ICH Q13 and What Is Next for Continuous Manufacturing

ICH Q13 defines CM as follows: “CM involves the continuous feeding of input materials into, the transformation of in-process materials within, and the concomitant removal of output materials from a manufacturing process.”1 Although CM technology has been around for decades, it does present some novel challenges to the pharmaceutical industry, especially when the goal is to supply therapeutics globally. This has stemmed from a lack of familiarity with the “new to pharma” technology among global regulatory bodies, or at least the perception thereof.

Meeting a New Need

Globally, there is an increased demand for new therapeutics and pressure to deliver them at a lower cost. And, as the COVID-19 pandemic has shown, being able to rapidly scale up and scale out the manufacturing process is a challenge for the pharmaceutical industry. CM has the potential to address several of these requests. Increased implementation can also help realize the other benefits inherent to CM, such as:

• Additional manufacturing options, which offer increased flexibility and faster to market development compared to traditional options, to address public health demands such as drug shortages and unmet medical needs
• More advanced controls to assure product quality, including improved robustness and manufacturing process capability
• Reduced environmental impact such as material consumption, waste generation, and reduced equipment and facility footprint

However, general guidance on CM will not address all the unmet needs for regulators and industry across different modalities and geographical regions. This article highlights the overall benefits and scope of Q13, as well as what we see as the next set of opportunities to further expand the adoption of CM across the globe.

Q13 Development Timeline

The process of drafting the new guidance document was initiated in earnest in November 2018 when the concept paper2 and business plan were endorsed. Over the next two and half years, the Expert Working Group (EWG), in collaboration with extended subteams from regulatory bodies and industry groups, crafted the guidance and had a draft ready for public commenting in July 2021.

Q13 generated significant interest. Over the next year, the EWG reviewed it and focused on reaching consensus around critical comments. An updated draft was reviewed by the EWG members and their organizations in October 2022. The timeline continued to follow what was originally proposed in the business plan: sign off (step 3) and then adoption (step 4) in November 2022. Since then, agencies have begun officially adopting the guidance, with the FDA doing so in March 2023. The European Medicines Agency (EMA) published an effective date of July 2023 and an Implementation Working Group (IWG) has been formed to develop accompanying training material.

Q13 Scope

The intent of Q13 is to build on existing ICH quality guidelines while providing clarification on CM concepts. This includes describing the scientific approaches that are unique to this manufacturing process methodology and presenting regulatory considerations that are specific to CM of drug substances and drug products, with a focus on an integrated system versus an individual continuous unit operation (which has already been employed in the pharmaceutical industry for decades).

The goal is to address the full life cycle of the manufacturing process, including development, implementation, commercial operations, and life cycle management. A key thrust of the guidance is to highlight when concepts that are unique to CM need to be part of the regulatory filing versus appropriately captured within each companies’ pharmaceutical quality system (PQS).

Overall, Q13 is focused on the “what” not the “how,” which is what manufacturers want to see to allow for product-, modality-, and company-specific approaches to be taken. However, this format can delay implementation within some companies because there is less prescriptive information on exactly how to do, or why not to do, something. Q13 seeks to enable CM while not being prescriptive and allowing for future innovation through the use of annexes that provide additional detail as far as how the specific concepts relate to small molecule drug substance, solid dose drug product, large molecule (proteins), and integrated end-to-end manufacturing processes.

Future updates to these annexes, in concert with training materials and similar public domain contributions from ISPE and others, are intended to aid adopters in defining their pathway. Because the use of CM is expected to continue to grow beyond the current most common implementation for small molecule drug product, the focus on the guidance has been on general concepts that can be applied to any technology, dosage form, or molecule type. However, this has the caveat that because small molecule drug product is the most mature CM platform, the guidance text may lean toward language and definitions for this modality; thus, some of the text may not apply to all modalities and platforms.

Due to the novelty of CM in our industry and the focus on the “what” in the guidance, it does require that each company clearly articulates how a specific approach addresses a required “what.” This is where the planned training material will become a critical aid, as it can and will highlight various approaches to meet a specific need (building on the guidance and especially the annexes). It should be noted that the guidance is focused on topics that are unique to CM, but not necessarily complementary or enabling technologies unless they are unique to CM.

Some items that are therefore out of scope of this guidance (beyond being mentioned as tools that can accompany CM) are process analytical technology (PAT), modeling, and in-depth discussion around continuous process verification. Many in the industry feel it’s critical to achieve global regulatory harmonization in some of these areas in the near future for full deployment and implementation of CM. Some of these potential bottlenecks are discussed in detail next.

Q13 Training Materials

Although the guidance document has been completed and was endorsed in January 2023, the work is not yet done. The EWG has now transformed to an IWG focused on developing training material throughout 2023 to complete the guidance in June 2024. The intent is for the training material to address the different levels of understanding of key scientific and regulatory concepts among regulators and industry stakeholders.

Presentations, video, industry-led training, regulatory-only training, and in-person training at CM facilities or labs (when possible) enable detailed dissemination and discussion of CM concepts and provide an opportunity to include practical examples to illustrate how Q13 can be applied in development, routine operation, and life cycle management of CM processes as well as potential examples of how complementary technology such as PAT and modeling is practically applied to CM.

Future Annexes and Training

Although Q13 goes a long way toward aligning global regulatory bodies and enabling the adoption of CM, there are still elements of implementation that would benefit from further support. Overall, while guidance helps with clarity on how to proceed for those who have chosen to move forward with a specific technology, there are aspects related to making the business case that remain unaddressed.

Whether using traditional batch manufacturing or CM, the final product delivered to the customer remains the same. Therefore if the bar is higher for the new technology, transition to it will remain slow, even when there are benefits to transitioning. Enabling adoption of technology is one of the driving forces for harmonization and ICH Q13.

As CM has been adopted in recent years, initially for solid dose processes, we have seen expansion and evolution of the equipment offerings to the point that we have a variety of options. Although a number of different manufacturing options exist, including different forms of wet granulation akin to traditional batch manufacturing, adoption and signals on future utilization have been primarily for direct compression processes. At the same time, as first adopters grow the number of products within their CM portfolio, network strategy decisions come into play.

Within Q13 there is very little guidance on process transfer and equivalency for CM processes. The guideline does address scale-up, but primarily from the standpoint of utilization within the same process train, or a “like-for-like.” It doesn’t really address process or equipment changes other than to say “it may be possible.” This creates a situation where technology users will either a) copy and paste the same equipment, controls strategies, PAT, etc., which limits the use of new and improved options; b) link a process to a single process train, limiting supply chain flexibility and creating risk; or c) adopt a costly strategy of what is essentially a new process development activity to move products within or in/out of network.

When considering the same situation for traditional batch manufacturing, there are guidelines like scale-up and post-approval changes (SUPAC) guidance that aid in identifying levels of change and associated chemistry, manufacturing, and controls (CMC) changes; testing; and reporting. Given the similarity in design and operating principles of continuous direct compression manufacturing trains and processes, it would benefit the adoption if the requirements for changing equipment or manufacturing site were outlined. While the extent to which this has been an obstacle presented to regulatory bodies may be small, the perception without guidance has led to an apprehension among early adopters.

With regard to network strategy, many early adopters have sought to minimize differences and to invoke a “like-for-like” strategy as outlined within the scale-up portion of ICH Q13. As already mentioned, this type of strategy limits the opportunities to make changes based on lessons learned or improvements available in the market. Additionally, it makes it more difficult to outsource manufacturing to a contract manufacturer because the like-for-like equipment may not be available even if there’s capacity on another highly similar process train.

This then makes it a more challenging situation for contract development and manufacturing organizations (CDMOs) to aid in expanding adoption (and address commercial demand), as it is not financially viable to have the like-for-like process train of multiple customers, particularly when competing against traditional batch manufacturing on price. Although there has been a push for modularity within CM systems in recent years that has been mostly embraced by equipment manufacturers, which would make it easier to modify systems to be more similar, additional guidance on equivalency would help provide clarity and ease the perception of the need for like-for-like systems.

Over the past decade or more, as CM has entered the market, there have simultaneously been significant advances in modeling techniques that can be used to develop and support product and process development. While there has been strong support for these advances from many of the leading regulatory authorities, the level to which this is addressed within ICH Q13 is quite minimal. Q13 essentially redirects to ICH Q8/Q9/Q10 implementation for regulatory expectations on process models,3 which was released more than a decade prior to Q13.

Although the ICH Q8/Q9/Q10 Implementation guide does a good job of defining the categorization of models and the corresponding requirements for their development, implementation, and reporting, some level of detail or example on what is the same and different when considering CM would be beneficial in aiding adoption. Q13 has a set of annexes that help relate the guidance elements more specifically to various implementations of CM for drug substance and drug product processes for small and large molecule. Still, there is not a great deal of emphasis on the modeling aspects within these annexes aside from residence time distributions (RTDs).

Process modeling of a process maintained under a state of control nearing steady-state operation allows for further utilization of modeling tools and models that bridge between development and process control. There have also been a number of advances in process modeling as well as PAT and real-time release modeling that could be further highlighted through a Q13 lens. There are plans to update the Q13 annexes in the future and additional emphasis on this topic with linkages to other updated or new guidance documents should be included at that time.

Conclusion

Over the course of the last decade, and even more so since the approval of the first product made by CM in 2015, there has been a significant amount of talk within the industry about the transition to the new technology. This paradigm shift has been slower than many expected at that time, with the main drivers being clarity on global regulatory expectation coupled with the fact that it didn’t enable a new class of therapies, only the manufacturing processes for existing ones.

ICH Q13 goes beyond what individual regulatory bodies (such as the FDA and the Pharmaceuticals and Medical Devices Agency [PMDA] who first published draft guidance documents) can do, by pulling the global regulatory and industrial community together to align or harmonize on the key aspects necessary for utilization of CM technology. While the work to transition the industry to this modern mode of manufacturing is not complete, ICH Q13 is a crucial step in the right direction. Especially because this will reach across the globe aiding in understanding of CM from health authorities that are less familiar with the topic to date.

The guidance will also make it feasible for smaller pharmaceutical companies that may have less internal expertise to employ this new manufacturing approach. The next phase of collaboratively developing training material to expand on the key topics in Q13 as well as complementary technology will further expand the deployment of CM as technology catches up for new modalities.