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Mar 9 -- The Food and Drug Administration (FDA or Agency) is announcing the establishment of a docket to solicit comments on changes to FDA's previously proposed quality metrics reporting program (QM Reporting Program). Comments are due by June 7, 2022.

For pharmaceutical manufacturing, quality metrics are objective means of measuring, evaluating, and monitoring the product and process life cycle to proactively identify and mitigate quality risks; thereby managing operations at higher levels of safety, efficacy, delivery, and performance. Quality metrics are used throughout the drug and biological product industry to monitor quality control systems and processes and drive continuous improvement efforts in manufacturing. Quality metrics are important because failure to update and innovate manufacturing practices and lack of operational reliability (i.e., state of control) can lead to quality problems that have a negative impact on public health.

The minimum standard for ensuring that a manufacturer's products are safe and effective is compliance with current good manufacturing practice (CGMP) requirements as outlined in current regulations and as recommended in current policies . . . . However, compliance with CGMP does not necessarily indicate whether a manufacturer is investing in improvements and striving for sustainable compliance, which is the state of having consistent control over manufacturing performance and quality. Sustainable CGMP compliance is difficult to achieve without a focus on continual improvement.

An effective Pharmaceutical Quality System (PQS) ensures both sustainable CGMP compliance and supply chain robustness. Quality metrics data can contribute to a manufacturer's ability to develop an effective PQS because metrics provide insight into manufacturing performance and enable the identification of opportunities for updates and innovation to manufacturing practices. Quality metrics also play an important role in supplier oversight and can be used to inform the oversight of outsourced activities and material suppliers as well as appropriate monitoring activities to minimize supply chain disruptions.

Quality metrics data provided by establishments can also be useful to FDA. These data can assist the Agency in developing compliance and inspection policies and practices to improve the Agency's ability to predict, and therefore possibly mitigate, future drug shortages, and to encourage the pharmaceutical industry to implement innovative quality management systems for pharmaceutical manufacturing. For example, quality metrics data can be applied to FDA's risk-based inspection scheduling, reducing the frequency and/or length of routine surveillance inspections for establishments with metrics data that suggest sustainable compliance. Additionally, the submission of quality metrics data can provide ongoing insight into an establishment's operations between inspections.

As part of FDA's shift towards a risk-based approach to regulation, the Agency proposed to develop and implement a QM Reporting Program to support its quality surveillance activities. Under this program, FDA intends to analyze the quality metrics data submitted by establishments to: (1) Obtain a more quantitative and objective measure of manufacturing quality and reliability at an establishment; (2) integrate the metrics and resulting analysis into FDA's comprehensive quality surveillance program; and (3) apply the results of the analysis to assist in identifying products at risk for quality problems (e.g., quality-related shortages and recalls).
 
FDA believes that a change in the entities responsible for collecting and submitting quality metrics data is not needed. . . . FDA is considering changes to other aspects of the QM Reporting Program. Stakeholders have indicated that different industry sectors may prefer different quality metrics. To provide flexibility to manufacturers, FDA would focus less on standardization of quality metrics and definitions. Instead, FDA would identify practice areas that are critical to ensure sustainable product quality and availability and would permit manufacturers to select a metric(s) from each practice area that are meaningful and enable establishments to identify continual improvement opportunities. The metric definitions would not specify how establishments calculate particular metrics. Rather, the reporting establishment would select the most appropriate metric(s) from each practice area and inform FDA how it was calculated. FDA has identified the following four general practice areas as appropriate at this time for the QM Reporting Program: (1) Manufacturing Process Performance, (2) PQS Effectiveness, (3) Laboratory Performance, (4) Supply Chain Robustness. Examples of quality metrics associated with each practice include the following:

1. Manufacturing Process Performance [4 metrics specified]
2. PQS Effectiveness [5 metrics specified]
3. Laboratory Performance [4 metrics specified]
4. Supply Chain Robustness [4 metrics specified]

Given that the majority of participants in the pilot programs prefer to report data at an establishment level, FDA is considering an approach for aggregating and reporting quality metrics data at the establishment level, with the option to segment by manufacturing train, product type, or product level (e.g., application number or product family).

Once the data are submitted, FDA intends to analyze the information with statistical and machine learning methods to provide useful insights for inspection resource allocation. Examples include examination of product trends and clusters; exploratory and time-series analyses for signal identification, thereby monitoring the health of the establishment over time; and utilizing quality metrics data as an input into machine learning models to assist in determining an establishment's overall PQS effectiveness.

We are seeking comment on the following aspects of FDA's proposed direction for its QM Reporting Program. . . .

A. Reporting Levels

1. Do you agree that reporting should be aggregated at an establishment level?
2. Would reporting at an establishment level facilitate submission of quality metrics data by contract manufacturing organizations?
3. If you normally assess metrics by product family at an establishment, what are useful definitions of “product family” from your industry sector?

B. Practice Areas and Quality Metrics

1. If you think the general practice areas listed in section II of this notice would not meet the objectives of FDA QM Reporting Program, what other practice areas should FDA consider?
2. If FDA were to consider Quality Culture as one of the general practice areas, what are the critical components of a robust quality culture and can any of these components be measured quantitatively? If so, how do you recommend quality culture information be captured as a quantitative metric ( e.g.,
near misses, APR on-time, binary response to Quality Culture survey, or other numerical metrics/KPIs)?
3. Do you think that any of the examples of quality metrics proposed by FDA would not be an appropriate measure for the designated practice area?
4. What other metrics should FDA consider for a designated practice area?
5. FDA is interested in an establishment's experience with implementing process capability and performance metrics. For example, how would you report Cpk and/or Ppk to FDA as part of the QM Reporting Program (e.g., reporting Cpk and/or Ppk for certain products, aggregated at the establishment level)?
6. A metric may need to be changed or adjusted by an establishment to better monitor PQS effectiveness, inform appropriate business strategy, or capture insightful trends, thereby driving continual improvement behaviors. What criteria should be applied to justify changing or modifying a quality metric (by either the establishment or by FDA)? How frequently would you expect changes or modifications to be needed?

7. When would you rely on multiple metrics versus a single metric as an indicator when assessing a particular practice area (e.g., two metrics are considered in combination because one metric influences the other)? What combination of metrics have been meaningful and useful?

C. Other Considerations

1. Are there considerations unique to specific product categories (e.g., generic drug products, OTC drug products, or biological products) that should be addressed in the QM Reporting Program?
2. What would be the optimal reporting frequency for quality metrics data submissions (e.g., monthly, quarterly, or yearly, and segmented by quarter or month)?
3. In instances where a manufacturer is not able to extract domestic data and its submission to FDA contains both U.S. and foreign data, how can these data be submitted to FDA in a manner that would still be informative?
4. Are there any other aspects of FDA's proposed direction for the program that FDA should address in future policy documents?

FDA Quality Metrics for Drug Manufacturing https://www.fda.gov/drugs/pharmaceutical-quality-resources/quality-metrics-drug-manufacturing
FR notice: https://www.federalregister.gov/d/2022-04972

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