The recent ICH Q9: Quality Risk Management revision includes new guidance on facilitating a risk-based decision-making approach using science and knowledge.

Warning Letters FY2020 and FY2021

Kevin O’Donnell, PhD, Market Compliance Manager, Irish Health Products Regulatory Authority (HPRA) provided an update on the ICH Q9 revision at the 2021 PDA/FDA Joint Regulatory Conference last fall, ahead of the December 2021 release of the revision.  

ICH Q9 originally was  finalized in 2005, “and as we all know, QRM (quality risk management) has  become very important in our industry…we have had many initiatives to embed risk management principles and risk-based approaches into our day-to-day work and into our strategic goals as well.”

O’Donnell’s agency proposed a revision to ICH Q9 in 2018, and he worked with two colleagues, Gregg Claycamp, Senior Scientist for Risk Analysis and Decision Analysis, U.S. FDA, and Emma Ramnarine, Senior Director, Global Head External Development Collaborations, Genentech/Roche, to prepare the initial proposal paper. 

In November 2019, ICH accepted the proposal to revise ICH Q9 and established an Expert Working Group in 2020.

“We have been working since then to come up with good and new guidance on QRM,” he said.

O’Donnell anticipates that the guidance will be finalized in September 2022, although the business plan states May 2022.

[Author’s Note: EMA published the draft revision on the agency’s website in December. Comments will be accepted by EMA until March 15. As the document is at Step 2 of the ICH process, the ICH Q9 revision has been sent to regulatory bodies within ICH regions for internal and external comments per the procedures of those agencies. For this reason, the document is not on the ICH website.]

In his PDA/FDA presentation, he further clarified this is only a targeted revision and not a full rewrite, as most of the existing guidance remains unchanged.

The revision focuses on six specific topics:

  • Subjectivity in QRM
  • Product availability risks
  • Formality in QRM
  • Risk-based decision-making
  • Risk review
  • Hazard identification

Subjectivity in QRM

Regarding subjectivity, “this is a pretty important part of understanding, assessing, and making decisions regarding risk, but it is quite a tricky area to get right, and it is quite a tricky area to write guidance on. High levels of subjectivity in risk assessments and QRM outputs is problematic.”

Subjectivity also is not in line with the first ICH Q9 principle: Risks to quality should be evaluated based on scientific knowledge.

“We know we cannot eliminate subjectivity from QRM, but we know we can control it, and there is a lot of peer-reviewed research out there from other industries telling us how one can control subjectivity using various strategies, which address bias and various behavioral factors, groupthink, group work, etc.,” O’Donnell explained. “We think addressing subjectivity will be beneficial because less subjective risk assessments should lead to more scientific control strategies, validation protocols, and, hopefully, fewer quality defects because processes will have better risk-based validation behind them.”

He added, “these improvements also, hopefully, will continue to support the implementation of ICH Q8, Q10, Q11, and Q12—all of which expect scientific approaches.”

[Author’s Note: For more on ICH Q10: Pharmaceutical Quality System, watch the following video clip featuring consultant Fenton Fong.]

Product Availability Risks

This type of risk can also be read as “drug shortage risks,” according to the HPRA regulator. 

“We know ICH Q9 is not a supply chain guidance, but quality and manufacturing issues that impact product availability do present risks to patients, so managing those risks is important,” he said. “We think addressing these risks across the lifecycle is very important given the globalization of medicine supply chains.”

The goal of the ICH Q9 revision in this area is for companies to develop risk-based drug shortage prevention and mitigation plans.

Formality in QRM

“Formality is an interesting topic in QRM,” O’Donnell said. “ICH Q9 currently states that the level of effort, formality, and documentation of the QRM process should be commensurate with the level of risk.”

There is a level of ambiguity regarding formality, however, and many stakeholders have told O’Donnell and his colleagues they do not understand what formality in QRM really means, resulting in confusion. Regulators are also uncertain about what “formality” means. 

The revision covers degrees of formality and approaches formality as a spectrum rather than a binary approach.

“We are going to be discussing the factors that might influence how much formality might be applied,” he said.

We know we cannot eliminate subjectivity from QRM, but we know we can control it

O’Donnell emphasized that flexibility is critical in determining how much formality to apply to QRM.

“Clarity here will help ensure that the extent of scientific rigor and the methodological rigor applied during QRM work is commensurate with risk levels,” he said. “We will have resources being used more efficiently in the future, where lower risk issues are dealt with more efficiently via less formal means, to free up resources for managing higher-risk issues and more complex problems.”

Risk-Based Decision-Making

Per O’Donnell, risk-based decision-making is a large topic as it “ultimately translates back to risk-based decision making…while ICH Q9 does make reference to this concept, there is currently some lack of clarity on what good risk-based decision making actually is, how it might be achieved, and how QRM may improve decision making generally.”

He noted that other sectors have conducted research about risk-based decision making, including nuclear power, aeronautics, the U.S. Coast Guard, and others.

“The revision work will hopefully provide clarity here, and address the expected benefits of investing in risk-based decision-making process activities,” he said. “Hopefully, this will all lead to lots of good things: better risk assessments, better control strategies in our manufacturing process, and more access to new medicines for patients, especially when we are looking at fast-tracked applications.”

Risk Review

The fifth topic, risk review, is a smaller topic within the overall revision. The revision does not include any new guidance on the topic because the team felt that the current guidance is sufficient. However, training materials addressing risk reviews will be included.

There is a level of ambiguity regarding formality

“The training materials we will generate will provide additional clarity on expectations relating to risk reviews and keeping risk assessment current, and linking that with continual improvement,” O’Donnell explained. “We will be looking at lifecycle types of examples to illustrate when it [risk review] is done well what it might look like, tying in with the concept of continuous improvement.”

Hazard Identification

ICH Q9 right now uses the term risk identification, “but we are going to revise the guideline to change that phrase to the phrase, ‘hazard identification,’ because this will better reflect what is already in ICH Q9, which does speak about how risk assessment consists of the identification of hazards, and the analysis and evaluation of their risks and the exposure to those hazards. We want to address that particular discrepancy right now.”

O’Donnell said his team thinks that this update will help with identifying patient hazards when evaluating risks, culminating in improvements in the classification of hazards, perceptions, assessments, etc.

ICH Q9 Revision Addresses New Tech

The GMP inspector’s experience with recent quality defects illustrates the importance of this revision, notably, the issue with nitrosamine contamination. 

“A revised Q9 could lead to more effective and science-based control strategies, improving consistency in manufacturing, and lowering costs, he said. “There is nothing wrong with mentioning lowering costs and reducing the likelihood of defects, recalls, and medicine shortages. We will also be trying to speak about the emergence and the use of new technologies and innovation and how the use of QRM is still very important when new technologies and innovation are being brought into manufacturing.”

As manufacturers adopt big data, automation, including robotics, O’Donnell views the ICH Q9 revision as critical.

“The use of QRM will become increasingly important when one is trying, for example, to validate those applications and those new ways of working, and things like robotics, automation, and data analytics which are based on advanced technologies,” he said.

Ultimately, O’Donnell and his colleagues who worked on the revision would like to see more risk-based oversight. 

“We are getting there, but we are going to get there more quickly, hopefully, with this revision of ICH Q9.”

Additional Resources

Taking a Risk-Based Approach to QMS

What is Risk-Based Thinking?

FDA: How Pharma Companies Are Unknowingly Introducing Risk Into Their Quality Management Systems

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