Shortages Task Force (“2019 Report”)[2], OPQ notes that 62% of drug shortages between 2013 and 2017 were associated with manufacturing or product quality problems (e.g., substandard manufacturing facilities/processes in improvements or quality defects in the finished product). These problems necessitate remediation, which can take time to address, interrupt production and lead to drug shortages, in addition to creating stress on the healthcare system. The report noted that a root cause of drug shortages is the fact that the market does not recognize and reward manufacturers for having mature quality management systems. As an example, FDA does not currently evaluate the maturity of a manufacturing quality system as part of its assessment, inspection, or surveillance processes.
The White Paper cites a recommendation in the 2019 Report to develop a rating system to incentivize drug manufacturers to invest in achieving Quality Management Maturity (QMM), described as a state of having consistent, reliable, and robust business processes to achieve quality objectives and promote continual improvement. Transparent QMM ratings could empower manufacturers to identify ways to improve the effectiveness of their product quality monitoring systems, realize regulatory flexibilities, and help move the pharmaceutical industry toward the six-sigma quality common in other industries.
Building an FDA Quality Management Maturity Program
In building out the QMM program, CDER engaged collaboratively with impacted stakeholders to ensure that the fundamental scientific premise of the program was well-reasoned and supported by objective evidence. CDER also extensively engaged with stakeholders potentially impacted by a QMM program to better understand their key concerns about the impact of drug manufacturing issues.
FDA also initiated development of key quality metrics to incentivize continual improvement and ultimately support risk-based scheduling of drug manufacturing facility inspections, with decreased inspection frequency for high performers. In addition to these metrics, FDA is evolving towards a more holistic approach that integrates metrics with other behaviors and attributes of effective quality programs.
Considerations for a QMM Rating System
FDA has formed a multidisciplinary, multi-Center working group to facilitate the development of a QMM rating program. This working group is developing a framework to objectively assess and rate the QMM of manufacturing sites using interactive site engagement along with surveillance intelligence. As part of the framework, FDA is considering standardized assessment tools, policy approaches, industry incentives, transparency, and communication programs.
Key challenges for the working group include:
- Developing a consistent meaning for “pharmaceutical quality” and other standards utilized in QMM ratings.
- Convincing stakeholders that the QMM ratings are additive to FDA approval of a drug and should be considered in any dispensing or purchasing decisions.
- Clarifying and separating the QMM appraisals from regulatory compliance.
- Encouraging manufacturers to share their supply chain information by using the QMM ratings.
- Rewarding the market for implementing QMM programs.
- Identifying the potential risks associated with using QMM ratings in marketing or promotion of drugs.
FDA has conducted two pilot programs with pharmaceutical manufacturers to inform the criteria used to objectively measure a manufacturing site’s QMM. One pilot is focused on domestic manufacturers of finished dosage form products, and the other on foreign manufacturers of APIs. Feedback from the participants in the pilot programs is now helping determine best practices for conducting the assessments, the assessment tool, and associated logistics.
FDA believes that a QMM rating system will foster a more robust drug supply chain and greater commitment to quality in pharmaceutical manufacturing. Further, FDA believes that a QMM rating system could provide highly-rated manufacturers with important recognition and a competitive advantage over other manufacturers, while providing purchasers and payors with more insight and confidence into the supply chain of the drugs or components they buy or reimburse. An equally important rationale is that patients, pharmacies, and healthcare professionals will get medicines with less likelihood of shortage.
The two-day workshop on May 24 and 25, 2022 will provide interested stakeholders an opportunity to provide feedback on the proposed QMM. Many manufacturers with mature quality systems could benefit from an FDA approach to inspections that is more holistic in nature, as opposed to the current system, where FDA does not reward or recognize more sophisticated and advanced quality programs.
[1] Quality Management Maturity: Essential for Stable U.S. Supply Chains of Quality Pharmaceuticals. https://fda.gov/media/157432/download
[2] Drug Shortages: Root Causes and Potential Solutions 2019. https://fda.gov/media/131130/download