ICH Released The Final Q13 Guideline For Continuous Manufacturing — Here's What It Means

By Nathan Parker, Principal Consultant, Parker Biopharmaceutical Consulting

On Nov. 16, 2022, the International Council for Harmonisation (ICH) adopted the Q13 guideline for Continuous Manufacturing of Drug Substances and Drug Products.¹ The guideline expands on the FDA Center for Drug Evaluation and Research's (CDER) draft guidance from February 2019, Quality Considerations for Continuous Manufacturing,² and more directly includes therapeutic proteins. The FDA has been promoting continuous manufacturing (CM) for some time as a way for industry to realize value from improved process understanding and control — as described in ICH Q8, Q9, and Q10 — while also benefiting patients. This new ICH guideline provides an overall approach with specific examples of how to implement and file CM processes.

It also signals global excitement for continuous manufacturing, and a desire among regulators, including in the European Medicines Agency and FDA, to synchronize standards.

Why Consider Continuous Manufacturing?

In FDA’s 2019 guidance, the agency promotes CM as:

… an emerging technology that can enable pharmaceutical modernization and deliver potential benefits to both industry and patients. CM can improve pharmaceutical manufacturing by, for example, using an integrated process with fewer steps and shorter processing times; requiring a smaller equipment footprint; supporting an enhanced development approach (e.g., quality by design (QbD) and use of process analytical technology (PAT) and models); enabling real-time product quality monitoring; and providing flexible operation to allow scale-up, scale-down, and scale-out to accommodate changing supply demands. We also expect that this operational flexibility may decrease the need for some post approval regulatory submissions. Therefore, FDA expects that adopting CM for pharmaceutical production will reduce drug product quality issues, lower manufacturing costs, and improve availability of quality medicines to patients.

The FDA further supported the value of CM through publication of an audit that was conducted to compare approval times and initial market release.³ From this audit, it was concluded that CM processes had faster approval times of up to three to eight months and made it to market four to 12 month faster than the comparator batch processes. These faster times were used to support conclusions that CM processes did not present any new regulatory constraints that would complicate the approval process and that CM potentially provides for monetary value by being able to bring products to market faster and realize a longer period of market exclusivity.

The new ICH Q13 guideline also provides support for CM by suggesting it can simplify the manufacturing operation. Examples included are fewer purification steps required due to enabling process intensification in continuous therapeutic protein manufacturing, leading to reduced cycle times and reduced formation and buildup of impurities in continuous small molecule reactors. The guideline also provides a clearer path to continuous process verification based on the controls and process understanding necessary to implement continuous processing.

The following key benefits sum up the case that has been developed for CM:

• Improved process control leading to better outcomes for patients, including better quality products with fewer supply upsets.
• Less capital cost owing to the smaller equipment that can be used in CM and simplified manufacturing processes.
• Ease in scaling the manufacturing process, for example, running longer with minimal adjustments and regulatory reporting.
• Reduced approval times and overall time to market.
• It facilitates a continuous process verification approach, which could reduce validation complexity and clerical burden.

How To Implement Continuous Manufacturing

The Q13 guideline gives a good road map to implementing CM. It clearly shows how the concepts from Q8, Q9, and Q10 can be integrated into a CM process or, conversely, how Q8, Q9, and Q10 enable continuous processing. The guideline begins with describing the different modes of CM and how batches are identified. This seems to have been included to provide context to the guideline and answer one of the basic questions regarding how CM is implemented.

The body of the guideline is divided into three parts: scientific approaches, regulatory considerations, and examples. The scientific approaches section describes a methodology for implementing CM and details how typical process development steps are completed. The guideline includes how the control strategy is developed by:

• Understanding process dynamics.
• Material characterization and control.
• Equipment design and system integration.
• Process monitoring and control.
• Material traceability and diversion.
• Process modeling.

This section of the guideline describes how concepts detailed in Q8, Q9, and Q10 are integrated into the control strategy for CM. These concepts include:

• Design space.
• Process modeling.
• Risk assessments.
• Process analytical technology (PAT).
• Feed forward control.
• Real-time release testing (RTRT).

The guideline also introduces parameters more specific to continuous processing that must be understood and controlled. This includes residence time distribution (RTD) and diversion. RTD is an understanding of how material moves through the continuous process. This understanding is necessary because portions of the processing components remaining in the process unit operations shorter or longer could result in impurities or unfinished product. Diversion is a necessary step in continuous processing to avoid collection of material that does not meet requirements (e.g., during start-up or process upsets). An annex within the guideline document provides an approach to managing disturbances and how to implement a control strategy, including when material should be diverted.

The remainder of the scientific approaches section discusses how batch processes can be converted to CM and implementing changes. It categorizes change types and describes how each change type can be assessed and implemented.

The regulatory considerations section describes specific areas that should be assessed and included in the dossier for CM processes. The section covers what should be included in:

• Description of manufacturing and process controls.
• Control strategy.
• Batch description and batch size.
• Process models.
• Drug substance and drug product stability.

The regulatory considerations section also contains a helpful table describing information and data that should be included in sections of the common technical document (CTD) submission. Additionally, this part of the guideline furthers the discussion of RTD and diversion controls and how to incorporate these concepts in the regulatory documents. How RTRT can be implemented and supported for CM is also covered in this section.

The final part of the guideline provides examples of how CM processes can be developed and implemented. These examples could prove to be helpful as they give detailed process examples. The examples include continuous manufacturing of:

• Small molecule drug substance.
• Drug product tablets.
• Therapeutic protein drug substance.
• Integrated drug substance and drug product.

The first two examples are worded in a way that implies they are real-life examples, although there is no statement to that effect. So, they may be real-life examples that have been modified to more wholistically include the concepts in the guideline. The last two examples appear to be more conceptual. In any case, all the examples illustrate a path to implementing CM.

What’s Next For Continuous Manufacturing

ICH Q13 furthers the guidance for CM and should help pharmaceutical manufacturers better understand the path to continuous manufacturing. This may help pharmaceutical companies take the encouragement from FDA and others to implement it.

There is, however, still quite a bit of activation energy required to implement CM. While the audit of continuous manufacturing regulatory submissions ³ showed reduction in approval times and market introduction, the audit did not take into account the time to develop the CM process and get it to a point where it was ready for submission. To implement the controls necessary to support CM, an in-depth engineering understanding of the process is required. Additionally, advanced controls are required, which take time and money to implement. While many larger pharmaceutical companies have the technical depth and resources to support this level of understanding, small and intermediate size pharmaceutical companies and contract manufacturers may not. It will take time, effort, and focus to develop the personnel and systems necessary to reach the level of process understanding and control required.

Hopefully, the Q13 guideline and the encouragement from the FDA will lead some companies to implement CM as their platform, as it will take this level of commitment to fully realize the benefits. Likely, a company’s first continuous process will take longer and cost more. However, if through the implementation, systems and controls are developed that can be replicated for CM of other products, the overall cost and time will decrease and potentially lead to the lower costs and increased revenues touted by the proponents of CM.

As properly implemented CM brings together recent guidance on process understanding and control, which can lead to improved outcomes for patients and pharmaceutical manufacturers, it is definitely a synergistic approach that will continue to be pursued. Optimistically, this Q13 guideline will help accelerate the implementation of CM.

References:

1. ICH Harmonized Guideline, Continuous Manufacturing of Drug Substances and Drug Products Q13, 16 Nov. 2022

2. FDA Draft Guidance, Quality Considerations for Continuous Manufacturing, Feb. 2019

3. International Journal of Pharmaceutics, An audit of pharmaceutical continuous manufacturing regulatory submissions and outcomes in the US, A.C. Fisher et al., 2022

About The Author:

Nathan Parker has 26 years of progressive experience in the pharmaceutical industry including executive roles in operations and quality. With a background in chemical engineering, Nathan has supported chemical API, biologic drug substance, cell therapy, medical device, drug product, and combination product manufacturing operations. In his leadership of manufacturing and quality, he has been able to improve the efficiency and compliance within the organizations he has led. Connect with Nathan on LinkedIn.