FDA is proposing the use of a model that would measure and rate the maturity of a pharma company facility’s quality management system. This model would eventually incentivize companies to improve their ratings in exchange for regulatory concessions such as flexibility in post-approval change management. FDA would not disclose a company’s rating, although companies could potentially share their ratings to differentiate their products based on quality for consumers and other purchasers.
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At the 2020 PDA Annual Meeting held virtually in July, FDA CDER Office of Pharmaceutical Quality (OPQ), Office of Policy for Pharmaceutical Quality (OPPQ) Director Ashley Boam discussed the proposed Quality Maturity Model (QMM). She positioned it as the next step in a progression that began in 2004 with the Pharmaceutical Quality for the 21st century report that laid out a vision of a “maximally efficient, agile, flexible manufacturing sector that reliably produces high quality drug products without extensive regulatory oversight.”
She explained that CGMP is a minimum standard for systems that assure proper design and monitoring and controls for manufacturing processes and their facilities. But to fully realize the pharmaceutical quality vision for the 21st century “requires moving more of the manufacturing sector into richer quality management systems.”
Boam notes that additional context for this topic came up in a report that FDA issued in October of 2019 on drug shortages, in which the agency looked at a number of factors and what might be causing drug shortages, as well as potential solutions to those issues.
The report identified three root causes for drug shortages, including that the market does not currently recognize and reward manufacturers who have mature quality management systems that focus on continuous improvement and early detection of supply chain issues that can lead to a drug shortage. One of the solutions recommended in the report was to develop a rating system to incentivize drug manufacturers to invest in quality management maturity and to incentivize purchasers to recognize and reward QMM.
From GMPs to ICH Q10 to QMM
CGMP is defined in the regulations for drugs in 21 CFR 211 for drug products and in ICH Q7: Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients. It sets out minimum expectations for quality. Regarding improvement, 21 CFR 211 outlines what is referred to as the at least annual product review, where a manufacturer is expected to go back and review a representative number of batches as well as complaints and recalls other quality defect reports to identify where there may have been issues in the process or product that should be addressed.
Similarly, ICH Q7 calls for a product quality review of APIs, looking for opportunities to verify and improve the consistency of the process.
ICH Q10: Pharmaceutical Quality System moved industry a step forward because it augments the concept of CGMP with the idea of the effective pharmaceutical quality system, which covers the entire lifecycle of the product.
Q10 walks through several sets of activities that should be conducted to not only manage but continually improve the pharmaceutical quality system. It also describes how knowledge management and quality risk management principles enable continual improvement. ICH Q10 looks back as well as forward and promotes taking steps to improve (Figure 1).
“How do we get to this idea of quality management maturity?” Boam asked. “The quality management system is a collection of business processes that are needed to consistently implement and maintain quality of product in the marketplace. It is not specific to drugs. It is not a new concept.”
“What we see in the pharmaceutical sector is that less mature quality management systems are generally reactive. They look back. They collect general or non-specific metrics about their processes and are primarily aimed at simply achieving compliance with CGMP.”
Stronger, more mature quality management systems look for sustainable compliance by focusing on performance and continual improvement and linking the metrics that talk about what success and improving on success looks like and that are tied to the patient.
These types of systems use data, predictive analytics, statistics, process capabilities, and other tools to help reduce quality issues that in the past have led to complaints, looking, for example, at supply disruptions and shortages.
“The quality management maturity umbrella, if you want to think about it that way, has lots of different components to it,” Boam pointed out. (Figure 2)
“You see here under this umbrella we have performance management and continual improvement, quality culture, predictive analytics, and supply chain management, to mention a few. A big piece that comes from ICH Q10 is management review and responsibility. One way to think of quality management maturity is how well and how thoroughly are you implementing ICH Q10?”
What Does QMM Look Like?
What does quality management maturity look like? (Figure 3)
QMM is embodied by manufacturers and as well as those who have responsibility for oversight and controls over manufacturing taking ownership for quality. That starts from the top. Management sets the tone for a commitment to quality. “We see investment in people, because it cannot just be those at the top—it must be folks at every level of the organization contributing to that commitment to quality to result in quality product,” Boam emphasized.
QMM is demonstrated by organizations where the objectives are set to drive equality. They are not business objectives and quality objectives, but they are linked together.
Quality systems shape culture. Quality culture is a big piece of quality management maturity. This is where the people come into play. A culture of quality is what is necessary to achieve these higher levels of maturity.
Focusing on innovation and continual improvement means identifying opportunities and then acting on those opportunities to improve the product quality system and to improve other aspects of the manufacturing process.
Moving into performance-based quality management means using data to drive actions and improvements. Part of that may be a robust metrics program with a focus on analytics and using those metrics to help identify areas for improvement.
Management sets the tone for a commitment to quality
Another element FDA sees as part of quality management maturity is the use of risk management plans and forecasting to be prepared for potential interruptions in the supply chain to ensure that there are contingencies in place and that these types of interruptions will not lead to an interruption in supply.
[Related: Busy quality leaders can stay on top of FDA 483 observation trends by downloading a personalized 483 observation report for free here.]
The Benefits of QMM
The benefits of QMM, Boam maintained, apply to patients and consumers as well as to industry and FDA.
In terms of patients and consumers, important medications are too often in shortage and not available for patients who need them. This means that quality management systems have to be more robust to help eliminate and minimize the potential for supply disruptions. This results in providing more reliable access to patients and consumers as well as fewer quality related issues that could lead to a supply disruption or a recall.
In terms of industry, we see this as fitting well within the requirement in section 501 of the statute that requires manufacturers to have oversight and control over the manufacturer of their drugs.
“In addition, we see more advanced levels of quality management maturity leading to fewer recalls, a better corporate image, and enabling improvement of not only process performance and product quality but also the pharmaceutical quality system as we saw in ICH Q10,” Boam said. “Overall, it leads to quality system efficiencies, cost savings and regulatory flexibility.”
There are benefits to FDA as well. QMM will provide additional quantitative and objective insight into the state of quality for products and facilities, which means that the agency will have better information as it considers where the risks exist in facilities that it needs to prioritize for surveillance inspections on a yearly basis.
“When we do go out and inspect, understanding the quality management maturity in that facility gives us an opportunity to be more focused in the inspection, which then may lead to a shorter overall inspection because we have a better idea of where we need to focus,” she maintained.
Quality systems shape culture
Importantly, quality management maturity also facilitates a more flexible regulatory approach, including implementation of ICH Q12 tools such as established conditions. “This is where we start to get more toward the goal of high-quality drug products being regulated without extensive regulatory oversight.”
From a CDER perspective, FDA has identified the need, as evidenced by the drug shortage report, for a system to measure and rate a drug manufacturing facility’s quality management maturity and its ability to deliver high-quality drug products reliably and without disruption.
The agency wants to be able to incentivize manufacturers to improve their quality management systems by rewarding those that achieve a high degree of maturity by encouraging the facility to provide transparency about its high level of maturity to purchasers, so that purchasers might choose to reward facilities that have a higher level of maturity when choosing where to make their purchasing decisions.
“Overall, we see implementing and improving and incentivizing levels of higher management maturity as reducing the likelihood of quality problems that could lead to drug shortages, because it will improve the robustness of quality management systems in general,” Boam explained.
Regarding the umbrella of quality management maturity (Figure 2), “I want to call your attention to the piece here on quality metrics. How do quality metrics fit into the idea of quality management maturity? We see quality metrics as a piece under that umbrella, and a key aspect of a mature quality management system.”
One of the characteristics of a mature quality management system is using data-driven approaches to reduce quality issues. And when you think about how FDA might be able to evaluate and establish a rating for a facility’s quality management maturity, that would likely be done through an assessment, which would represent an evaluation at a point in time.
“Quality metrics data would be important to provide information about what is going on in that facility in between on-site assessments, providing ongoing confidence that what we saw in an assessment of the firm’s quality management maturity is continuing to play out as time goes by,” the OPPQ Director maintained.
Building a QMM System
Regarding building a quality management maturity program, Boam explained that first, it makes sense to learn from the efforts that have been completed and are still ongoing at this point:
- The PDA Quality Culture Initiative
- The ISPE Advancing Pharmaceutical Quality program
- Research and ongoing work from the University of St. Gallen
- The CDRH Case for Quality pilot program
Second, FDA envisions this to be a voluntary program. And third, FDA plans to incorporate stakeholder input.
“There are lots of folks out there who have done a lot of work, some as part of the programs we named here, but a lot of work regarding quality culture and quality management maturity, which would be a critical piece of any program,” she said.
In conclusion, mature quality management systems enable sustainable compliance, focus on continuous improvement, and improved supply chain robustness. Together these result in improved business practices and increased opportunities to benefit from ICH Q12: Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management tools such as established conditions, and ultimately, and most importantly, increased confidence for patients in the safety and effectiveness of their next dose.
Q&A Focuses on Sharing Assessments
The Q&A session after Boam’s presentation focused on sharing QMM assessment information with other stakeholders.
In response to a question regarding sharing of information, Boam replied, “The idea is to provide metrics to the site so that information can be shared—for example, with purchasers, who we understand are increasingly requesting supply chain information.
“They are trying to [determine the quality profile of the site] by looking at 483s and inspection outcomes that FDA makes available to make decisions about which drugs to purchase based on that information. And while inspection information is important and is something that weighs into our risk model, it is not the only piece of information.
“We believe that quality management maturity is a more holistic way to understand what is going on in the facility from a quality perspective and would be more meaningful to those making decisions about which drugs to purchase from where based on supply chain information.”
Amgen Senior Advisor Steve Mendivil commented, “That could be a paradigm shift. If payers would pay a premium for higher quality and a more secure drug supply in the future, that becomes a marketing tool, enabling a company to compete in the marketplace based on quality. And that will drive quality to an even higher maturity. This could be a game-changer in the pharma industry.”
“That is what we are hoping for,” Boam replied.
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