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Quality and regulatory alignment of the BioPhorum technical workstreams

BioPhorum has made significant progress over the last year and it continues to deliver benefits to its members. For example, there is a new Sustainability Phorum, an increasingly diverse webinar program, and the workstreams have delivered more than 100+ technical publications. Yet, there is always more to do.

L1 members have requested that BioPhorum becomes the ‘one voice’ of the industry and makes things happen. To do this, the idea of a quality mindset and a common cause with regulators will be critical to industry’s success. This article describes what this ‘one voice’ means for senior members and industry, particularly in the quality and regulatory space. It will discuss how it applies in practice and the importance of quality and regulatory alignment within companies and across industry. Aligned with the strategy set out through its member leaders, BioPhorum is evolving from a technical collaboration of subject matter experts (SMEs) to include a multi-function approach and means quality and regulatory principles and functions are now involved from the inception of new workstreams. Adding the quality and regulatory aspects to BioPhorum projects ‘by design’ or ‘from design’ is now an essential part of their deliverables. The benefits of this enhanced approach are starting to be realized across the biomanufacturing industry, and BioPhorum is preparing to support this approach to maximize value realization. It will not change the way workstreams operate, i.e., using a cross-industry collaboration of the best technical experts in the field to design and implement changes. However, this new focus will enhance workstream deliverables and ensure that BioPhorum-designed changes have considered the potential impact on regulatory and quality aspects and become recognized industry best practices by other industry groups, supply partners, and regulators.

“The guidelines that come out of BioPhorum need to be implementable, not something that will get pushed back by every quality or regulatory affairs team or agency,” said Philippe Baumgartner, Director of Manufacturing Sciences at Takeda. “For example, I have no doubt that from a quality standpoint, there will be no obstacle to implementing BioPhorum’s guidance on CPV and APR. The obstacles will be in software, IT, and internal processes.”

Baumgartner added that some topics would be more challenging to implement than others, such as ILM/RTR. “RTR will need a lot of careful thinking when it comes to implementation and what it means for the quality departments because it is their prerogative to release a product, not the scientists’. In that case, we’re stepping onto their field, so we must produce guidance that they feel they can follow. But part of BioPhorum’s credibility is not selling dreams but things that can be implemented.”

BioPhorum is supporting the technical workstreams through different modalities. For example, refreshing existing workstream charters, bringing the quality and regulatory functions to workstreams as ‘one of the team’, and training BioPhorum facilitators in the principles of modern quality and regulatory functions and the creation of this new workstream role.

In the next few months, BioPhorum will review these new opportunities across workstreams and with its members’ SMEs, leaders, and sponsors, build on them to make change happen, accelerate adoption, deliver higher strategic value and create industry alignment.

Desired state for BioPhorum and benefits to its members

Through these enhancements, BioPhorum is putting in place a support structure and process that ensures the global and successful implementation of the changes designed through its collaborations. Everything starts with a common vision, language, and framework, and none of these are possible in the isolation of a ‘technical bubble’, however collaborative it is.

Including the quality and regulatory functions in our workstreams ensures that the vision of the ‘endgame’ is shared. In our highly regulated industry, that endgame will always be shared with regulators for their knowledge, review and/or approval, and with standard organizations, pharmacopeias and other trade organizations for increased alignment and productivity.

Having a common language is also key to the new and enhanced process. If there are already terms and principles defined by other industry groups, standard organizations or regulatory agencies, these should be used as widely as possible. This will not only facilitate external communication but also ease the technical collaborations.

Baumgartner agreed with the importance of a common language. “I regularly engage with agencies and having that common language is a success factor. Within Takeda, it’s not too difficult to find a common language with quality and regulatory, regulatory partners and other companies. But it’s sometimes a little more difficult with authorities because not everybody is at the same level. So when you talk about things like Quality by Design, the level of understanding is different depending on who you address.”

The quality and regulatory functions are a great support to the technical SMEs by bringing the external environment to the team, e.g., industry standards already in place and their regulatory status. Quality and regulatory experts are also the ones who will be the first voice of their organizations with the regulators – either through hosting site or product inspections or by designing and writing regulatory submissions and responses to reviewers’ questions.

“When you talk about operating ‘in the zone’, whether it’s efficiency or driving value, BioPhorum allows the intersection of the SMEs for the technology and operation of drug substance with a quality mindset, recognizing that there is also compliance. So it’s not just science over compliance or compliance over science; it’s that intersection,” explained Marcella Goodnight, Senior Director at AstraZeneca. “When regulators are added through that lens, we can accelerate value to the industry.”

Finally, understanding the existing framework and context of using a new concept, way of working, manufacturing or analytical technology is essential, especially if that framework does not yet exist and needs to be built. The quality function will bring in the quality framework (e.g., through the Quality Management System, Good Manufacturing Practices, compendial and industry-recognized standards). The regulatory function will bring the regulator’s understanding and expectations for the change to ensure they can assess the impact of the change on the quality, safety, and efficacy of the product.

The phrase ‘quality mindset’ is something that BioPhorum has started using to bring even more focus to its work, especially in very technical workstreams. Sometimes, engineers and scientists might regard the quality and regulatory departments as blockers rather than allies. This will only change through education and using the correct approach to solving industry’s problems.

“Everything we do in Drug Substance workstreams is risk-based, and this is what matters to quality departments – that products are consistent and safe,” added Baumgartner. “BioPhorum makes a big difference by bringing a more pragmatic risk-based approach to certain topics, such as ILM/RTR and single-use. This delivers a key part of BioPhorum’s role, that of removing obstacles from the industry and helping us to be leaner, faster, and more pragmatic.”

Stefan Paschen, Manager of Downstream Processing Lab Scale and Troubleshooting at Roche, said the BioPhorum approach makes it more straightforward to implement solutions at a company level. “It’s easier if we have an external reference paper from BioPhorum as it allows us to show that other companies are using a certain approach. This helps us convince our quality and regulatory colleagues to move in this simplified way.”

A more holistic vision of a technical change also makes it easier to plan for success, i.e., the activities needed to ensure that the change will meet quality and regulatory expectations will be defined from the start, and a plan for the technical change can be put in place.

These activities may include:

Engagement with industry’s key opinion leaders (outside BioPhorum) and senior stakeholders (within BioPhorum) to promote the collaborative work at high-level industry conferences and in sponsor publications
Presentations and discussions at conferences attended by regulators (reviewers and inspectors) to present a change that is being defined, piloted, about to be implemented or reviewed for continuous improvement, or when direct feedback is helpful
Consensual peer-reviewed approaches developed by industry and published on the BioPhorum website or in other journals that can be referenced as a new strategy or way of working in a regulatory submission or inspection situation
Short, generic presentations that can introduce regulators to a new way of working (e.g., at a pre-submission meeting or during an inspection) or a generic response to reviewers’ questions during the review of a file using a new technology
Sharing our work with relevant groups working on the same topic, e.g., other industry groups, standard organizations, pharmacopeias, individual regulatory agencies or working together through the ICH. These groups also have expert working teams to design or refresh standards, regulations, and guidelines, and a globally endorsed industry proposal on the same topic will always be useful.

BioPhorum and its members have had great successes with this new approach, which is driving the proposed enhancements – much more than when the ‘technical bubble’ approach was used.

Case Study 1 – Raw materials

The Raw Materials Workstream has existed for several years and has delivered valuable outputs for the industry, such as A holistic approach to raw material risk assessments through industry collaboration. This aimed to:

Proactively identify risks that could contribute to the interruption of raw material sourcing, performance, and qualification that are essential to the supply of safe, efficacious, biopharmaceutical drug products
Prioritize resources in the pursuit of risk mitigation/resolutions that are proportionate to the potential for impact on patient safety and public health due to interruptions of supply.

The paper defines a raw material based on user requirements and suppliers’ expertise, material attributes and security of supply.

However, in the current pandemic situation and the challenges our supply chains face, this needed to be augmented by a regulatory and quality aspect, which is indispensable to allow flexibility of supply. This has now been addressed by the team.

Paschen said that the quality mindset had been used to adapt the approach of the Raw Materials Workstream and influence the Raw material risk assessments white paper. “Originally, it was a technical discussion; for example, what needs to be done at lab-scale to demonstrate the equivalency of a protein A resin. But we decided we wanted a different focus – not on what the technical SMEs wanted to do but to define what they needed to deliver and what the quality and regulatory functions expect from them for a filing. So we concentrated the paper on just the essential critical material attributes.”

Looking to the longer term, this approach will also enable the implementation of modern manufacturing platforms such as in-line monitoring and real-time release (ILM/RTR) and continuous processing. The enhanced approach will be described in a white paper to be published shortly that will explain how the registration of raw materials in Europe can nurture flexibility of supply.

Case Study 2 – Alternative rapid methods

The Alternative and Rapid Micro Methods (ARMM) team in the Fill Finish Phorum was formed to address the industry gap between analytical technologies that had been developed over 20 years and their poor rate of adoption in the industry. The review of the technologies by the technical SMEs demonstrated that these were ready for implementation; from a scientific point of view, they were sound, robust, and provided equivalent-to-superior results to traditional methods. The team concluded that scarce implementation was not due to technical aspects.

Engaging with the quality and regulatory functions in their organizations, the technical SMEs realized that the issues were due to ‘regulatory blockers’. This resulted in questions such as, how do we demonstrate the equivalency of technologies that do not measure the same thing? How do we collect data to demonstrate equivalency? How do we validate the new methods as an industry (not as an individual company or site) for a global and harmonized implementation?

With the support of their quality and regulatory colleagues, the ARMM team set up informal discussions with the FDA and EMA to answer these questions. It is now also working with standard organizations to move the alternative methods to an industry-standard status and will be collaborating with the Rapid Method for Adventitious Agents Workstream in the Technology Roadmapping Phorum to implement a cross-industry collaborative validation.

Following the start of collaboration with the quality and regulatory functions, the rate of adoption of ARMM went from two to 16 BioPhorum member organizations in six months.

Future opportunities

The BioPhorum regulatory vision published in 2019 aimed at ‘One product. One standard. One submission. One review’, thereby driving close collaboration across industry and between industry groups, standard organizations, regulatory agencies, and worldwide organizations. All the changes that BioPhorum is implementing are strategically aligned with this vision.

Projecting BioPhorum activities forwards to 2025, the quality and regulatory alignment of the technical workstreams would look like this:

Technical workstreams in BioPhorum work in partnership with the relevant standards organizations and/or regulatory agencies’ expert working groups to proactively solve challenges encountered when implementing new technologies (e.g., analytical methods, manufacturing platforms, ILM/RTR, continuous manufacturing from raw materials to drug product). This is enabled through a strategic alignment and shared picture between all parties, an agreed way of working for maximum benefit to all and a high speed of implementation, with the initial thinking and industry alignment achieved through the BioPhorum collaboration
Continuous strong collaboration with the quality and regulatory functions to support the teams in their interaction with external partners
Recognition that BioPhorum presents the ‘one voice’ of the biomanufacturing industry to worldwide organizations, such as the ICH.

“As well as ILM/RTR, there are discussions about protein A, especially in light of the availability of resins for the industry, and the reuse of resins for clinical consumption or how to continue to address interactable contamination issues,” added Goodnight. “When we can address these industry issues with that one voice and accelerate best-practice change for the industry, there’s a tremendous value for us to continue to provide life-saving medicines for patients.”

These BioPhorum ideas are already in action. For example, the ILM/RTR cross-Phorum team is setting itself up for future success in terms of quality and regulatory alignment, as described in the following case study.

Case study 3 – Global implementation of ILM/RTR in the biomanufacturing industry

A cross-Phorum team of SMEs has been created to develop a framework for the global implementation of ILM/RTR in the biomanufacturing industry. This will not look at the technologies required (these are already established through the BioPhorum Technology Roadmap¹, for example) but at the other contributors to the successful implementation of technologies. From a quality and regulatory alignment perspective, this includes asking questions such as:

What needs to change in the biomanufacturers’ quality management system?
How does a product control strategy need to be structured to reflect the continuous build of product quality?
How is an ILM/RTR strategy best presented in a regulatory submission for a global product?
How is an ILM/RTR strategy best presented during Good Manufacturing Practices and/or regulatory inspections?

The team is setting itself up to:

State which standards are missing from the current environment, define a parallel standards roadmap and select the best industry partners for their development and publication
Proactively work with regulatory agencies that are leading the design of regulations that will frame the implementation of ILM/RTR and have been liaising with the FDA on the registration and regulatory lifecycle management of manufacturing models² and with the Danish agency on augmented intelligence/machine learning principles³. Both topics are key enablers for the implementation of manufacturing platforms using ILM/RTR
Share with ICH the industry-wide consensual approaches that are relevant to its current Expert Working Groups (ICH Q13 and ICH Q14).

Quality and regulatory alignment

The ‘one voice’ approach is closely linked to consensus within a company and across the industry. If a document is considered best practice because it has been agreed by many in the industry, and has been run past the regulators, then there is a compelling case to start aligning how organizations and industry approach problems and implement solutions. Removing member organizations’ customized solutions to similar problems will help with quality and regulatory simplification.

“A significant benefit of this ‘one voice’ approach is that it will also help drive internal alignment with quality and regulatory teams,” said Paschen. “This will only be possible if we can align this one voice at BioPhorum and implement it internally in each company, because otherwise it wouldn’t work. For example, we might want to drive alignment for raw material qualification. We have seen through the many pandemic issues with raw material supply that qualification within and between companies is often very different. Internal and external alignment to address raw material qualification would bring huge benefits for everyone.”

Starting this alignment process needs some understanding of BioPhorum’s approach and then for everyone to collaborate. “There needs to be some awareness within your company that contributing to BioPhorum is an essential part of your success,” Paschen suggested. “This is critical if companies want to be aligned internally and with their peers and regulators, to be driving simplification. We need to keep things simple, which is why, for example, it’s essential to define the minimum viable setup that is aligned with the regulators. A company acting alone would never be able to do this.

“BioPhorum is a benchmark and adds some peer pressure on companies,” added Paschen. “If I can reference a BioPhorum paper or share team experiences, then this gives me support when trying to drive change and gives me an example of how to drive simplification.”

Conclusion

In line with its sponsors and leaders’ expectations, BioPhorum is changing to realize more value and benefits for its members. Enhanced and encouraged quality and regulatory alignment is a key contributor to this added value, the work delivered by the technical workstreams and their SMEs – all facilitated through BioPhorum.

BioPhorum’s regulatory vision provides the same strategic direction and will continue to inform potential further changes and opportunities.

Our members are driving both initiatives, and we will ensure we deliver to their expectations – this will create value for them and the whole biopharmaceutical industry.

References

¹ Biomanufacturing technology roadmap: 6. In-line monitoring and real-time release, BioPhorum, www.biophorum.com/in-line-monitoring-and-real-time-release

² How to simplify the registration and regulatory lifecycle management of models, BioPhorum, www.biophorum.com/how-to-simplify-the-registration-and-regulatory-lifecycle-management-of-models

³ Feedback to DMKA questions to critical GXP augmented intelligence, BioPhorum, www.biophorum.com/download/regulatory-feedback-to-dmka-questions-to-critical-gxp-augmented-intelligence