Regulatory Aspects of Global Acceptance of Continuous Manufacturing

Compared with previous manufacturing approaches, continuous manufacturing offers greater process understanding and control combined with enhanced monitoring capabilities during manufacturing. The continuous manufacturing process may also incorporate process analytics and elements of real-time release testing (RTRT). As such, this emerging technology has potential for improving efficiency and flexibility of the manufacturing process. Therefore, some pharmaceutical companies are very eager to apply continuous manufacturing, as this enables acceleration of development timelines and improvement of supply chain flexibility.

Given the innovative nature of advanced manufacturing technologies, there may be a perceived regulatory risk with the application of such new technologies like continuous manufacturing on new chemical entities (NCEs) or already commercialized products. However, several interactions over the past decade with multiple regulatory agencies across the US, Europe, Japan, and many other regions have revealed that those agencies encourage the adoption of modern manufacturing approaches. This has been clear throughout regulators’ site visits, as well as formal and informal interactions with multiple regulatory agencies across the globe.

Additionally, information presented at numerous conferences, workshops, and other scientific exchanges has highlighted robust manufacturing approaches and higher assurance of quality possible through adoption of continuous manufacturing. In the past 10 years, the value of continuous manufacturing has been supported across the industry, academia, and regulatory agencies through various forums sponsored by organizations such as ISPE, the Product Quality Research Institute, the American Institute of Chemical Engineers, the Massachusetts Institute of Technology and the Manufacturing and Crystallisation Consortium, the International Foundation–Process Analytical Chemistry, the American Association of Pharmaceutical Sciences, and others.

An examination of the currently available regulatory guidance documents, GMPs, quality systems, scientific publications, and various mechanisms for regulatory interactions as well as the increasing number of regulatory approvals with continuous manufacturing highlight that continuous manufacturing is compatible with the existing regulatory framework. Moreover, there are specific avenues for pharma manufacturers to interact with regulators to seek advice on specific continuous manufacturing questions, if needed, including the US FDA’s Emerging Technology Team (ETT), EMA’s Process Analytical Technology (PAT) team, and Japan’s Pharmaceuticals and Medical Devices Agency (PMDA) Innovative Manufacturing Technology Working Group (IMT-WG). FDA’s ETT was established in 2015 for discussions of all types of emerging technologies. FDA encouraged utilizing the ETT mechanism to discuss plans for development and commercialization of continuous manufacturing applications. EMA’s PAT team was established in 2006, and continuous manufacturing topics were considered for discussions. PMDA’s IMT-WG was established in 2016 for discussions of all types of innovative technologies, including continuous manufacturing topics.

Further, recently published regulatory guidance documents amplify the overall acceptance of continuous manufacturing. These include:

• FDA’s 2019 draft guidance for industry “Quality Considerations for Continuous Manufacturing”1
• PDMA’s 2018 provisional draft document “PMDA Views on Applying Continuous Manufacturing to Pharmaceutical Products for Industry”2
• “Points to Consider Regarding Continuous Manufacturing” from the National Institute of Health Sciences, Japan3
• “State of Control in Continuous Pharmaceutical Manufacturing,” also from the National Institute of Health Sciences, Japan4
• EMA’s 2017 “Guideline on Manufacture of the Finished Dosage Form” (EMA/CHMP/QWP/245074/2015), a non-CM-specific guidance document that includes expectations for situations in which the manufacturing processes are CM5
• The upcoming ICH Q13, “Continuous Manufacturing of Drug Substances and Drug Products”6

Case Studies

Eli Lilly’s Application of Continuous Manufacturing on NCEs

Application of continuous manufacturing at Eli Lilly and Company has focused on NCEs, mainly driven by the realization that continuous manufacturing could help accelerate the development and commercialization of new medicines. As such, the drug product chemistry, manufacturing, and controls (CMC) development has focused on use of CM for commercialization and launch of NCEs, without leveraging parallel or backup batch manufacturing process development options.

Lilly’s first product on the market manufactured with continuous manufacturing was Verzenio (abemaciclib tablets), which was approved by the FDA in 2017, and approved soon after in Europe, Japan, and multiple other countries. Verzenio is currently approved in more than 50 countries around the world.7

As Verzenio was Lilly’s first commercial implementation of continuous manufacturing for drug products, and its development took place prior to the publication of the recent continuous manufacturing-specific draft guidelines, Lilly did leverage some of the avenues mentioned previously to share plans and seek advice from regulatory agencies on various continuous manufacturing topics. Such topics included items related to:

• The approach proposed for definition of “batch”
• Equipment design
• Control strategies
• Application of existing regulatory guidelines
• Process and PAT models and what these models are used for
• RTRT plans
• Plans for process validation

In Lilly’s experience, continuous manufacturing has been globally accepted and there has been no pushback on use of continuous manufacturing for the production of pharmaceuticals. Most of regulators’ questions during marketing authorization application processes have been driven by the need to obtain clarity. This is to be expected given some of the unique aspects of continuous manufacturing that needed additional considerations. Examples of such items include:

• Clarity around commercial batch size and whether a batch size range is proposed
• Clarity regarding controls of critical steps and whether process or PAT models were used for those controls
• If process or PAT models are used, clarity of their intended purpose, as well as their planned life-cycle management approaches
• Clarity around RTRT approaches

In Lilly’s experience, it is clear that regulatory agencies are supportive of continuous manufacturing, as evidenced by the large number of countries where products manufactured with continuous manufacturing have been registered. Although existing regulatory guidelines can serve as the foundation for implementing continuous manufacturing, continuous manufacturing presents some complexities that may require unique approaches. As such, Lilly’ experience is that communication with regulators to receive feedback and guidance is essential, especially until new specific regulatory guidance on continuous manufacturing is available and the industry has more experience with continuous manufacturing filings.

In Lilly’s experience, CM has been globally accepted and there has been no pushback on use of CM for the production of pharmaceuticals.

Janssen’s Batch to Continuous Manufacturing Conversions

The current experience of Janssen is based on postapproval batch to continuous manufacturing conversions, starting with Prezista (darunavir) 600-mg tablets.

Prezista 300-mg tablets were initially approved for standard batch manufacturing in 2006 in the United States. Subsequent regulatory supplements were approved to introduce 75-, 150-, 400-, and 600-mg tablets. These dosage strengths are all made from a common blend and then compressed to the appropriate strength. Janssen selected the approved Prezista 600-mg tablets manufactured by direct compression of a dry powder blend using standard batch manufacturing equipment as a proof-of-concept candidate for the application of continuous manufacturing technology. The selection of this strength was due to the robustness and stability of the formulation and manufacturing process. Janssen’s intention was to leverage this experience and use continuous manufacturing in the development and commercialization of future projects as a preferred platform for oral solid dosage forms. In 2016, Janssen received the FDA’s first approval for the use of continuous manufacturing as an alternate process to the batch manufacturing process for Prezista 600-mg tablets.8

The switch from a batch to continuous process for a marketed product presented many regulatory challenges. The company’s strategy was to file the continuous manufacturing process as an alternate manufacturing process to the batch process to allow for supply chain flexibility. Janssen did not introduce any significant differences to the nature of the unit operations (e.g., blending, compression, and coating) used in the proposed continuous manufacturing process compared to the batch process. For manufacturability reasons, a minor adaption was required in the quantitative composition of the tablet formulation.

Janssen selected the US as the initial country to file the Prezista 600-mg continuous manufacturing process because the FDA’s ETT had the infrastructure in place to meet and discuss the continuous manufacturing strategy with Janssen.

Similar to the Lilly case, because the development of the continuous manufacturing for Prezista 600-mg tablets took place prior to the publication of continuous manufacturing-related guidance documents, Janssen interacted with the FDA early on several continuous manufacturing topics, such as:

• Demonstration of comparability of the tablets manufactured using the continuous manufacturing process to the tablets manufactured using the conventional batch process
• Definition of batch size
• Amount of required stability data
• Process validation strategy
• Elements of RTRT

Janssen used the review and approval process by the FDA to gain insights and experience, which were used for submission preparations in other regions. Janssen also conducted meetings with, or otherwise requested scientific advice from, other health authorities such as EMA (PAT), Health Canada, Swiss-medic, the Therapeutic Goods Administration of Australia, PMDA, and the Brazil National Health Surveillance Agency (ANVISA). Similar topics to those listed previously were discussed.

Given the potential impact on the quality of the product and the magnitude of the manufacturing change, the postapproval variation file was considered a “wait for approval” change (e.g., Prior Approval Supplement, Type II) in all countries.

Another case study within Janssen was the postapproval conversion in Japan of Tramcet (tramadol hydrochloride + acetaminophen) combination tab-lets from batch manufacturing to continuous manufacturing, using the wet granulation platform. Approval for this Partial Change Application (PCA) was granted by PMDA in 2019. Early and frequent interactions with PMDA were key. During the review process, the questions from PMDA mainly focused on the process parameters justification and control strategy aspects.

Janssen received approval in all countries where continuous manufacturing post-approval variation files were submitted. However, the acceptance of two different manufacturing techniques in parallel for the same product may be more challenging. Potential formulation changes may be necessary to accommodate the conversion to continuous manufacturing, thereby adding complexities to the dossier. In general, Janssen’s experience is that no differences were encountered in review timelines for the continuous manufacturing-related post-approval variations compared to conventional postapproval variations.

Lessons Learned

As can be seen from both the Lilly and Janssen experiences, it is advisable to communicate early and frequently with health authorities, at least until additional industry experience is available and CM-specific regulatory guidance documents are published. Inviting health authorities to visit continuous manufacturing sites proves to be valuable to gain mutual understanding of the proposed strategies. The additional avenues installed for regulatory interactions to seek advice on specific continuous manufacturing questions, such as FDA’s ETT, EMA’s PAT, and PMDA’s IMT-WG, encourage early engagement. The ICH Q13 Expert Working Group has made visits to early-adopter companies to learn about their implementation strategies to ensure the Q13 guidance is as practical as possible.

Overall, the companies’ experience has been that regulators are supportive of innovation as the global acceptance and understanding of continuous manufacturing increases rapidly. Additional specific regulatory guidance on continuous manufacturing will be helpful as more experience is gained; thus, efforts like the new draft FDA guidance on continuous manufacturing, the provisional draft document from PMDA, as well as the ongoing drafting of ICH Q13 are key in the continued continuous manufacturing journey.

Considerations When Introducing Continuous Manufacturing Projects

Given the complexity of pharmaceutical development, it may be necessary to initiate product development with conventional batch processes, with the intent to pivot to continuous manufacturing processes for commercial production. For example, companies may need to consider a conversion from batch manufacturing to continuous manufacturing processes during the later stages of the development program prior to initial marketing authorization applications. Additionally, some companies may consider batch to continuous manufacturing conversion for approved products that are already on the market.

Potential changes to the formulation composition to address manufacturability considerations upon conversion to continuous manufacturing may add regulatory complexities, especially if these changes are introduced late in development, or as a postapproval change. Similarly, changes to the main manufacturing platform as part of the batch to continuous manufacturing conversion may introduce complexities as well (e.g., changes from dry to wet manufacturing platforms). While initially not applicable to continuous manufacturing, the 1995 US FDA guideline on scale-up and postapproval changes (SUPAC) for immediate-release (IR) OSD forms9 may be consulted to assess the level of changes and justification that needs to be provided.

Based on the case studies, it is advisable that companies carefully assess the potential formulation or main manufacturing platform changes as part of the process conversion, as well as the time of introduction of continuous manufacturing. In general, the earlier changes can be introduced, the easier it will be to build a suitable package to justify the conversion to continuous manufacturing, including considerations involving in vivo performance or stability data packages of the drug product. Science- and risk-based approaches should be leveraged in these cases. Additionally, early dialogue with regulators to seek advice in such cases may be warranted, at least until additional industry experience is gained, and continuous manufacturing-specific regulatory guidance documents are made available.

Guidance Documents

The upcoming ICH Q13 guideline, “Continuous Manufacturing of Drug Substances and Drug Products,” is intended to describe scientific and regulatory considerations for development, implementation, assessment, and life-cycle management of continuous manufacturing processes. It will build upon the existing ICH guidelines, many of which remain relevant to continuous manufacturing, by adding clarifications and additional scientific and regulatory considerations specific to continuous manufacturing. ICH Q13 will facilitate international harmonization of regulatory expectations and could reduce barriers to the adoption of continuous manufacturing technology across regions. It will encompass drug substances, and drug products in both the chemical entities (small molecules), and therapeutic proteins (biologics) domains for both NCEs and approved products. From the published final concept paper,6 it can be seen that the upcoming ICH Q13 guideline will cover aspects such as continuous manufacturing-specific definitions and regulatory concepts (e.g., start-up/shutdown, state of control), key scientific approaches (e.g., material traceability, detection and diversion of nonconforming material, process models), and regulatory expectations with regard to initial marketing applications and batch to continuous manufacturing conversions.

As noted earlier, the US FDA published a draft guidance, “Quality Considerations for Continuous Manufacturing: Guidance for Industry,” in 2019.1 This guidance delineates in detail the quality system considerations for continuous manufacturing, such as control strategy and process validation. Although it is a document in draft stage, it provides valuable detail in all aspects of continuous manufacturing implementation, from input material control to regulatory filing considerations, with important technological concepts described in between.

In Japan, the published provisional draft of “PMDA Views on Applying Continuous Manufacturing to Pharmaceutical Products for Industry”2 provides insights for OSD small molecules on the following continuous manufacturing-specific aspects: control strategy, batch definition, validation, and stability testing. The two publications from the National Institute of Health Sciences, Japan, mentioned earlier3^, 4 provide additional details on continuous manufacturing-specific aspects such as understanding of process dynamics, handling of products obtained during process disturbance, and understanding steady state versus state of control.

These guidelines were preceded by ASTM E2968-14: Standard Guide for Application of Continuous Processing in the Pharmaceutical Industry.10 This standard aimed to present key concepts and principles related to continuous manufacturing and its implementation, while focusing on definitions of terms and concepts such as feedback/forward control, process dynamics and operational aspects, process design and quality assessment and quality control.

While the application of RTRT is optional with continuous manufacturing, the integrated and data-rich intensity nature of continuous manufacturing processes can facilitate the adoption of RTRT. An important element of RTRT may be near-infrared spectroscopy (NIR), one of the major techniques applied in PAT. Several regulatory guidance documents relevant to PAT are available, including FDA’s 2015 draft guidance document “Development and Submission of Near Infrared Analytical Procedures,” 11 as well as FDA’s 2004 guidance for industry on PAT.12 In Europe, there are also relevant guidance documents.13^, 14 In Japan, the 2014 Sakura Bloom example for registering RTRT provides insight into the content of the pharmaceutical development section of a Common Technical Document when the drug product is developed using elements of the quality by design methodology, where RTRT and PAT are applied.15

Conclusion

Continuous manufacturing is a globally accepted manufacturing technology, which is being achieved without unexpected regulatory hurdles, for both NCEs and postapproval batch to continuous manufacturing conversions. Although initial cases for application of continuous manufacturing to produce pharmaceuticals required additional efforts by regulators and the industry to enhance understanding and gain alignment on approaches, more products are now being approved with continuous manufacturing in multiple markets, indicating continued global acceptability and support. Where the current continuous manufacturing experience is focused on OSD forms for small molecules, there are opportunities for continuous manufacturing in other classifications, such as for drug substances, generics, over-the-counter products, as well as continuous manufacturing by contract manufacturers. Ongoing activities in creating and updating continuous manufacturing-specific regulatory guidance documents are highlighting the support of regulators and their interest in seeing more adoption of continuous manufacturing going forward. Efforts like the finalization of FDA’s guidance on continuous manufacturing, continued publications of Japanese continuous manufacturing-specific guidelines, as well as the adoption of ICH Q13 will be key milestones in the pharmaceutical industry’s journey with continuous manufacturing.

Acknowledgments

The authors acknowledge Gabriella Dahlgren, Janssen; Atul Dubey, United States Pharmacopeia; William F. Kluttz, Lilly; Leslie Weiss, Janssen; and Willi Simmler, Janssen.