In the world of pharmaceutical production, it is universally understood that a robust pharmaceutical quality system provides key elements of assurance and oversight for pharmaceutical manufacturing processes. It ensures that patients are provided with medications that are safe, effective, and reliably produced at a high level of quality. However, despite recent advances in the manufacturing sector, quality issues remain a frequent occurrence, and can result in recalls, withdrawals, or harm to patients. Quality issues have also been linked to the rise in critical drug shortages.¹
Regulatory agencies currently assesses the risk profile of manufacturing sites based primarily on their compliance history, as seen in warning letters and field reports, in conjunction with records on product recalls and market-based quality problems. These are not necessarily the most informative measures, and by their nature, provide historical or lagging data or signal detection. More relevant data relating to the state-of-quality, provided in advance, would better inform the risk factors that might predict quality problems and future drug shortages.
FDA’s approach to quality oversight has evolved in recent years, and the new Office of Pharmaceutical Quality (OPQ) has made it a priority to establish a sounder basis for ensuring that pharmaceutical products meet high quality standards throughout the product lifecycle
This FDA led Research Project initiates a program aimed at developing and implementing a set of standardized manufacturing quality metrics. The establishment and collection of these metrics should provide various stakeholders – from industry to regulators – with greater insight into the state-of-quality at a given manufacturing facility, and allow stakeholders to better anticipate and address quality issues while simultaneously reducing unnecessary regulatory burden.
RECENT DEVELOPMENTS IN THE QUALITY METRICS INITIATIVE
Since early 2013, FDA has been working with the pharmaceutical industry to develop goals and objectives for a metrics program. In response, several industry stakeholder groups have worked with FDA to develop consensus around the goals, as well as identify potential metric sets, including developing recommendations for their implementation and interpretation. Through a series of extensive engagements between industry and FDA there has been an acknowledgement of the complexity of the problem at hand, which is to develop a recommeded set of metrics which are objective and meaningful, easy to capture yet normalized to account for factors such as process differences and technical complexity. Furthermore, it is required that those elements selected will promote acceptable behaviors and not lead to any unintended consquences or unwanted behaviors.
Key Research Questions to Address in the Selection of a Proposed Metrics Set:
1. What is the appropriate set of metrics to collect for establishing the state-of-quality at a manufacturing facility?
2. Will this set of metrics provide adequate information for all types of pharmaceutical manufacturing, such as sterile injectables, bio-pharmaceuticals?
3. How should these metrics be defined?
4. What is the optimal reporting process and what support will be necessary to facilitate timely and uniform reporting.
5. What are the potential unintended consequences which may arise with chosen metrics?
a. Such as measuring OOS rate may result in companies not reporting OOS results or changing their standards of identifying OOS results to minimize the numbers.
b. Review of complaint trending might lead firms to resolve problems superficially without getting to root cause.
6. How can the FDA prevent manipulation of data and its unintended consequences?
7. How does company culture impact the data collection and the metrics?
8. How does the underlying quality culture of a manufacturing facility influence quality performance and how does one correlate its impact through these metrics?
9. How can one represent a set of complex behavior and performance criteria via a set of simple metrics?
10. How can these set of metrics be linked to operating efficiency and performance of the plants? Plants are naturally focused towards improving their profitability and cost. Significant efforts such as six sigma, lean, right-first-time programs are underway across the industry and have deep rooted support in many pharmaceutical operations around the world. Can the reportable quality metrics be a natural offshoot of such improvement programs?
ROLE OF QUALITY METRICS IN RISK-BASED SURVEILLANCE
Quality metrics are widely used throughout the pharmaceutical industry to monitor quality control systems and processes, and many of the components that inform those metrics (e.g., data on process capability output or statistical process control) are already collected and maintained as part of cGMP compliance. Several measures of performance are already common throughout the industry. The challenege is that they are currently defined differently across manufacturers, and even between sites operated by the same manufacturer.
The proposed FDA Quality Metrics program is not the first of its kind; rather, it draws from the example of existing private sector quality improvement programs that collect voluntarily reported, standardized quality metrics from a large and varying array of manufacturing sites, which are then used by participating manufacturers to benchmark their performance against industry standards and their peers.
The collection and analysis of standardized quality metrics can serve several functions:
• At a basic level, metrics should provide a quantitative and objective measure of quality at the manufacturing site, and provide a window at a systems level, to the effectiveness of the oversight and control of operations at a given site.