ISPE holds “Expert Xchange: Regulatory Summit on ICH Q9 Revision”

The ICH Q9 guideline, first published in 2005 by the International Council for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH), described the science and risk-based approaches to drug product, drug substance development, and manufacturing during the product lifecycle. ICH Q9 also was instrumental in introducing quality risk management approaches to industry and regulators.

A draft of the revised version, ICH Q9(R1), was issued in November 2021 and made available for public comment. Important questions were raised during the public comment period, including those submitted by ISPE.

ISPE’s “Expert Xchange: Regulatory Summit on ICH Q9” aimed at providing an understanding of key focus areas of ICH Q9(R1) and its implementation as well as the understanding of risk assessment, application of QRM, and how the revised ICH Q9 guidelines can help improve communication with regulators. During the Summit, members of the EWG clarified and qualified ICH Q9(R1)’s content as well as explained recent changes to the draft version made in response to public comments. The Summit program included presentations, breakout sessions, and a discussion panel with regulators and members of the EWG focused on practical implementation of the key focus areas of ICHQ9(R1): subjectivity; product availability, formality versus informality in risk assessment; decision-making; digitization, and new technology/modalities.

Highlights of the “Expert Xchange: Regulatory Summit on ICH Q9 Revision”

Attendees were welcomed by John Groskoph, Pfizer, and Alice Redmond, CAI, who offered an introduction and thanked participants, presenters, and panelists for their attendance.

The program kicked-off with a presentation by Kevin O’Donnell of the Irish Health Authority (HPRA) and a member of the ICH Q9(R1) EWG. O’Donnell provided an overview of the outcomes from the recent EWG meeting in Athens, Greece and provided a detailed explanation of comments submitted by industry, especially by ISPE members. Many of the suggestions made by industry will be incorporated into the final version, and others are expected to be reflected in the accompanying examples.

The program continued with a presentation by Christine M. V. Moore, PhD, Executive Director, External Advocacy & Policy, Organon, titled “An Industry Perspective of the ICH Q9(R1) Step 2 Draft.” Moore began by saying that everyone might not be aware of the history and the “broad reach” of ICH, or of its full process and the original goals of ICH Q9. ICH began decades ago, she said, with the U.S., the European Union and Japan as original members. However, the regulatory members of ICH have now expanded to 12 members and 18 “observers.”

She explained how ICH employs step-by-step processes that starts with a concept paper and an approved business plan before an Expert Working Group is formed to develop the documents, which when approved are sent out to ICH and regulatory authorities for consultation. ICH Q9(R1) is at the draft stage now and it is expected to be finalized and then proceed to training and implementation.

“This provides an interesting opportunity for industry to get involved and submit comments,” she said.

Moore identified the scope of ICH Q9(R1) and its areas for revision including subjectivity, formality, risk assessment, product availability, risk-based decision-making, and management of risk over the product’s life cycle.

In her presentation, Moore provided both an overview of the content of the draft, and industry reaction to it, based on publicly available comments submitted to the European Medicines Agency (EMA). She said she learned a lot by the excellent comments that came into the EMA. For example, many industry respondents agreed that “formality” in risk assessment should include a sliding scale or a spectrum, however, more examples of formality were requested. Industry respondents also stated that not all risk management activities need to be documented, especially for less formal risk assessment activities. Clarity was also requested on how complexity ties with uncertainty and formality Finally, industry respondents recommended “shifting” the risk discussion to a patient benefit perspective.

Moore then presented four examples developed by ISPE members and submitted to the ICH Q9(R1) EWG as potential training material.

Example # 1 looked at “New Product Development QRM for Process Design” and laid out strategies for QRM to develop a commercial control strategy.

Example #2 offered information on “Clinical Supply Risk Assessment” to evaluate the use of a clinical material site for commercial production under an urgent health crisis. The example laid out a systematic approach, including creating cross-functional SME teams, addressing subjectivity, adding an ‘objective’ team member from a different discipline to be an independent voice, challenging assumptions in formulating risk questions, and determining the formality involved on decision-making.

Example #3 addressed “Risk Management in Equipment and Supplier Selection” and explained ranking risk in several categories from “high” to “medium” to “low” based on criticality. Management oversight would be adjusted based on the outcome of the assessment.

Example #4 examined “Drug Availability Risk Management” which begins with identifying priority products based on therapeutic importance, regulatory requirements, and business significance. Nodal analysis is recommended for each manufacturing material, component, and site. Preventative measures to reduce risk should be put into place to mitigate risks to an acceptable level, followed by periodic review and updates for incorporating changes to product, operations, or the market.

Moore concluded that there were no “showstopper” issues in the draft ICH Q9(R1). The document, once finalized, has the potential to increase general understanding of risk management principles by both industry and regulators. Practical examples, such as those prepared by the ISPE team will help with understanding and implementation of the final revised guideline to support QRM throughout product lifecycle.

“ISPE will continue to be on the forefront of Quality Risk Management in pharmaceutical manufacturing and supply and will continue to support industry and regulators,” she said.

Breakout Groups: Discussion and Conclusions

In breakout sessions, conference participants discussed issues related to the ICH Q9 Revision. Topics in the six groups included: subjectivity in risk identification and management; product availability; decision-making; formality vs. informality in applying QRM; hazard (as opposed to risk) identification; and new technologies and innovation. Breakout group moderators reported the results of their discussions back to the full, reconvened conference.

Topic 1 “Subjectivity” (Moderator: Rosemary Orciari, Pfizer)

This group explored ideas of how to reduce subjectivity in risk analysis. Starting with the realization that some subjectivity will always be present, the group suggested that subjectivity may be reduced by:

• Making clear the risk problem statement
• Bringing the right “level of knowledge” to support decision-making, by employing cross-functional teams
• Including the appropriate “range of expertise,” which included bringing in the right SMEs

While it was also suggested that using “subjectivity risk scoring methods” may be useful, having the risk statement correct was of primary importance.

Topic 2 “Product Availability” (Moderator: Diane Hustead, Merck)

The group recognized that the COVID-19 pandemic illustrated supply complexity well as clarified supply chain risk. ICH Q9(R1) offers an opportunity to improve product availability but that it is difficult to have redundancy for every supply chain “node.”

Given these realities, companies with interactions along the supply chain (MAH holders, CMOs, API developers and packagers) should develop their own supply chain risk management plans.

Topic 3 “Formality vs. Informality” (Moderator: Chris Potter, ISPE Advisor)

The group established that while there is no definition for “formality,” it is relatively easy to have procedure for high formality when initiating QRM; however, it is not so easy to demonstrate, find an approach for, and offer guidance for, “low formality.” QRM training could include examples of formality and informality. They suggested that:

• The PQS manual could allow and give reference to formality
• Leveraging examples of each from ICH Q9(R1) could help
• Procedures employed early in development when a low level or formality is applied to determine QTPP and proposed CQAs

Topic 4 Decision-making (Moderator: Jane Duncan, AZ)

Formality levels and decision-making are linked.

• Complexity is key to levels of formality
• A step-by-step approach is needed; don’t jump to a decision
• Consider collaboration with an outside SME to facilitate the process
• Subjectivity may be over expressed if there is just on area of focus, one area of expertise
• Risks should be ranked before developing a risk statement
• Ask about risk impact in other areas of the business

Topic 5 “Hazard Identification/Risk Review” (Moderators: John Groskoph; Mette Hansen, Novo Nordisk A/S)

The group agreed that changing “risk” to “hazard” in ICH Q9(R1) was beneficial because the term hazard was “easier to work with” while the term “risk” had led to misunderstandings. The group also agreed on the importance of developing good risk questions and the right risk questions. Also important is to have strong management support and understanding for identifying hazards/risks and have a RM “mindset.”

Topic 6 “New Technologies and Innovation” (Moderators, Teresa Minero, LifeBee Digitalizing Life Sciences; Jean François Duliere, ISPE Advisor)

The moderators asked about the level of digitalization in participants’ organizations and whether they were on-going, pilot programs, just starting, or not started yet. The challenges that emerged included:

• Having sufficient data to apply to a systematic hazards model
• Lacked data integrity
• Risk analysis was not yet properly formalized
• High levels of subjectivity
• Lack of clarity on risk-based decision-making

Improvements will require:

• Data integrity “by design”
• Data availability and usability

Panel Discussion Q&A

Members of the panel included: Kevin O’Donnell, HPRA; Rick Friedman, FDA; Felipe Augusto Gomes Sales, ANVISA; Jacques Morenas, ANSM & PIC/S; and Tim Watson, Pfizer.

The discussion was facilitated by Alice Redmond and John Groskoph. Questions were generated in the breakout groups while other questions were generated by polling the global audience. Highlights of the discussion are summarized below.

Is a risk to quality a risk to patients? How can we better focus on the patient perspective?

O’Donnell said that recognizing that a risk to quality is a risk to patients is important, but that concept is challenging and, to fully recognize it and act upon it, may require medical knowledge that industry might not have. He added that over the years risk to quality has become associated with risk to patients, and that is valid so long as the quality and target profiles are focused on patients.

Friedman suggested that “linking” risk to patients is most important and should be revisited as part of risk assessment (RA) process. He agreed with O’Donnell that sometimes a clinician needs to be brought in to determine the efficacy link.

How can subjectivity be minimized?

O’Donnell said that subjectivity relates to people’s biases and the psychology of how people make decisions. Does subjectivity enter into our risk assessment efforts, he asked? He suggested revisiting past risk assessments to look for evidence subjectivity. He also suggested that subjectivity may come from scoring methods. He concluded by saying that more needs to be learned about identifying subjectivity and to think about developing training materials that help to avoid subjectivity in risk assessment.

Morenas agreed that training in identifying subjectivity is key so that we all have the same understanding of what subjectivity is, as well as linking the concepts from ICH Q9, Q10, and Q12.

Groskoph noted that with regard to subjectivity, team members bring in their own biases, even when developing the risk question. Risk questions define the “roadmap” for the team, he said, but if there is subjectivity in risk questions, it can lead down the wrong path. He asked: how do you build the right team, and what makes a good risk question?

Friedman said that team leaders need to know the competencies of their staff and that the risk question should determine the team composition. The right team for the question needs to be selected.

Watson added that a diverse staff can develop the best process and that everyone on the team should be allowed to speak their mind – all opinions should be welcomed.

O’Donnell added that a good risk question should not be too broad and that team members must find out if the question is workable.

How can companies - both large and small (without as many resources) – implement ICH Q9(R1)?

Sales said that companies should understand that risk management is a live and dynamic process. As companies progress, experts may need to be brought in to help understand the increased data.

Watson noted that guidelines, such as ICH Q9(R1), are not going to tell you what to do but, rather, tell you what to consider. Training materials must be developed for the “how to.” He suggested that ISPE could take a leadership role in providing tools to smaller companies needing to implement ICH Q9(R1).

What are the elements of formal and informal risk assessment? Should all risk assessment levels be documented?

Groskoph observed that the pharmaceutical industry is a conservative industry, one that encourages over formalized informal documentation. He asked how companies can be assured that minimum documentation around low risk situations can be acceptable.

Watson noted that while ICH Q9(R1) will discuss the elements of less formal and more formal assessments and when they might be considered, the EWG is hoping to provide examples in the training material that is being developed of what a less formal risk assessment would look like. This is an area of opportunity for organizations such as ISPE to provide additional workshops and training.

O’Donnell noted that moving away from the terms informal and formal in favor of “higher levels of formality” and “lower levels of formality” may help assure companies, and that ICH Q9(R1) provides flexibility in what lower levels of formality may look like. He also advocated the benefits of using examples and developing training materials to help industry understand how to apply lower levels of formality.

Next Summit to take place on 14 September

ISPE will present its next Expert Xchange: Regulatory Summit on 14 September 2022 which will focused on Modernizing Inspections.

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