Regulatory Science Research Needs Initiative, ICH Q9 & More: Feb. News Update

This first revision of Q9 was given Step 2 approval at the ICH meeting on November 18, 2021, and the Step 3 draft of this revision has now been published on the ICH website.

This revision is being made to address four areas for improvement with the application of QRM:

1. High levels of subjectivity in risk assessments and in QRM outputs
2. Product availability risks
   • Quality/manufacturing issues impacting the supply chain and product availability can present risks to patients, and managing these risks is important.
3. Lack of understanding as to what constitutes formality in QRM work
4. Lack of clarity on risk-based decision-making

This revision has, quite rightly, taken the opportunity to change the terminology for the start of the risk assessment process from “risk identification” to “hazard identification.”

On subjectivity, the draft revision states that this can be introduced through:

• differences in how risks are assessed and in how different stakeholders perceive hazards, harms and risks; and
• the use of tools with poorly designed risk-scoring scales.

It goes on to note, “While subjectivity cannot be eliminated from QRM activities, it may be controlled by addressing bias, the proper use of QRM tools and maximizing the use of relevant data and sources of knowledge.”

On formality, the new draft gives examples of the factors to be considered to determine the appropriate level of formality:

• Uncertainty, i.e., when there is a lack of knowledge about the risks
• The importance of the decision to be made
• The complexity of the project or subject area

The draft then gives characteristics of higher and lower levels of formality.

There is a new section on risk-based decision-making. The new section states, “Effective risk-based decision-making begins with determining the level of effort, formality and documentation that should be applied during the quality risk management process.” It goes on to describe highly structured versus less structured processes, as well as rule-based processes when making risk-based decisions.

The FDA has recently issued its long-promised draft guidance on inspecting injectable products for visible particulates.

The guidance outlines the requirement for the development and implementation of a holistic, risk-based approach to visible particulate control that should start in product development and encompass manufacturing controls, visual inspection techniques, particulate identification and investigation, and corrective actions designed to assess, correct and prevent the risk of visible particulate contamination. The guidance also clarifies that meeting an applicable USP compendial standard alone is not generally sufficient for meeting the current Good Manufacturing Practice requirements for injectable products.

Key points from the new draft guidance that emphasize its focus on building in a risk-based quality control of particulates throughout a product's life cycle include the following:

• To help ensure product quality and limit clinical risk, manufacturers should conduct a risk assessment during product development. The risk assessment should identify the typically visible particulates and characterize their size range, quantity and composition; determine the risk for each type; and provide a visual description. Manufacturers should also consider the potential sources of particulates, appropriate analytical methods to monitor them and mitigation strategies to prevent their presence in the final product.
• Manufacturers should not rely on downstream adjustments to justify a poorly designed product or process. Instead, quality should be built into the manufacturing process, starting with the development phase and continuing during scale-up, qualification studies and commercial manufacturing.

Proactively addressing risk is an important part of a life-cycle approach to visible particulate control.

• Risk assessment results should be used to establish adequate product-specific production controls and clearly defined in-process alert and action limits for particulates.
• Visual inspection can be viewed as part of a larger program to help ensure that injectable products are essentially free of visible particulates. During process scale-up or transfer to contract manufacturers, the visual inspection methods should be assessed to confirm they are still appropriate and valid at the new scale or manufacturing site. The visual inspection program should allow for appropriate adaptations based on knowledge gained throughout the product’s life cycle.
• In addition to inspection, a visible particulate control program should include the training and qualification of operators and the investigation of discrepancies, including root cause analysis, corrective actions and preventive actions.
• Process performance and product quality monitoring systems should provide information to help ensure process control throughout a product’s life cycle. Trends of increased particulate contamination, identification of new particulates, or particulates exceeding alert or action limits may indicate a flaw in the product or process design. If an investigation reveals such a defect or flaw, it is important to redesign the product or process to achieve reproducible product quality and reduction of particulate matter.

The European Medicines Agency (EMA) has published its Regulatory Science Research Needs initiative. The initiative has identified a list of almost 100 regulatory science topics that require further research to improve the development of medicinal products.

The EMA has divided the topics into four categories:

• integration of science and technology in medicines development;
• collaborative evidence generation to improve the scientific quality of evaluations;
• patient-centered access to medicines in partnership with health care systems; and
• emerging health threats and availability/therapeutic challenges.

The initiative encourages researchers and funding organizations to consider the research agenda’s topics and share their findings with the European Medicines Agency.

Further information on the initiative can be found here.

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