Next-Generation Biotechnology Product Development, Manufacturing, and Control Strategies, Part 1: Upstream and Downstream Strategies

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Example of an alternating tangential-flow (ATF) technology as developed for perfusion culture systems by Refine Technology, now Repligen
(https://www.repligen.com/
technologies/xcell-atf)

Future biomanufacturing must address industry drivers, including the need for decreasing cost of goods (CoG), increasing market globalization, shortening development time for pipeline products, reducing risk to patient supply, and improving product quality. A CASSS chemistry, manufacturing, and controls (CMC) forum entitled “Next-Generation Biotechnology Product Development, Manufacturing, and Control Strategies” took place on 16–17 July 2018 in Gaithersburg, MD, to address those opportunities.

Advanced technologies include single-use bioreactors, alternating tangential-flow (ATF) systems used during fermentation, modular and closed process equipment, process analytical technologies (PAT), and other analytical systems. When used in future biomanufacturing, such systems should enable robust processing, reduce waste, increase titers, decrease nonconformances, lessen the number of required staff, and dramatically lower risks associated with technology transfers to new sites.

Implementation of single-use bags for mixing and storage of media components and buffers and single-use, presterilized bioreactors in a closed process eliminates some need for cleaning in place (CIP) and steaming in place (SIP) while reducing the risk of contamination. The ability to create modular, essentially identical manufacturing sites in different locations reduces the effort and risk of technology transfer. PAT and future analytics should enable more real-time process control and less reliance on lot-release assays. These innovations also should drive testing on manufacturing floors and reduction in the footprints of quality control laboratories. Advances in molecular modeling, cell cloning, and the biopharmaceutical industry’s ability to model processes such as column chromatography should improve titers, lessen molecular variability, and speed up process development. However, use of such novel technologies and implementation of advanced designs for future biomanufacturing sites will challenge regulatory paradigms, thus requiring partnerships with regulatory authorities as the ideals for future bioprocessing are realized.

CMC Issues
The CMC Strategy Forum series provides a venue for biotechnology and biological product discussion. These meetings focus on relevant chemistry, manufacturing, and controls (CMC) issues throughout the lifecycle of such products and thereby foster collaborative technical and regulatory interaction. The Forum strives to share information with regulatory agencies to assist them in merging good scientific and regulatory practices. Outcomes of the Forum meetings are published in this peer-reviewed journal to help assure that biopharmaceutical products manufactured in a regulated environment will continue to be safe and efficacious. The CMC Strategy Forum is organized by CASSS–Sharing Science Solutions and is supported by the US Food and Drug Administration (FDA).

Upstream Strategies: Presentations
The first forum session, “Continuous and Advances in Manufacturing: Upstream,” focused on the processing of recombinant protein products with continuous manufacturing systems (e.g., perfusion cultures) and other advances in upstream manufacturing. Such processes increasingly are adopted by manufacturers and introduced for different biological modalities. This session explored the use of advanced technologies for upstream processes and associated changes to process control strategies, including PAT applications for manufacturing biopharmaceuticals. Presenters provided case studies, which were followed by discussions about the opportunities, challenges, and solutions associated with using advances in manufacturing and control strategies for cell cultivating and harvesting.

The first presentation of this session was “Second-Generation Cell Culture Processes for Therapeutic Enzymes,” by Brian Turner (Sanofi Genzyme). The company has a long history of manufacturing recombinant enzyme therapies to treat patients with rare lysosomal storage diseases. Currently, Cerezyme (imiglucerase), Fabrazyme (agalsidase beta), and Myozyme (alglucosidase alfa) drug substances are manufactured in large stainless-steel bioreactors using a microcarrier-based perfusion technology platform developed over 25 years ago.

Second-generation process development programs have been launched to increase bioreactor productivity, simplify operations, increase process robustness, and decrease CoG to better ensure a reliable supply of products. Examples of specific improvements included the implementation of single-use technologies with smaller footprints than previous systems; use of chemically defined, animal-component–free media that support volumetric productivities >5× over the legacy perfusion process; and a more reliable ATF filter device for cell separation. Turner highlighted upcoming changes to implementation including the start-up of a single-use manufacturing facility, the resulting technology transfer, and subsequent confirmation of comparability.

The second presentation was “Next Generations Manufacturing with a Focus on Bioreactor Perfusion Technology,” by Frank V. Ritacco (Bristol-Myers Squibb). He discussed N – 1 perfusion coupled with high-inoculum fed-batch culture of Chinese hamster ovary (CHO) cells. Such manufacturing processes have been shown to increase volumetric productivity and shorten the duration of fed-batch production. Implementation of N – 1 perfusion as part of a platform process requires high-throughput screening of multiple clones and optimization of media and process parameters.

BMS has developed an N – 1 perfusion process and a series of scale-down models for N – 1 perfusion using shake flasks, cell culture tubes, and deep-well plates. Optimized scale-down models of N – 1 perfusion, coupled with Ambr15 fed-batch production microbioreactors (Sartorius Stedim), have been integrated into a high-throughput and robust workflow to enable design of experiments (DoE) and screening experiments for clone selection, media development, and parameter optimization in a platform N – 1 perfusion process for monoclonal antibody (MAb) manufacturing.

The third presentation was “Evaluation of Raman Spectroscopy for On-line Monitoring of Cell Culture Product Quality,” by Gordon Magill and Brian Horvath (Genentech, a member of the Roche Group). Horvath discussed increasing interest in the development and application of Raman spectroscopy for bioprocess monitoring and control. Although Raman methods have been used to predict cell density and conventional metabolites, limited work has been presented on using Raman to measure product titer and quality.

Magill and Horvath discussed the use of Raman spectroscopy to make on-line predictions of CHO antibody titer, charge variants, size variants, and glycan species across several products and cell lines. Products assessed included standard antibodies and complex molecular formats. Results support the utility of Raman to guide operational decisions during manufacturing. But transitioning Raman methods into a good manufacturing practice (GMP) setting requires additional work, including familiarizing regulators with such applications of the technology.

The final presentation of the session was “Upstream Manufacturing Platforms for Viral Vectors,” by Christopher Murphy (Brammer Bio). He described the rapid advancement of gene therapies and gene-modified cell therapies through clinical development — with a number of new medicines approved in the past year. Viral vectors used for such drug products are complex to manufacture, and their upstream processes involve a wide range of technologies and reagents. Murphy highlighted those upstream platforms and their scalability and discussed the management of critical raw materials required to make viral vectors.

CMC Strategy Forum July 2018 Scientific Organizing Committee
Anthony Mire-Sluis (AstraZeneca), Sarah Kennett (Genentech, a member of the Roche Group), Siddharth Advant (Celgene Corporation), Cristina Ausin-Moreno (CDER, FDA), Barry Cherney (Amgen Inc.), Steven Falcone (Sanofi), Jie He (CBER, FDA), Alexey Khrenov (CBER, FDA), Michael Tarlov (NIST-National Institute of Standards and Technology), and Kimberly Wolfram (Biogen)

Upstream Strategies: Panel Discussion
The morning session concluded with a panel discussion. Attendees of the CMC Strategy Forum were asked to discuss best practices and other aspects of the session that needed further clarity. Panelists included Brian Horvath, Nobuko Katagiri (the Center for Biologics Evaluation and Research, CBER, of the US Food and Drug Administration, FDA), Christopher Murphy, Frank Ritacco, Brian Turner, and Haoheng Yan (the FDA Center for Drug Evaluation and Research). Session topics, questions, and responses follow.

Perfusion/ATF Systems: Perfusion production processes can increase product consistency and productivity. They also shorten the cell-expansion phase because media are refreshed, thus enabling a more consistent extracellular environment over time than other production formats provide. Perfusion technology can be applied throughout a cell culture process, including production, but implementing perfusion at the N – 1 stage is an easier way to begin adopting such technology. That is because perfusion at this stage is less likely to affect the quality of a protein expressed during the production phase of cell culture, so determining comparability is not as challenging as it would be otherwise. ATF appears to be the preferred method for separating out cell debris rather than centrifugation or other systems.

Screening is particularly important for selecting a clone that fits a perfusion platform. Perfusion scale-down clone-screening models appear to offer major benefits because they allow detection of cell lines that do not respond well to perfusion in the actual ATF process. It’s important to screen clones both for productivity and to ensure production of a desired product. It is important to screen clones both for productivity and to ensure production of the desired product in the perfusion platform. For example, glycosylation can be a critical attribute that is influenced by the clone selected. So whether the clone is suitable to meet the product quality target profile (PQTP) for glycosylation as well as other CQAs must be evaluated.

Shear/Sieving Issues with ATF: Shear stress is an issue for ATF processes and can lead to a decline in cell variability and viability. It is unclear whether that is caused by stressed cells or other factors. Shear stress usually is not an issue with newer cell lines that are selected for optimal performance in ATF, but it could be a problem for older cell lines. In scale-down models, shear can be caused by increased aeration of cells. Sieving and clumping also can be problematic in ATF processes, but that depends on the specific product.

During the discussion, a question was asked about whether small-scale ATF models are predictive. Experience with small-scale models (2.5–50 L) show a similar sieving phenomenon to large-scale processes. Sieving is high at the start of a run but then decreases by day 30 (30% sieving coefficient). With sieving, changes to oligosaccharide profiles have been observed because of high cell densities and cell lysis.

Increased cell densities also can lead to fouling in ATF systems as more cells lyse. Anticlumping agents help, but fouling is inherent to the use of filters in cell culture. The only way to mitigate those issues completely is to change out filters.

Effect on Analytics from Disposable, Continuous Upstream Systems: Converting from stainless-steel to a disposable platform does not change the number and type of analytics required, but removing serum does reduce the number of analytics because serum-free media are less complex than those containing serum. Using quality by design (QbD) also reduces the amount of testing needed (e.g., supporting studies of serum proteins).

PAT and dynamic control can decrease the frequency of end-product testing and provide an opportunity to obtain high-quality data that enable companies to take proactive actions. Implementation of Raman spectroscopy into a control strategy is being evaluated. Currently, Raman methods provide results every 15 minutes, but some suppliers have faster systems.

For Raman spectroscopy, RMSC predictive model using 50 or more different measurements (e.g., amino acids, glucose, cell density and viability) is only as good as the precision of the individual assays used (typically single-digit percent of the averages).

Panelists also were asked whether process control can be relied upon in lieu of product testing and whether real-time release testing (RTRT) can be implemented based on such assurance. Real-time release requires knowledge and maintenance of the established state, which can be a difficult technical challenge. Some participants emphasized process control instead of focusing on a goal of RTRT because the latter should come only after a manufacturer has gained a thorough understanding and control of its process.

Regarding validation expectations for Raman spectroscopy or other advanced sensors, a generic approach for indirect measurement of product quality such as by measuring glucose, cell density, or similar analytes should be acceptable. For critical product-specific attributes, however, a more specific and higher-level approach might be necessary. Some panelists and session attendees thought that applying such technologies in a GMP environment would be a challenge both within a company and with regulators. They said that modeling could replace a release test, but the bioprocess industry is not at this stage yet, and the model would need stringent validation.

Advantages and Disadvantages of Using Continuous Manufacturing or Other Newer Technologies: Typically, continuous manufacturing for upstream processes involves using perfusion cultures. Perfusion processes can be implemented in different ways such as at the N – 1 stage or through an entire cell cultivation process. Hybrid systems also are being used.

Advantages: Advanced process technologies can

  • increase volumetric productivity
  • decrease costs of goods manufactured (CoGM)
  • simplify clarification within a process (with ATF)
  • provide process robustness
  • improve microbial safety
  • shorten production times (limit product degradation for labile proteins)
  • decrease footprint (scale out rather than scale up).

In addition, using a perfusion system at the N– 1 stage allows biomanufacturers to keep existing large tanks. And perfusion at that stage is easy to implement because the production stage is unchanged.

Continuous systems for large molecules are not the same as those for small molecules, but some regulators encourage even a stepwise N – 1 approach with a downstream fed-batch system if the efficiency of that system is improved and as long as product quality is not adversely affected.

Disadvantages/Challenges: Implementing a continuous upstream processes and other advanced technologies also present challenges. One of those is associated with the definition of a batch. Is a batch tied to the changeout of an ATF or drug-substance lot? How are process performance qualification (PPQ) runs performed? Where do you draw the line with a deviation in a long process? Can you bracket the impact? In general, the panel and session attendees thought that deviations in continuous batches present a risk for affecting an entire run, depending on what deviation occurs and when it’s found.

Perfusion processes also require large amounts of media because of the volumes processed. Another disadvantage is asset use. What do biomanufacturers do with steel tanks that are still useful? N – 1 perfusion system is one approach to address that issue.

Another challenge is how to purify large volumes of material and product coming from high-productivity bioreactors. Extensive development work can be required for downstream processing and must be integrated prospectively into an entire manufacturing process. Finally, disposal of large amounts of disposables also can be a problem.

What other technical or regulatory challenges are associated with advances in technologies for upstream processes? Platforms of legacy or well-known processes offer faster and efficient execution, reduced headcount, effective use of assets, fewer deviations, and simplified supply-chain management. Without substantial knowledge to rely on, using new technologies does not provide such advantages. Because regulators also are unlikely to be familiar with novel technologies, biomanufacturers using those systems could face increased regulatory questions and/or will need to submit more data in filings than manufacturers that do not use those technologies.

Material Suppliers: Biomanufacturers seldom represent a large part of a vendor’s market, so the resulting lack of influence can pose challenges for ensuring supply of unique reagents, bags, and other equipment. The vendor-selection process must be well thought out and should take into account manufacturing risks. For viral vectors, the industry needs to consider the entire supply chain (e.g., how to get supplier agreements for critical reagents such as plasmids).

Comparability: Any movement toward a more advanced process that entails major changes to a cultivation process needs a robust comparability study, which can be complex and might even require clinical trials. Comparability also must be demonstrated for long production processes to ensure that product quality remains high throughout cell cultivation, including characterization at the limit of in vitro cell age (end of production).

Other considerations include not only the number of analytical tools, but also the number of replicates, which might be beyond what is required for a simple change. One manufacturer showed minor differences but used many replicates to decrease assay variability to demonstrate the actual variability in a new process. This approach made both the European Medicines Agency (EMA) and FDA comfortable with the extent of variability, which led to a determination of comparability.

If a cell line must be changed for a marketed product, then there are higher expectations for comparability, but the need for clinical or nonclinical data would be determined case by case. One company genetically modified a cell line without changing target protein sequence and introduced changes to manufacturing process. The company chose to submit a new biologics license application (BLA) rather than show comparability (including new clinical data) as part of the comparability exercise.

Although differences between the pre- and postchange product were not discussed, the cell line was genetically modified, suggesting that some significant differences would be noted. There was general agreement that change only at the N – 1 stage is less risky on several fronts, including comparability.

Regulatory: CDER has formed an Emerging Technology Team (ETT), which can be an important mechanism for interactions with the agency on new technologies. However, each biomanufacturer should ensure that the ETT has biotechnology-specific experts because the team might not involve the relevant CMC reviewers. Feedback on such interactions with the agency has been positive. CBER also was interested in establishing an ETT-like process for CBER-regulated products. (At the time of this publication, CBER Advanced Technology Team (CATT) has been established.) The panel recommended that biomanufacturers contact the agency for advice before starting a comparability program for a major change involving a new technology because regulators often have questions in filings related to using a new technology. Discussion in industry forums such as the CMC Strategy Forum series also is highly valued.

PPQ: With advanced process changes come many opportunities for pooling to produce a drug-substance batch. Significant process characterization is needed before PPQ runs, but session participants wondered whether demonstration of a well-controlled process could replace the need for additional PPQ lots. For breakthrough products that require rapid clinical timelines, process characterization and PPQ activities also are compressed, but a path forward is not yet clear.

CMC Strategy Forum Global Steering Committee
(as of July 2018)

Siddharth Advant (Celgene Corporation), Daniela Cerqueria (ANVISA-Brazilian National Health Surveillance Agency), Yasuhiro Kishioka (PMDA-Pharmaceutical and Medical Devices Agency), Junichi Koga (Daiichi Sankyo Co., Ltd.), Steven Kozlowski (CDER, FDA), Rohin Mhatre (Biogen), Anthony Mire-Sluis (AstraZeneca), Wassim Nashabeh (F. Hoffmann-La Roche Ltd.), Ilona Reischl (BASG-Federal Office for Safety in Health Care), Anthony Ridgway (Health Canada), Nadine Ritter (Global Biotech Experts, LLC), Mark Schenerman (CMC Biotech-MAS Consulting), Thomas Schreitmüller (F. Hoffmann-La Roche Ltd.), and Karin Sewerin (BioTech Development AB)

Downstream Strategies: Presentations
The second forum session was “Continuous and Advances in Manufacturing: Downstream.” Presenters noted that continuous manufacturing techniques have been used for several years in the upstream part of biomanufacturing. For example, multiple biopharmaceutical products produced with perfusion fermentation have been approved to date. By contrast, use of continuous manufacturing techniques in downstream manufacturing processes has been much more limited. However, the technology exists to implement continuous manufacturing for clarification, initial capture, purification, and polishing.

Presenters highlighted different technology strategies. They reviewed examples of migrating legacy products to next-generation manufacturing platforms and provided early points to consider for both inclusion and exclusion in process development. Presenters shared multiple perspectives, and the panel discussion included participation of key experts and opinion leaders from regulatory agencies, academia, and industry.

The first presentation was “Regulatory Perspective on New Developments in Manufacture of Biological Products,” by Scott Nichols (CDER). He pointed out that the FDA has several initiatives and resources to support new developments in the manufacture of biotechnology products. They include the 21st century CGMP initiative, process analytical technology initiative, and the ETT.

Traditional biotechnology processes and products are prone to microbial contamination. Production processes for commercial biotechnology products are embracing new technologies that inherently and effectively control contamination through their design and application. Two such technologies, single-use systems and multicolumn chromatography, were discussed from a microbial control perspective. In addition, potential sources of contamination can be caused by improperly used or validated connectors (e.g., loose fittings, incorrect specifications, components from different suppliers, and incompatible parts). Nichols presented the FDA’s comments on recent submissions of new technologies.

The second talk was titled “Multicolumn Chromatography: A Major Step Toward Continuous Purification of Biopharmaceuticals,” by Rickey Lu (MedImmune, a member of the AstraZeneca Group). Although continuous manufacturing represents a major change in the bioprocess industry, it need not be attempted in one step. Many challenges and questions arise when biomanufacturers move from one process platform to another. Such concerns include what to do with the burden of installed capital assets, the likelihood of technical success, regulatory acceptance hurdles, and the pressures of launching new products on time. Lu described AstraZeneca’s approach to initiating the transition to continuous manufacturing by discussing the technical and business benefits of multicolumn chromatography.

Multicolumn chromatography presents an opportunity to develop and implement a technology that lends itself to connection into a fully continuous manufacturing process while also providing near-term benefits. Those benefits create a stand-alone return on investment that does not require the promise of continuous manufacturing. This stepwise approach to the implementation of continuous-enabling unit operations provides companies with the ability to develop expertise and comfort with new unit operations while reducing the technical risk and capital expense of leaping into a fully continuous process.

The third presentation was “Recent Developments in Downstream Bioprocessing: Multimodal Chromatography, Affinity Precipitation and Integrated Bioprocessing,” by Steven Cramer (Rensselaer Polytechnic Institute). He presented developments from an academic laboratory for three areas of downstream bioprocessing: multimodal chromatography, affinity precipitation, and integrated bioprocessing. For multimodal chromatography, his two main points were that subtle changes in libraries of multimodal cation- and anion-exchange ligands have noticeable effects on protein retention and selectivity; and that different selectivity trends were observed for three antibodies in four multimodal cation-exchange systems, with unique domain contributions for those MAbs. In affinity precipitation work conducted in Cramer’s laboratory, researchers showed high MAb recoveries and minimal aggregation under a proof-of-concept study with comparability to protein A. Finally, Cramer presented an efficient workflow for discovery of affinity peptides to enable integrated biomanufacturing approaches, illustrated by the rapid development of a three-step purification processes for several biological products.

The final presentation of this session was “Commercialization of an Integrated Continuous Biomanufacturing Process,” by Franqui Jimenez (Sanofi Specialty Care Operation). Sanofi has been operating continuous processes for the production of recombinant proteins for over two decades. Jimenez showed how implementation of integrated continuous processes for downstream operations that meet health authority regulations offers opportunities to formulate new approaches to efforts such as process and analytical development, facility design and validation, and operating paradigms. As the biomanufacturing industry works toward intensifying production and increasing the use of continuous operations, such approaches will become even more important.

Downstream Strategies: Panel Discussion
A question-and-answer panel discussion followed the presentations. Sarah Nilou Arden (CDER) conducted the panel, which included Steven Cramer, Franqui Jimenez, Rickey Lu, and Scott Nichols. During this session, the following topics were discussed.

Downstream Continuous Processes: “In-series” processing has been implemented and introduced at small scales, and experience has progressed in the translation of such models to large scale — especially for impurity clearance. With practical constraints, the most likely approach to date is to have a hybrid process that is product dependent. For example, if you accept that the chromatography mode dictates the type of continuous processing (e.g., mode bind–elute or gradient), then a “pseudocontinuous system” can use duplicated equipment that can be switched (e.g., using two tanks for viral inactivation). This discussion led to the consideration that scientific justification for expenditure and financial support are not there for downstream continuous processing in current commercial settings.

CMC Strategy Forum North America Scientific Organizing Committee
(as of July 2018)

Siddharth Advant (Celgene Corporation), Kristopher Barnthouse (Janssen Pharmaceuticals R&D LLC), Barry Cherney (Amgen Inc.), Fiona Cornel (Health Canada), John Dobbins (Eli Lilly and Company), Taro Fujimori (AbbVie Bioresearch Center, Inc.), Carmilia Jiménez Ramírez (Gilead Sciences, Inc.), Michael Kennedy (CBER, FDA), Sarah Kennett (Genentech, a member of the Roche Group), Joseph Kutza (MedImmune, a member of the AstraZeneca Group), Emanuela Lacana (CDER, FDA), Kimberly May (Merck & Co., Inc.), Anthony Mire-Sluis (AstraZeneca), Stefanie Pluschkell (Pfizer, Inc.), Nadine Ritter (Global Biotech Experts, LLC), Timothy Schofield (GlaxoSmithKline), Zahra Shahrokh (ZDev Consulting), Jason Starkey (Pfizer, Inc.), Andrew Weiskopf (Biogen), and Heidi Zhang (Juno Therapeutics, a Celgene Company)

Potential Advantages of Continuous Manufacturing in Downstream: Most advantages from the introduction of continuous and other novel strategies in downstream manufacturing relate to decreasing costs and risks. Continuous manufacturing enables the use of single-use chromatography skids. Other benefits include reduced column-size requirements, improved resin use (which means reduced upfront and ongoing costs), lowered buffer requirements (which helps manufacturing capacity and throughput), shortened purification times, higher productivity, decreased storage costs and cycle times, and lessened microbial risk (no storing and packing of resins). From personnel and facility perspectives, companies implementing continuous downstream processing could have fewer problems associated with large chromatographic columns.

Needs of Continuous Manufacturing in Downstream Processes: Implementation of continuous manufacturing and new technologies requires development of additional information. The panel and attendees discussed several examples:

  • Changing from batch to continuous requires comparability.
  • Complex unit operations inevitably require more monitoring than other operations.
  • Analytical methods need fast turn-around times.
  • Failure of long processes creates the need to find stop steps.
  • Materials need strong microbial control because of long continuous-processing times.

In-line/at-line analytics for downstream processing are improving. For example, dynamic light scattering analysis is evolving for industrial use. Meanwhile, testing for HCPs is much more difficult in a continuous environment, but on-line mass spectrometry might address that concern.

A good strategy for continuous manufacturing includes upfront and advanced scenario planning. Questions to consider include the following: What happens if there is an unexpected hold in a continuous process? How do we plan for holds in process validation? Similarly, how do we consider reprocessing in the event that the life of a resin was exceeded?

Careful consideration needs to be given to the range of variability observed in continuous approaches and how that translates to a robust and meaningful validation strategy. For example, the range of variability in residence time for viral inactivation should be characterized as early and as thoroughly as possible.

New models can be used to simplify the design of new processes. It would be optimal, for instance, to have a mechanistic model-based feedback control that helps operators predict what would happen in a column and to include sensors to see what is happening. That brings up again the need for the right in-line or at-line sensors. The FDA is open to modeling, but biomanufacturers need to demonstrate how models are comparable to what goes on in real cases and where the models fit into control strategies.

Definition of a Batch: Continuous manufacturing introduces the need to establish new approaches for defining where sampling happens and where a process can be stopped and material can be separated. Potential break points (or defining points) would come at stages in the process where cleaning or a change-out occurs (e.g., changing a virus filter or filling a container). Those are discrete stopping points where natural segregation can happen.

Not all continuous columns have the same flow, and surge tanks are needed. Because a process could have mixing steps, it is not always clear how a batch is defined. A good starting point for consideration is that the definition of batch is captured in both the FDA regulations and in the ICH Q7 guideline. The definition is flexible for each biomanufacturer and typically will be based on a set time or amount of material. The challenge is not in defining a batch, but rather ensuring uniform character and quality throughout a batch. That can be difficult especially in continuous systems that have time dependencies. From a regulatory perspective, what constitutes a batch must be defined prospectively, and traceability is important. A good strategy can make the difference between unnecessarily tagging affected batches or (far worse) missing batches that should be tagged. Setting a strategy that includes a mock disposition execution of accepting and rejecting material ahead of time can provide valuable feedback on what otherwise might be limits of traceability during commercial execution.

21 CFR 600.3 Definition: “Lot means that quantity of uniform material identified by the manufacturer as having been thoroughly mixed in a single vessel.”

21 CFR 210.3 Definition: (10) “Lot means a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits.”

ICH Q7 Definitions of Batch (or Lot): “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.”

Microbiology Considerations: Complex processing systems can be harder to clean than legacy systems and thus have a higher potential to become contaminated. Recently, risk assessments for new processing strategies sent to the FDA have had issues such as not including a supplier qualification strategy, a closure assessment for single-use systems, and contingency plans in the event of failures. Biomanufacturers have proposed processing in ISO-9/CNC areas when using closed systems. However, leaks can compromise entire downstream processes. So in general, microbial mapping, routine microbial monitoring at critical process points, and mitigation strategies for failures should be developed.

The industry needs a common understanding of what a closed system truly means. In general, ultrafiltration and diafiltration (UF/DF) membrane changes and resin changeover and packing tend to be open process steps, so they should occur under controlled conditions. For new technologies, a closed system tends to contain design aspects such as single-use, gamma-irradiated containers with defined ports of entry that limit microbial ingress and use validated aseptic connectors. However, hard-piped stainless-steel vessels that undergo qualified SIP cycles also can be considered closed.
In addition, companies need to consider how clinical assessments are differentiated from commercial assessments when the same processing equipment or manufacturing suites are used. A poorly controlled clinical and developmental process can compromise the microbial control of a commercial process when the same processing equipment is used. Usually, little information regarding microbial performance of clinical products is available, which elevates that risk.

Implementation of Continuous Downstream Manufacturing: Although a lot of work is going into development of continuous and next-generation processes, their implementation in downstream processes seems to be limited for now, with most solutions being hybrid or “pseudocontinuous” strategies. The panel and session attendees discussed key reasons for this lack of implementation. First, currently available systems don’t always suit what is needed (e.g., gradients or only two column setups). Second, there is a need to identify the “problem that continuous downstream processing can solve” before a company will be willing to invest. Is there no driver and only risk? If a company is starting from scratch with a new process or facility, can continuous downstream processing be of value? Third, continuous downstream processing can be hard to implement because of most companies’ apprehension about being first to adopt new technologies and the sourcing longevity risks. However, vendors are willing to support the bioprocess industry by building demonstration versions to facilitate adoption. The fourth reason for a lack of implementation is that companies must decide when to make the switch if they currently use traditional technology, given the need to invest in time, people, and facilities for such a change.

Looking Ahead
Part 2 of this article will be published in the November–December issue of BioProcess International and will focus on modeling and control strategies.

Disclaimer
The content of this manuscript reflects discussions that occurred during the CMC Strategy Forum. This document does not represent officially sanctioned FDA policy or opinions and should not be used in lieu of published FDA guidance documents, points-to-consider documents, or direct discussions with the agency.

Corresponding author Anthony Mire-Sluis is head of global quality at AstraZeneca, (anthony.mire-sluis@astrazeneca.com). Sarah Kennett is principle regulatory program sirector for biologics at Genentech, a member of the Roche Group. Siddharth Advant is executive director of biologic manufacturing at Celgene Corporation. Cristina Ausin-Moreno is a senior staff fellow at CDER, FDA. Barry Cherney is executive director of product quality at Amgen, Inc. Steven Falcone is vice president of quality at Sanofi. Jie He is a consumer safety officer at CBER, FDA. Alexey Khrenov is a biologist at CBER, FDA. Michael Tarlov is division chief at the US National Institute of Standards and Technology. Kimberly Wolfram is director of regulatory CMC at Biogen.

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