Robert Dream (1), Jeff Odum (2), José C. Menezes (3), Antonio Moreira (4)
(1) Managing Director, HDR Company LLC (2) Vice President, Biopharma Life Sciences, US for Exyte, Inc. (3) Chairman, 4Tune Engineering Ltd (4) Vice Provost, University of Maryland, Baltimore County
Abstract
Continuous manufacturing has attracted significant interest over the past decade for small molecules formulated as drug products. The case for adopting continuous manufacturing platforms for manufacturing biologics (i.e., large proteins or biologic products such as vaccines) would in principle be even more justified for both quality and business gains. These are very large molecules, complex to produce, with stringent aspects on interchangeability. Therefore, they present a considerable bigger challenge and have higher criticality in terms of manufacturing sciences and technologies, availability to patients and the regulatory processes involved. Here we briefly review continuous biomanufacturing (CBM) at a time of very high and global demand for vaccines as well as of increased demand for cell and gene therapy products.
Introduction
ISPE has recently hosted a meeting where continuous manufacturing for both small and large molecules was addressed as drug substances and formulated drug products [1]. The reader is referred to ISPE’s award winning Paper of the Year 2019 [2] and also the online ISPE meeting and recorded presentations in 2020 [1], for a broader perspective on emerging continuous and integrated platforms for recombinant proteins, a review of novel technologies to enable continuous manufacturing of biologics, and specific analytics considerations for continuous biomanufacturing (CBM). There is a well-established “business case” and significant support from the US FDA as CBM is seen as a very effective way to ensure product supply, mitigate drug shortages, and more recently for shoring operations close to drug product demand with significant shorter and more resilient supply chains [3]. A recent report [4] indicates that the demand for continuous bioprocessing is increasing and expenditures in both upstream and downstream continuous bioprocessing equipment are among the top three new expenditures by the companies surveyed. In this article, we focus on the drivers for moving to a CBM platform and on providing updates in a more compact view about technical aspects. Our aim is to provide insights into lifecycle and regulatory considerations and the potential for continuous manufacturing in emergency preparedness and rapid response efforts.
Design and Operation Considerations: need for clarity on terminology and modalities
Continuous manufacturing represents the highest level of integrated design and processing currently available in biomanufacturing (Figure 1). The different modalities that map out the boundaries of possible Upstream Process (USP) and Downstream Process (DSP) designs vary in terms of end-to-end (E2E) integration and the seamless operability integration of USP and DSP components. Several in-between modalities are defined, especially if USP or DSP are treated separately. Figure 1 attempts to define CBM in terms of other designs and clarify the distinction to modular or integrated designs.
Figure 1– Design and Operation Considerations
The Drivers for Moving to a Continuous Biomanufacturing Platform
Continuous manufacturing of biologic products has a number of promising “paradigm shifts” that make the prospect attractive to many organizations but there are also sources of resistance that can be identified. Table 1 summarizes some key factors to take into consideration when evaluating if CBM is a feasible platform for your specific application.
Table 1. “Should you or should you not” commit to CBM Platforms?
Table 2 provides just one example of the benefits of moving to a continuous manufacturing platform. Improvements in facility area reduction, increase in upstream productivity, downstream column size reduction, and reduced buffer usage are just some of the benefits that can be realized when CBM is implemented.
Table 2. Upstream Productivity Increases Impact Process Area
Example from a flexible facility concept with 300 kg annual capacity
Implementing New Technologies
How organizations choose to implement a new technology is based on their business, operational, risk, and market strategies. Generally, all industries fall into one of the five categories shown on the X-axis of Figure 2.
Figure 2 – The Law of Diffusion of Innovations [5]
A company’s decision to implement a CBM process will be somewhat influenced by this basic principle. The black arrow represents where the current movement to continuous manufacturing seems to be for both pharmaceutical and biological products. The red arrow represents where disruptive technologies, single use systems and digital sensors, are perceived to be in today’s manufacturing environment. While one may not be totally aligned to these advances, the point of implementation can be seen (Box 1).
If continuous manufacturing is implemented, the impact on any new facility assets should also be factored into the decision process. Reduced facility footprint due to smaller/less equipment needs can result in facility cost savings. The Business Case will also include discussion around scale of operations and whether the process can be “right sized” in critical unit operations, such as chromatography, to produce the desired outputs while controlling aspects such as column sizing, resin selection, and resin utilization. Resin storage and inventory can be reduced, thus improving the Business Case as well. A change of this magnitude will disrupt significantly the current cadence of day-to-day manufacturing. This cadence has a number of elements that must be addressed. USP and DSP unit operations are required to be scheduled in advance as well as robust production planning. These will ensure long-term operational integrity and allow leaner start-up and shutdown sequences in terms of volumetric productivity, product quality, and contamination safeguards.
Many manufacturing processes are initially developed in a batch-driven mode of operations, and subsequently “transferred” to a CBM platform. When implementing a new manufacturing strategy, there must be a plan. This plan must have some key elements that render it able to address questions that will be asked both internally and during the external regulatory review.
A key driver of continuous manufacturing implementation is the opportunity to reduce the cost of goods (COGS). CBM will allow one to make more product faster with lower capital costs and less operator intervention. For example, a company could make more material by using the N-1 bioreactors in perfusion mode rather than the N bioreactors in batch mode. A new capital facility could be less expensive to build by only installing an N-1 perfusion mode bioreactor configuration. Continuous manufacturing also has positive impacts in reducing the risk of contamination over successive campaigns since DSP resin lifetime could be consumed during a single campaign, allowing for timing of new campaigns and resin replacements.
If the answers to all the questions posed by activities A through G shown in Box 1 result in a positive response, then the decision to implement a continuous manufacturing platform should be strongly investigated and serious consideration given to its implementation.
Box 1. How well will your organization address these questions?
Continuous Biomanufacturing Platform and Regulatory Requirements
Current regulations and guidelines are supportive of innovative biopharmaceutical development and manufacturing approaches. Although continuous manufacture is not specifically addressed in guidelines, it fits well into the “enhanced approach”. Some of the points that are intertwined and integrated into continuous manufacturing that do improve on regulatory compliance are:
- High purity cell lines
- Chemically defined media
- Optimized and stable buffers
- Universal, standardized platform (various proteins)
- Steady State (metabolism)
- Closed system (minimized microbial issues)
- No scale-up (same scale from pilot to commercial manufacturing – scale-out)
- Compatible with disposable technology
- Minimized hold time (Eliminate hold tanks and non-essential equipment – improved stability for labile products)
- Continuous flow (minimized residence time)
- High volumetric productivity
- Integrated, modular, simplified operation
- Flexible capacity increase/decrease (within the operating range then scale-out, if desired)
CBM platforms have a small footprint (as shown diagrammatically in Figure 3) with feedback-feedforward control that allows for collecting data on the operation/manufacturing process continuously. The importance of Process Analytical Technology (PAT) as the main enabler of a robust monitoring and control strategy for continuous manufacturing has been delineated in recent publications [2, 7]. PAT can support the implementation of continuous manufacturing throughout the entire life cycle. This will provide a state of control of the manufacturing process at all times [2], namely:
- Productivity (Cell growth and apoptosis, and all Critical Material Attributes (CMAs) and Critical Process Parameters (CPPs))
- Quality (Critical Quality Attributes (CQAs))
- Flexibility
- Cost (reduced: equipment and equipment size, footprint, operational services)
- Simplicity
- Mobility (operate at any site near patients)
- Standardization (a technology platform, minimize design and validation)
When capacity demand increases, manufacturing requirements will be accomplished via scale-out (i.e., by repeating the same line over). Building an additional production line with the same specifications allows for a quicker design and build, as well as it simplifies the commissioning, qualification, and validation activities. One can utilize existing protocols and know how (from base line) to document and execute all needed requirements. It may be faster going through regulatory approvals since no drastic changes have been made.
Figure 3 – The future use of CBM platforms in multi-product facilities [2, 6]
The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has initiated the development of a new guidance (ICH Q13) on the topic of Continuous Manufacturing of Drug Substances and Drug Products. Currently projected to reach adoption as a final guideline in November of 2022, this guide will:
- capture key technical and regulatory considerations that promote harmonization, including certain CGMP elements specific to continuous manufacturing
- allow drug manufacturers to employ flexible approaches to develop, implement, or integrate continuous manufacturing for the manufacture – drug substances and drug products – of small molecules and therapeutic proteins for new and existing products, and
- provide guidance to industry and regulatory agencies regarding regulatory expectations on the development, implementation, and assessment of continuous manufacturing technologies used in the manufacture of drug substances and drug products.
The ICH Q13 position paper (8) states: “There is a general consensus that continuous manufacturing (CM) has potential for improving the efficiency, agility, and flexibility of drug substance and drug product manufacturing. Regulatory agencies have seen more companies engaged in the development and implementation of CM in recent years than in the past. Although current regulatory frameworks allow for commercialization of products using CM technology, a lack of regulatory guidelines can make implementation, regulatory approval, and lifecycle management challenging, particularly for products intended for commercialization internationally. An ICH guideline would facilitate international harmonization and could reduce barriers to the adoption of CM technology.”
Table 3 captures from a regulatory considerations landscape point of view the future opportunities for impacting the scientific understanding of the use of continuous manufacturing technologies for the production of biologic molecules.
Table 3. Future Opportunities for Large Molecules
(a) Definition of batch size should be stated prior to manufacture. A specific quantity of material produced in a process or series of processes so that it is expected to be homogeneous within specified limits. In the case of continuous production, a batch may correspond to a defined fraction of the production. The batch size can be defined either by a fixed quantity or by the amount produced in a fixed time interval
(b) Raw Material (general term used to denote starting materials, reagents, and solvents intended for use in the production of intermediates or drug substance-drug product).
(c) EudraLex Volume 2B; Notice to Applicants and Regulatory Guidelines for Medicinal Products for Human Use. Presentation and format of the dossier Common Technical Document (CTD)); Differences to a batch process
(d) Manufacturing process produces product of intended quality in a reproducible way (batch process)
(e) Discussed during a pre-approval inspection (GMP)
(f) Guidance (ICH)
A number of issues in the regulatory domain require resolution in order to make CBM a viable technology platform for the manufacture of large molecules. These include:
- Differences from batch manufacture: many CBM related definitions and terminologies require further clarification and explanation in the regulatory context.
- Definitions of continuous manufacturing: e.g., startup/shutdown, state of control, process qualification and validation, and continuous process verification, etc.
- Harmonizing regulatory common understanding and consistent usage of terminology across different regions will lead to improved communication among stakeholders.
- Establishing key scientific approaches for continuous manufacturing; fundamental scientific approaches for continuous manufacturing may differ from those encountered in batch processes, e.g., concepts of system dynamics, monitoring frequency, detection and removal of non-conforming material, material traceability, process models, and advanced process controls.
- A common understanding of scientific approaches will facilitate consistent science, risk-based implementation, and regulatory assessment of continuous manufacturing across different regions.
- Identifying regulatory expectations related to continuous manufacturing: harmonized regulatory expectations for approval and aspects of lifecycle management that are pertinent to continuous manufacturing can facilitate the adoption of continuous manufacturing and result in consistent regulatory assessment and oversight.
- Given the technology and manufacturing of drug substances and drug products for therapeutic proteins, new and existing products need to be addressed. The regulatory expectations with respect to marketing applications and post-approval changes, site implementation, and biopharmaceutical quality systems need to be addressed as well.
Conclusions
Continuous manufacturing represents the highest level of integrated design and processing currently available. These qualities enable unique functionality and platforms that are potentially capable of rapid deployment and of delivering agile and accelerated timelines from development to on-demand manufacturing. The drivers for adoption of CBM relate to improved productivity, reduced plant footprint and overall CAPEX/OPEX, many of which are favorable lifecycle considerations. All these come at the cost of more sophistication (i.e., supervisory controls) to enable consistent quality and in-process continued verification. Regulatory considerations for biologics are a level higher than for small molecules. As such companies considering CBM platforms must be ready to support their applications with robust control strategies that are very sound in evidence-based considerations as well as risk-based justifications. Though CBM is not suited for all companies and may only be advantageous to specific products in a portfolio, the future seems quite promising for those committing to enable faster response times to global emergencies and to improved drug product availability (i.e., supply reliability and patient access). As demonstrated in the recent ISPE meeting [1] continuous manufacturing and CBM will contribute to shape pharma and biopharma as true bio-industry 4.0 technologies given the level of science, technology, automation and knowledge management involved and required for their effective deployment. It will be fascinating to witness what the future holds in this regard!
References
[1] Continuous Manufacturing Virtual Workshop. A New Decade for Continuous Manufacturing: Current Landscape and Future Opportunities. ISPE June 3rd & 4th 2020.
[2] Dream R, Herwig C, Pelletier E, CM. Biotech Processes – Challenges for Implementation, Pharm. Eng., November-December 2018. https://ispe.org/pharmaceutical-engineering/november-december-2018/continuous-manufacturing-biotech-processes
[3] Lee S, O’Connor T, Yang X, Cruz C, Chatterjee S, Madurawe R, Moore C,, Yu L, Woodcock J (2015). Modernizing Pharmaceutical Manufacturing: from Batch to Continuous Production. J Phar. Innov. 10(3),191-199. DOI: 10.1007/s12247-015-9215-8
[4] Langer E, et al., 17th Annual Report and Survey on Biopharmaceutical Manufacturing Capacity and Production, April 2020, 527 pages (see www.bioplanassociates.com/17th).
[5] “Diffusion of Innovations”, Corporate Finance Institute, 2019 CFI Education.
[6] Dream R, “Integrated Continuous Bioprocessing: An Implementation Approach”; The Bioprocessing Summit, Boston, MA, August 14, 2018.
[7] Dahlgren G, Macias K, Moreira A, Thompson D, Herwig C, Dream R, Quality and Regulatory Solutions for PAT in Continuous Manufacturing, Pharm. Eng., September-October 2020. https://ispe.org/pharmaceutical-engineering/september-october-2020/quality-regulatory-solutions-pat-continuous
[8] ICH Q13 EWG – Continuous Manufacturing of Drug Substances and Drug Products, Final Concept Paper, dated 14 November 2018. https://www.ich.org/page/quality-guidelines.
[9] EU GMP Annex 17: Real Time Release Testing and Parametric Release, https://www.gmp-compliance.org/guidelines/gmp-guideline/eu-gmp-annex-17-real-time-release-testing-and-parametric-release
[10] EudraLex – Volume 2 – Pharmaceutical legislation on notice to applicants and regulatory guidelines for medicinal products for human use, https://ec.europa.eu/health/documents/eudralex/vol-2_en
[11] EudraLex – Volume 4 –Good Manufacturing Practice (GMP) Guidelines Part II – Basic Requirements for Active Substances used as Starting Materials, https://ec.europa.eu/health/documents/eudralex/vol-4_en
[12] ICH Q5D – Derivation and Characterization of Cell Substrates Used for Production of Biotechnological/Biological Products, https://database.ich.org/sites/default/files/Q5D%20Guideline.pdf
