Feliza Mirasol

The focus on developing emerging therapies, especially cell and gene therapies, has intensified, making the need for good manufacturing practices (GMP) guidance more imperative. In its specific efforts to promote the development of novel gene therapies, FDA published six final guidance documents on gene therapy manufacturing and clinical development and released a draft guidance on gene therapy products under orphan drug regulations in January 2020. To date, the agency has approved four gene therapy products (1).

Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

(2) guidance provides a comprehensive framework to guide the development of a broad range of products, says Karen Magers, head of Regulatory Affairs Cell and Gene Therapy Technologies, Lonza. The guidance document provides many recommendations that help to clarify the expectations for product development, characterization, manufacturing, and testing of these products, she points out.

	“Stakeholders, including Lonza, submitted comments [to FDA] requesting clarification on the information to be submitted prior to a first-in-human clinical study and information to be submitted in a phased approach, as more manufacturing experience is obtained during product clinical development. FDA acknowledged in the final document that ‘information may be limited in the early phases of development and recommends that sponsors provide additional information and updates as product development proceeds’,” she states. However, because limited specific recommendations and examples were provided in the guidance, there are remaining challenges in determining the requirements for first-in-human studies and subsequent clinical studies, she continues.

	The challenges to gene therapy development and manufacturing are what they have always been. “I don’t think there is anything unexpected in the final CMC guidance,” says James Blackwell, PhD, principal consultant and president of The Windshire Group, a Boston, MA-based biopharmaceutical consulting group. “The challenges are what they have always been. However, there are numerous challenges posed in the guidance for developers.”

	Blackwell narrows down challenges his group has experienced, which will likely be the same experiences that other stakeholders in gene therapy development will also experience. First, for any combination product or potential combination gene therapy product, developers should carefully assess the available guidance and make early assessments in the program because the regulatory and documentation requirements can vary significantly for various components. “For areas of doubt, one should engage the Health Authorities early. This can be a challenging area for emerging technologies,” Blackwell says.

	Blackwell also points out that there is a higher burden, compared to traditional products, for gene therapies to understand critical attributes and parameters earlier in the development cycle while trying to establish as robust of a process as early as possible. This burden stems from the complexity of a gene therapy product. 

	“The benefits of doing so are dual. First, you minimize the need for change later and, if change is needed, you have a more solid basis for rationalizing and approaching it to minimize impact to development timelines. The latter point is always important but will be a key consideration for many of these programs,” Blackwell states.

	“Containers used for drug substance and drug product need to be closely scrutinized for products that can’t be filtered,” he continues. “The level of particulates may not be controlled as closely as needed during the manufacture of these components, and the particulates will end up in your product if not controlled or removed in advance. For some of these suppliers, a gene therapy developer represents such a small part of their overall business that the supplier will not accommodate changes deemed necessary by the developer. Particulates and their potential to cause adverse events have been the subject of increasing regulatory scrutiny.”

	The bottom line to having these gene therapy guidance documents is to facilitate not only the development and current good manufacturing practice (CGMP) compliance of gene therapies, but also the regulatory pathway to drug approval. 

	The two guidance documents (2,3) that include CMC-specific recommendations also provide clarity on many aspects related to the manufacturing and testing requirements for gene therapy products, Magers asserts. “[These] documents provide both general guidelines and specific recommendations. As an example of a general guideline, FDA provided information supporting the classification of viral vectors. Comments on the draft 

document sought this clarification. In the final version, FDA cited regulation to confirm their position that a vector ‘used to transduce cells 

and which furnishes a pharmacological activity for the treatment of disease is a critical component. Without the vector, the resulting cell product would not have the same pharmacological activity. Similarly, a vector in its final formulation for administration of the genetic material is generally considered a DP [drug product]’,” Magers cites.

	She notes that FDA gave examples of specific vector recommendations, which include replication competent retrovirus (RCR) testing of cell banks, vector-harvested material, and 

transduced cells. FDA had also given an example of the derivation in its recommendation for an appropriate test volume for RCR detection.

	At present, there are still hurdles to overcome in the manufacturing of gene therapies, and a number of biopharmaceutical companies as well as contract manufacturing organizations/contract development and manufacturing organizations are tackling these challenges. 

	For one, gene therapy (and cell therapy) manufacturing is still a highly manual aseptic manufacturing process, which poses several challenges, says Magers. It is important to consider the correct and functional layout of cleanrooms and the number of trained operators needed for those cleanrooms, she points out. She also emphasizes the high importance of ensuring the qualification of sterile consumables and raw materials because, often, only research-grade material is available and there is no GMP material available to replace them when manufacturing is scaled up. 

	“We are also observing a high investment in infrastructure and facilities in contrast to low throughput areas (personalized medicine, small batch sizes-down to one batch per patient), as well as unclear expectations for concurrent manufacturing of several batches and product segregation strategies,” Magers notes.

	Navigating the regulatory landscape and complying with regulations can be difficult as an international manufacturer, Magers also observes. “There are three main regulatory systems: European Union (EU) GMP regulations, United States (US) GMP regulations, and Pharmaceutical Inspection Co-operation Scheme (PIC/S) regulations,” she states. “The new 

Good Manufacturing Practice Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products

(EU GMP part IV) (4) does not provide the most straightforward guidance and expectations. Moreover, it refers to risk management, which is not easy to navigate, as the perception of risk is subjective to a certain extent.”

	Magers also points out that these new EU guidelines exclude the link and reference to GMPs for other pharmaceuticals, including in 

Annex 1, Manufacture of Sterile Medicinal Products (Corrected Version)

(5). “However, the PIC/S and the US will not adapt to this move. Therefore, the ‘classical’ pharmaceutical regulations apply to products that will be licensed in those regions. Furthermore, many countries are part of more than one of these regulatory systems (e.g., EU GMP and PIC/S, US regulations and PIC/S); navigating through expectations from different regulatory bodies will soon arise and need to be complied with,” she adds.

	“I think one of the biggest challenges will be the complexity of the supply chain demands, both on the front end (starting with supply of materials or patient samples) and back-end (delivery to the patient),” observes Blackwell. 

	“Some of these products and technologies use relatively novel materials, and the suppliers are not mature from the standpoint of their manufacturing processes and quality systems. In some cases, the sponsor will need to help the supplier and improve and reduce risk. The bar keeps getting raised as the products enter Phase III and commercial manufacturing. So how these critical components will be sourced in a compliant manner needs to be assessed early in development and planned for with risk-reduction strategies,” Blackwell adds.

	Further, the definition of the “control space” around the product is becoming another hurdle. For traditional products the “control space” has entailed batch manufacturing, batch area clearance, and various room checks to limit the risk of cross contamination and product mixups. For many of the newer technologies, Blackwell asserts, the traditional manufacturing model simply won’t be economical. 

	“The control space around the product will need to shrink to accommodate simultaneous and parallel manufacturing on the same production floor. Again, the interplay of data technologies (e.g., radio frequency identification, wireless, mobile, barcode, manufacturing execution system) and engineered controls (e.g., electronic batch records) to ensure compliance and the safety, identity, strength, purity, and quality (SISPQ) of the product will be essential. These systems will need to interact with the quality system in real time and be validated to support release by exception. Unexpected events will need to be investigated immediately and alerted by the electronic process monitoring systems,” Blackwell explains.

	Gene therapy stakeholders would do well to have a set of best practices that will help keep the development of a novel gene therapy in compliance with new regulatory guidelines. Early and frequent use of risk assessments is a good practice that can greatly enhance process understanding and focus efforts, for instance. Gene therapy, as well as other emerging therapy products, required a broad and deep understanding of the science behind them in order to do proper risk assessments, Blackwell says. “This will often entail close collaboration between R&D scientists, process scientists, and quality control, especially early in the development program before little process data and manufacturing history has been garnered,” he adds.

	Blackwell considers that stakeholders for a number of these products will seek expedited approval pathways, which will compound the challenges with CMC because of the shortened timelines. He notes that it is always challenging to keep CMC off the critical pathway under any circumstance, and when these pathways get expedited, the pressures on CMC activities are enormous. Unfortunately, there will be no relief from FDA in terms of meeting the expectations and spirit of the guidance documents. “Again, strategic and project planning that links to the data and technical reports requirement and regulatory expectations is clearly a best practice,” Blackwell says. 

	Blackwell believes it is helpful to always keep the end-goal (i.e., commercialization) in mind. “Is a change really needed now, or can it wait until after approval and commercial launch? But, having the end-in-mind is not enough. Starting early with a strategic and project plan focused on regulatory requirements and guidance pays tremendous dividends. It helps to make sure things are not overlooked, and helps the team make appropriate adjustments quickly when things don’t go as planned. They almost never do,” he says.

	Another best practice Blackwell recommends, though on a different tact, relates to process, equipment, and facility validation. “Many of these processes will need to scale up on parallel and not in scale like traditional products. Thus, the master validation plan should accommodate this by simplifying the level of qualification needed for new product lines and suites,” Blackwell says.

	He also advocates using quality-by-design and product lifecycle approaches, which are the best ways to meet all these challenges. “For example, the target product profile is one of the few tools in an organization that brings most of the key stakeholders together, including commercial, medical, CMC, regulatory, and quality; keeps everyone on the same page; and focuses efforts. Start early with it since it becomes a living document that has the end-in-mind,” Blackwell states. 

	Meanwhile, although the new gene therapy guidelines issued by FDA are a significant step forward in moving new gene therapies through the regulatory process toward approval, some note that further GMP guidelines are still needed. Magers points out that although GMP requirements have been issued that are specific to gene therapy products, FDA has not yet issued a guidance document that contains detailed GMP recommendations.

	The EC’s GMP guidelines for advanced therapy medicinal products (4) that went into effect in May 2018 contain detailed recommendations, Magers observes. “Some of these recommendations were included in the PIC/S GMP Guide 

Annex 2A Manufacture of Advanced Therapy Medicinal Products for Human Use

(6), which was issued for public comment from September to December 2019. FDA is providing recommendations to address specific topics (e.g., recommendations for multiproduct cell and gene therapy manufacturing facilities) in public forums, however, no guidelines have been issued,” Magers states.

	“In addition, it would be beneficial if FDA would update some CMC guidance documents to reflect their current thinking. Guidelines that should be updated include the 

Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)

Potency Tests for Cellular and Gene Therapy Products Final Guidance for Industry

, issued January 2011. Further, a guideline addressing comparability approaches for cell and gene therapy products is needed, as changes are often made during the development of these products that require an assessment of comparability,” Magers adds.

	Blackwell points to an area where future guidance will likely be needed, and that is in “bedside manufacturing” and “distributed manufacturing” in non-GMP environments. “The CGMPs, guidances, and technology will be pushed to its limits to ensure the SISPQ of the product is ensured. Guidances that will be particularly useful will be on process analytic technology (PAT), 

] Part 11, and risk assessment, but I expect new guidance that tie these together in conjunction with these types of technologies will be needed. For example, how will the quality unit oversee and interact with these technologies? What will be deemed acceptable? Appropriate engineering controls; analytics, testing, and release; validation; data integrity; handling unexpected events; handling and control over the manufacturing equipment will be especially challenging,” he concludes.

FDA Continues Strong Support of Innovation in Development of Gene Therapy Products

,” Press Release, Jan. 28, 2020.
	2. FDA, 

Guidance for Industry, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)

Guidance for Industry, Testing of Retroviral Vector-Based Human Gene Therapy Products for Replication Competent Retrovirus During Product Manufacture and Patient Follow-up

Guidelines on Good Manufacturing Practice Specific to Advanced Therapy Medicinal Products

Annex 2A, Manufacture of Advanced Therapy Medicinal Products for Human Use


	Vol. 44, No. 3
	March 2020
	Pages: 44–47

	When referring to this article, please cite it as F. Mirasol, “Navigating GMPs for Gene Therapies,” 

Articles

While new industry guidance documents issued by FDA speak to the agency’s efforts to promote the development of new gene therapies, certain hurdles remain to challenge stakeholders.

Navigating GMPs for Gene Therapies

An early start on process development helps optimize biomanufacturing processes, shorten time to market, potentially cut costs, and keep product in line with current good manufacturing practices. While the approach to process development for emerging therapies (e.g., gene therapies and cell therapies) is similar to the approach used for more traditional biologic medicines (e.g., monoclonal antibodies [mAbs]), the nature of emerging therapies means there are further nuances to consider in optimizing their manufacturing processes.

	“Many of the general bioproduction concepts for gene therapies are similar to the more mature protein therapeutic market; however, there are many nuances in raw material costs, supply chain, technologies, regulatory standards, and overall scale that make gene therapy production a more dynamic process,” says George Buchman, vice-president of Pre-Clinical and Process Development at Catalent’s Paragon Gene Therapy. 

	Viral vector manufacturing, for example, is a complex process, Buchman notes. Add to that the influx of various and ever-evolving enabling technologies and growth platforms, and viral vector manufacturing becomes even more dynamic. “For example, the supply chain process for standard biologics is more mature and optimized, offering a relatively clear path for manufacturers to follow. However, due to the exponential growth being experienced with increasing numbers of gene therapy molecules with regulatory agency fast-track status, and a large influx of gene therapy assets in the clinical pipeline, raw material supply can be outpaced,” Buchman says. “Additionally, the cost of gene therapy raw materials is generally higher and more varied than what is seen in traditional biologics. Therefore, it is critical to plan ahead and have a risk mitigation strategy for secure supply and cost management.”

	Process modeling is also critical to any good development and scale-up process, Buchman points out. Various scale-down approaches can replicate large-scale conditions at small scale, and this is a relatively inexpensive modeling method. It is often highly predictable at large scale for both upstream and downstream processes. 

	However, there are cases in which process modeling is not very predictive, Buchman notes. “A good example is when a given platform may not scale linearly. However, if you focus on the relative data rather than the absolute data, side-by-side comparison rather than the actual numbers, it is still somewhat effective. All of these modeling approaches take time and deep gene therapy production expertise to develop a trustworthy and predictive model,” he says.

	For viral vector manufacturing, yield and recovery are key factors considered when optimizing processes. A good deal of focus is on developing a process that creates more full capsids versus empty ones and optimizes the percentage of material that can be recovered from the total production, Buchman explains. Optimization can also occur in the downstream development process by removing the empty capsids while decreasing the full ones that are removed at the same time, he continues. 

	“Additionally, we are always focused on vector safety (making sure non-vector components are removed) and vector function (making sure the vector not only is properly isolated but also transduces correctly). For lentivirus production, a key factor is reducing stability issues during viral recovery,” Buchman says.

	“For gene therapy manufacturing, material costs (virus and plasmids) are actually higher than the cost to manufacture the product, so reducing material costs is essential for economical production. Of course, creating an optimized manufacturing process to achieve an economy of scale is the goal for the industry, but with so many changes and new technologies and platforms, this will need to evolve over time. We are in a great position as a focused development and manufacturer because we have experience and exposure to a variety of biologic entities, platforms, and processes,” Buchman adds.

	Cell therapies have their own set of process development challenges. Cell therapies can be either autologous (one individual is both the source and the recipient of the therapy) or allogeneic (a donor is the source of cells used for the therapy, which can be administered to a number of recipients). In both approaches, it is critical that the therapeutic cell be characterized to define which properties of the cell determine that is has been produced to acceptable standards and quality. This characterization is necessary to ensure that the risk of incorporating anomalies or shifts in cell function have been minimized, because such discrepancies may compromise the safety or efficacy of the therapeutic cell (1). 

	To be successful from a clinical or commercial standpoint, cell therapy manufacturing processes must create a consistent, safe, and effective cell therapy product, regardless of the cell type or the application for which it is used. Process development for a cell therapy must therefore apply to all elements of the manufacturing cycle-cell isolation, cell characterization, cell culture media, scale-up, and removal of impurities. 

	Process development for a cell therapy, whether autologous or allogeneic, must address at least the basic questions about how the therapeutic cells will be expanded and manufactured in ways that will retain their potency. Process development should additionally consider what characteristics must be monitored that define the particular cell product of interest. Further, what assays should be used to measure these desirable cell characteristics? The process development approach (1) must also consider how the cell therapy product will be stored and administered as well as take into account the lot size dictated by the market for that specific product.

	Monoclonal antibodies have had decades to establish robust and economical commercial biomanufacturing processes and are today considered the leading modality for biotherapeutics (2). Blockbuster success with some mAb therapeutics has also encouraged refinement and innovation in bioprocessing steps, making the manufacture of mAbs further efficient and more productive while retaining safety and efficacy. 

	Lessons learned during the growing pains of mAb process development may also benefit cell and gene therapies. The introduction of single-use bioreactors, for instance, offers more flexibility in the cell culture approaches that can be taken for a cell therapy or vector manufacturing for gene therapy. While the traditional cell-culture methods for cells used in cell therapy or for vectors used in gene therapy have primarily relied on adherent-based cell culture (i.e., a surface must be provided to which the cells/vector can adhere to and be grown out), there is more movement toward suspension-based cell culture (i.e., cells/vectors are grown in a vessel without the need to attach to a surface). Single-use bioreactors offer that flexibility and are offered in sizes more appropriate to the smaller lot sizes (compared to mAbs) at which a cell therapy or a gene therapy are produced. 

	“Dynamic changes in platform processes and scale are prevalent in gene therapy bioproduction,” says Buchman. “Many companies have moved-or will move-from cell factory-based growth platforms to suspension bioreactors. Additionally, there have been changes with the implementation of nanofiltration to make processes more robust. It is this type of constant process evolution that requires developers to be open to all emerging ways to increase efficiency and scale.”

	Buchman also emphasizes that any actions taken to maximize efficiency, generate more patient material, and improve vector yields safely and effectively and at a better cost are shaping the gene therapy industry today. “Early in our gene therapy experience, we were using centrifugation, which ultimately wasn’t scalable, so we moved to chromatography, and now, most recently, to affinity resins,” he says.

	Another example of constant industry growth and change lies in the versatility and use of multiple viral serotypes with the various technologies available for gene therapy manufacture. “It used to be limited to a few serotypes, but now there are resins that will work with all adeno-associated virus serotypes,” Buchman notes. 

	Overall, the gene therapy industry can take some lessons from the mAb world, Buchman concludes. Moving toward the use of stable cell lines and improving critical and inefficient steps, such as plasmid transfection, are more examples of how gene therapy can learn from mAbs. “However, innovators should not dismiss various incremental improvements, such as the use of more efficient resins or the optimization of reactor feeds. These types of efficiencies might not be game changers, but every incremental improvement will help reduce costs and time,” Buchman adds.

 4 (10) 1155–1163 (2015).
	2. A. Abhinav, et al., 


	Vol. 44, No. 3
	March 2020
	Pages: 32–33

	When referring to this article, please cite it as F. Mirasol, “Optimizing Process Development for Emerging Therapies,” 

Tackling process development early on can better optimize manufacturing processes for emerging therapies.

Optimizing Process Development for Emerging Therapies

With the hard-fought road to commercialization won by cell and gene therapies in the past few years, biopharmaceutical companies have stepped up their interests in developing these emerging therapies. Some biopharma companies are also building capacity by investing in expansions and/or new facilities. In anticipation of growing demand for capacity and services, contract manufacturing organizations (CMOs) and contract development and manufacturing organizations (CDMOs) have also been investing in expanding manufacturing capacity and capabilities for cell and gene therapies.

	Building capacity now and for the future

	One such example is biopharmaceutical company Gilead Sciences, which acquired Kite Pharma in October 2017 for approximately $11.9 billion. That same month, Kite’s cell therapy product, Yescarta (axicabtagene ciloleucel) for large B-cell lymphoma, was approved by FDA. Through Kite, Gilead has established a global manufacturing network to meet patients’ needs for cell therapies today and in the future. “Outside of California, key investments include the opening of a manufacturing site in Amsterdam later this year [2020] and ongoing construction of our newest automated facility in Frederick County, MD, that will significantly expand our ability to manufacture a variety of chimeric antigen receptor T (CAR T) therapies, and our new clinical manufacturing facility in Gaithersburg, MD will produce investigational T-cell receptor (TCR) cell therapies being evaluated in solid tumors,” says Charles Calderaro, Kite’s global head of Technical Operations. 

	In addition, in July 2019 the company announced the development of a new facility in Oceanside, CA (1) that will be dedicated to the development and manufacturing of viral vectors. Viral vectors are a critical starting material in the production of cell therapies, Calderaro notes. 

	Also looking to leverage itself with capacity for now and in the future, Orchard Therapeutics, a London-headquartered biopharmaceutical company, has been organizing its CDMO network as well as its in-house capabilities. “In anticipation of a potential launch, we will be leveraging our existing CDMO infrastructure to produce the required vector and drug product. At the same time, we understand that we must invest in our own, in-house manufacturing capabilities given the depth of our clinical-stage pipeline,” says Ran Zheng, chief technical officer, Orchard Therapeutics. “We are beginning construction of a manufacturing facility in Fremont, CA, in order to meet the need for greater capacity, and expect it to be operational in 2021. In addition to vector and drug product manufacturing, the Fremont facility will house process development, quality control, and other support functions.”

	Meanwhile, CDMO Catalent made a significant investment with its $1.2-billion acquisition in May 2019 of Paragon Bioservices, a CDMO specializing in viral vector development and manufacturing for gene therapies (2). Paragon had just opened its second good manufacturing practices (GMP) gene therapy manufacturing facility in Harmans, MD, in April 2019, notes Colleen Floreck, senior director of Marketing and Communications at Catalent’s Paragon Gene Therapy. “The 425,000-ft

facility offers individualized manufacturing suites specially designed to handle the unique needs of gene therapy products,” Floreck says. 

	Soon after the acquisition, Catalent Biologics and Novavax partnered in a strategic deal under which Paragon Gene Therapy would assume the leases to two of Novavax’s product development and manufacturing facilities in Gaithersburg and Rockville, MD. The deal gave Paragon immediate access to state-of-the-art manufacturing equipment and a further 54,000 ft

of current good manufacturing practice (CGMP) space that the company needs to grow its gene therapy development and manufacturing business. One hundred of Novavax’s employees transferred to Paragon.

	“Each of these announcements included commitments from customers for dedicated capacity for their programs, but also provides additional capacity for technology expansion and new development customers. Since then, Catalent’s Paragon Gene Therapy business has announced further collaborations, validating its proactive investment strategy,” Floreck says.

	In addition to building up capacity for cell and gene therapies, companies are also making strategic investments to support advancing product candidates through the pipeline. “We are investing across a number of areas to support the advancement of our investigational 

 autologous gene therapy programs for rare, inherited diseases,” says Zheng. 

	Orchard Therapeutics’ additional investments include research and development for new indications; technological innovations, such as stable cell lines for vector production and hematopoietic stem cell transduction enhancers; automated cell processing; and initiatives to identify metachromatic leukodystrophy (MLD) patients, including diagnostic testing and newborn screening pilot programs. “We view all of these activities as crucial to our long-term success,” Zheng emphasizes.

	Catalent’s additional investments include its February 2020 acquisition of MaSTherCell Global, a cell therapy CDMO, for $315 million. “This creates an industry-leading platform spanning both cell and gene therapy and complementing Catalent’s cell line, analytical, and biologics fill/finish capabilities,” Floreck says.

facility in Gosselies, Belgium, that provides clinical services and a 32,000-ft

facility in Houston, TX, which is currently undergoing validation activities to undertake development-scale projects before the end of 2020, Floreck explains. “Like Paragon, MaSTherCell already has expansion plans in progress and construction is underway on a dedicated 60,000-ft

commercial-scale production and fill/finish facility adjacent to its existing Belgian facility, which is scheduled to open in the fall of 2021. MaSTherCell adds a unique portfolio of capabilities and technologies to Catalent that include the development and manufacture of autologous and allogeneic cell therapies and related analytical services,” Floreck adds. 

	MaSTherCell’s expertise includes therapies based on CAR-T cells, TCR, tumor-infiltrating lymphocytes (TIL), and mesenchymal stem cells (MSC).

	Gilead’s investments beyond building capacity is based on Kite’s commitment to continuous innovation in platform services and logistics support, both necessary to improve the cell therapy experience for patients and healthcare professionals. “We have a customized program, Kite Konnect, which is designed to help enable rapid and reliable delivery of Yescarta to treatment centers. Kite Konnect uses an integrated technology platform to provide real-time status updates to patients and doctors throughout treatment,” explains Calderaro.

	The increased focus on developing cell and gene therapies and the significant number of product candidates in the clinical pipeline means that there is need for capacity upgrades on the market. “With so many cell and gene therapy companies looking to bring products through clinical trials to the market, capacity is tight,” Zheng concurs. “We’re increasingly seeing companies adjusting to this dynamic by securing supply agreements with CDMOs, building internal manufacturing capabilities, and improving manufacturing processes and efficiency by exploring new technologies.”

	In gene therapy manufacturing, Catalent focuses on growing with its clients. “It is critical that we can support our customers’ pipelines and increasing asset portfolio with GMP viral facilities,” says Floreck. 

	With the number of gene therapy clinical trials on the increase and many gene therapy programs carrying expedited status, it is additionally important to Catalent that the company offers not only dedicated space for clinical trial and commercial production, but also scale-up expertise to support increased manufacturing efficiency, Floreck explains.

	“It should be the goal of any successful gene therapy CDMO to offer an end-to-end solution for its customers. From the raw materials through to development, scale-up, manufacturing, and fill/finish, we want to be able to guide our customers through the process and increase their chances of final approval and patient material. At Catalent, we are committed to expanding capacity to meet industry demand; however, without the viral vector expertise, it is just empty space. Early phase clients need to lock-in early with manufacturing partners, to not only secure the production suite but also to have the necessary technical expertise in place to optimize their program,” Floreck stresses.

	On the cell therapy front, the constraint isn’t so much about capacity but more about getting into the field early. Floreck points out that the barrier to entry in the cell therapy field is low, but the real challenge involves the people and expertise. “There are many manufacturers who can build upstream and downstream cell culture suites, especially without the challenges of virus production, but it takes a minimum of six months to effectively train personnel across various platforms,” say says. 

	“Additionally, you are so close to the end user (i.e., the patient) that the cell production and the need to lock down a process early is even more critical. Knowledge and expertise across a variety of cell types and modalities are important to offer customers the speed they need to get to the clinic faster. Many cell therapy indications and products are similar, making speed to market of paramount importance to customers,” Floreck says.

	In the field of autologous cell therapy, in particular, there is no option but to build out. “Since you are treating one patient at a time, clients often do not even know how many patients they will have during each month of the trial. With enrollment being the biggest unknown, the numbers also challenge the affordability of the treatment,” Floreck explains.

	In comparison, for allogeneic cell therapy, it is not known yet what the final bioproduction process will be. “At Catalent’s most recent acquisition, MaSTherCell, we are designing the processes, including stirred-tank reactors all the way through to fill and finish. We are working with clinically advanced companies like CRISPR Therapeutics and Servier as they navigate the defining of the allogeneic production process,” Floreck says.

	Furthermore, unlike traditional biomanufacturing, current CAR T therapies require a complex and carefully controlled, multi-step process that can be difficult to optimize, adds Calderaro. “Manufacturing speed and quality in cell therapy is critical because people waiting for these medicines are typically very ill and have the potential for rapid disease progression. In addition to our global, industry-leading manufacturing network, Kite continues to explore ways to optimize the quality of manufacturing and has currently set the bar for the industry with a rapid and reliable median 16-day turnaround time in the United States,” Calderaro states.

	Calderaro goes on to say that the progress of cell therapy is closely tied to innovation in manufacturing and technical operations. “In addition to our US and European locations, we are investing in other areas around the globe to ensure our operational footprint allows us to meet the needs of potential patients worldwide. We are actively advancing cell therapy technology across all aspects of the manufacturing process, including technologies such as next-generation autologous and allogeneic development platforms.”

	Because Kite’s singular focus is cell therapy, it’s strategic drive into the future is also very focused. Today, the company is exploring cell therapies in more than 10 cancers, including hematologic malignancies and solid tumors, and is also exploring varied technologies. “As we advance our industry-leading cell therapy pipeline, expanding and investing in our capabilities is essential to ensuring we are able to improve outcomes for people with cancer now and in the future,” says Calderaro.

	Catalent is taking its cue from its customers and intends to build a future with them. “It is critical for Catalent to grow with its customers. We are committed to developing the capacity needed to support their programs as they grow and expand,” Floreck says.

	Meanwhile, Orchard Therapeutics is considering several factors looking toward the future as it develops and executes its manufacturing strategy. “Our first consideration is about patients and our ability to produce and deliver products to them reliably. With the construction of our facility in Fremont, we will work to ensure increased manufacturing capacity to make products for these patients. Given the nature of our investigational products-

 autologous gene therapies, which use a gene-corrected version of a patient’s own cells-reliable supply chain management is also necessary to ensure quality and timely delivery of our products. We are committed to working closely with regulators in the European Union, the US, and globally to ensure compliance and efficient product approvals,” Zheng says.

	1. Gilead Sciences, “Kite Announces Plans to Bolster Industry-Leading Cell Therapy Manufacturing Capabilities with New Viral Vector Facility,” Press Release, July 16, 2019.
	2. Catalent, “Catalent Completes Acquisition of Gene Therapy Leader Paragon Bioservices, Inc. for $1.2 Billion,” Press Release, May 20, 2019.


	Vol. 44, No. 3
	March 2020
	Pages: 16–21

	When referring to this article, please cite it as F. Mirasol, “Investments Inject Growth in Cell and Gene Therapies,” 

The growing interest in developing cell and gene therapies has prompted industry investment to grow manufacturing capacity.

Investments Inject Growth in Cell and Gene Therapies

	The successes of winning regulatory approval from FDA and further approvals in Europe have sparked an increase in the further development of new cell and gene therapies, many of which aim to treat difficult-to-treat or previously untreated diseases. As a result of a growing clinical pipeline for these therapies, manufacturing capacity on the market is tight. Biopharmaceutical companies, contract manufacturing organizations (CMOs), and contract development and manufacturing organizations (CDMOs) have turned an interested eye toward boosting manufacturing capacity. A summary of some of the manufacturing investments made during 2019 and up to the present in the cell and gene therapy fields follows.

In January 2019, Fujifilm announced that it will add current good manufacturing practices (CGMP) aseptic filling of recombinant proteins to its existing fill/finish services at its Fujifilm Diosynth Biotechnologies (FDB) facility at College Station, TX, by March 2021 (1). The services will also apply to gene therapy fill/finish. The company previously announced that it would start offering gene therapy fill/finish services. Fujifilm followed this up with a $55-million investment to establish a new gene therapy innovation center adjacent to its FDB CDMO’s existing gene therapy manufacturing facility at College Station (2). The new 60,000-ft

innovation center will house state-of-the-art upstream, downstream, and analytical development technologies, the company announced in November 2019. The facility will be operational in autumn 2021. 

GE Healthcare Life Sciences commercially launched a KUBio box in October 2019 intended to accelerate the production of viral-vector-based gene therapies and increase capacity in the viral vector space (3). The new KUBio box features a Germfree biosafety level 2 modular bioprocessing environment and is equipped with the FlexFactory single-use biomanufacturing platform, which has been tailored specifically for the production of viral vectors, according to the company.

Hitachi Chemical Advanced Therapeutics Solutions (HCATS), a subsidiary of Hitachi Chemical and the North America representative of Hitachi Chemical’s Regenerative Medicine Business Sector, opened a new commercial-scale cell and gene therapy manufacturing facility in Allendale, NJ, in late January 2020 (4). The new facility houses six classified environment rooms and has the capacity to add more rooms that can be specifically configured according to need. The facility includes manufacturing and development labs as well as quality control and microbiology labs. 

Nationwide Children’s Hospital, based in Columbus, OH, in conjunction with key partners created an affiliate company named Andelyn Biosciences in January 2020 to manufacture gene therapy products. The new company is scheduled to begin operations in 2023 (5). The new startup will establish the first commercial-scale CGMP clinical manufacturing facility in Ohio devoted to gene therapies, according to Nationwide Children’s Hospital. The new company is the result of the hospital’s clinical manufacturing success and work with gene therapy via its Abigail Wexner Research Institute (AWRI). AWRI has operated a small-scale CGMP gene therapy manufacturing facility on-site for several years focused on early-stage gene therapy products for Phase I and II clinical trials. Beginning in summer 2020, the current facility will manufacture products compliant with Phase III clinical trial regulations while the new commercial-scale manufacturing site under Andelyn Biosciences is being built and validated.

Novartis opened its new cell and gene therapies manufacturing facility in Stein, Switzerland, in November 2019 following on the heels of the company’s first successfully completed clinical production of a cell and gene therapy batch at Stein in September 2019 (6). The new facility houses manufacturing areas for novel chimeric antigen receptor T cell (CAR-T) cell therapies in addition to hosting production of innovative, difficult-to-manufacture solid dosage forms. 

In August 2019, Pfizer announced that it is investing $500 million to construct a new gene therapy manufacturing facility in Sanford, NC (7). The facility is expected to support Pfizer’s ongoing investment in gene therapy R&D. The facility would increase Pfizer’s ability to supply both clinical- and commercial-scale quantities of gene therapies, specifically, highly specialized, potentially one-time gene therapies that use custom-made recombinant adeno-associated virus (rAAV) vectors. 

The Discovery Labs, an MLP Venture company and provider of CGMP manufacturing, turnkey laboratory solutions, critical materials, and office space, formed a new CDMO and specialty investment company in January 2020 in partnership with Deerfield Management, a healthcare investment management firm. Under the new CDMO, named The Center for Breakthrough Medicines, The Discovery Labs and Deerfield will invest $1.1 billion to build a manufacturing facility for cell and gene therapies in King of Prussia, PA, which is expected to provide instant capacity to the market (8). The new CDMO will provide manufacturing from preclinical- through to commercial-scale of cell therapies, gene therapies, and component raw materials. It will also offer process development, plasmid DNA, viral vectors, cell banking, cell processing, and support testing capabilities, all housed under one roof.  Renovations are also underway at the King of Prussia site to construct a total of 86 plasmid, viral-vector production, universal cell processing, CGMP testing, process development, and cell banking suites. 

Thermo Fisher Scientific opened its new $90-million viral vector CDMO site in Lexington, MA, in December 2019 (9). The 50,000-ft

facility will support development, testing, and manufacture of viral vectors for gene and cell therapies. The new facility adds much-needed capacity for viral vector development and manufacturing, which has been a bottleneck area for biotech companies, according to Thermo Fisher, which has noted that the demand for new gene therapies has outpaced capacity. The investment is expected to accelerate commercialization of new cell and gene therapies by providing a range of services-from drug development through clinical trials to commercial manufacturing.

	1. Fujifilm, “Fujifilm Announces the Extension of Its Fill Finish Services to Include Recombinant Protein Aseptic Filling Market,” Press Release, Jan. 15, 2019.
	2. Fujifim Diosynth Biotechnologies, “Fujifilm Diosynth Biotechnologies Announces $55-Million USD Investment to Expand Gene Therapy Development Capabilities,” Press Release, Nov. 14, 2019.
	3. GE Healthcare, “New KUBio Box for Viral Vectors Boosts Gene Therapy Manufacturing,” Press Release, Oct. 28, 2019.
	4. PCT, “Hitachi Chemical Opens New Cell and Gene Therapy Manufacturing Facility,” Press Release, Jan. 30, 2020.
	5. Nation Wide Children’s Hospital, “Nationwide Children’s Hospital Announces Plans for Andelyn Biosciences,” Press Release, Jan. 13, 2020.
	6. Novartis, “Novartis Opens Facility for Innovative Cell and Gene Therapies in Switzerland,” Press Release, Nov. 28, 2019.
	7. Pfizer, “Pfizer Invests Half Billion Dollars to Advance State-of-the-Art Gene Therapy Facility in Sanford, North Carolina,” Press Release, Aug. 21, 2019.
	8. The Discovery Labs, “The Center for Breakthrough Medicines is Building the World’s Largest Cell and Gene Therapy Contract Development and Manufacturing Organization (CDMO) to Launch in King of Prussia, PA,” Press Release, Jan. 22, 2020.
	9. Thermo Fisher Scientific, “Thermo Fisher Scientific Opens $90-Million Viral Vector Manufacturing Site in Massachusetts,” Press Release, Dec. 4, 2019.

	When referring to this article, please cite it as F. Mirasol, “Industry Pushes Forward with Cell and Gene Therapies,” 

The last year has seen intense investment activity into raising cell and gene therapy manufacturing capacity.

Industry pushes forward with cell and gene therapies

This article was published in the July 2019 issue of Pharmaceutical Technology Europe

Digitizing manufacturing processes, and replacing paper-based systems with digital platforms, promises to improve the quality and efficiency of bio/pharmaceutical manufacturing, enabling companies to meet existing and future demands more effectively. One way digitization accomplishes this is by allowing operators to locate and use essential data in real time, to make smarter decisions on the fly. As the biopharma industry moves into precision medicines, this advantage will become increasingly important.

	In addition, regulators’ calls to modernize drug manufacturing exerts more pressure on the industry to step up its game, and to harness the power of emerging technologies to prevent quality and compliance problems and costly product recalls (1). Manufacturing failures such as compromised sterility, the presence of mold in manufacturing areas, and contaminated containers have resulted in product quality problems and delayed product launches. Over time, they have worsened existing drug shortages and prevented patients from getting much needed medicines.

	The push to modernize biopharmaceutical manufacturing has been intensified by the US Government, whose National Science and Technology Council’s (NSTC) Subcommittee of Advanced Manufacturing (SAM) issued a revised call to action in 2016, calling for manufacturers to employ advanced manufacturing methods and to train and employ a skilled workforce to implement these techniques (2). The report emphasized biomanufacturing, regenerative medicines, and the continuous manufacturing of pharmaceuticals as priority areas.

	The report highlighted defined digital manufacturing and established it as a priority technology.

	“Digital manufacturing is the use of an integrated, computer-based system comprised of simulation, three-dimensional visualization, analytics, and various collaboration tools to create product and manufacturing process definitions simultaneously. Design innovation is the ability to apply these technologies, tools, and products to re-imagine the entire manufacturing process from end to end,” according to SAM.

	To help advance the goals stated in the report, the US Department of Defense (DoD) has established a public-private partnership with the Digital Manufacturing and Design Innovation Institute (DMDII), based in Chicago, IL. DMDII focuses on the enterprise-wide application of digital technology to enable highly integrated design and manufacturing of complex products with the goal of reducing time and cost while accelerating the pace of new products coming to market (2).

	As industry, government, academia, and other groups seek to improve the production and quality of biotherapeutics, digitizing biopharma manufacturing processes will be a prerequisite for competing in the market in the future. Billy Sisk, life-sciences industry manager EMEA at Rockwell Automation, a Milwaukee, WI-based company specializing in smart manufacturing, shared insights with 

 into automation trends and what will be required for biopharma digitization.

: What factors are driving the trend toward automation in bioprocessing?

: Biotechnology and pharmaceutical companies are looking for new technologies and solutions that can help them remain competitive during demanding times. Cellular biology and gene therapy advancements have opened the door for smaller volume drugs, shifting manufacturing facilities to focus on multiproduct production. These facilities often require complicated batching, meticulous product tracking, and frequent changeovers.

	Additionally, lifecycles have shortened, counterfeits have flooded the market, and there is pressure to get drugs to the market faster while still maintaining compliance and data integrity. Moving to automation in bioprocessing allows for increased production and improved decision making.

: It seems that a next logical step following automation of the bioprocess is to digitize processes. Is that so, and why?

: Yes, this is definitely the next step for bioprocessing. With automation comes some level of connectivity. Pharmaceutical producers can build on that foundation to connect their systems horizontally and vertically, making more data available to improve decision-making, performance and compliance.

: What are the benefits of digitizing aspects of the bioprocess?

: Companies can see an increase in flexibility, speed, and agility, which will reduce overall time to market. Additionally, digitization will give operators more visibility into their operations and enable them to make real-time decisions.

: What are the challenges of digitizing in biopharma?

: A seamless transition to digitization calls for the correct systems and technology to be available and updated. Implementing a connected plant will not be possible with outdated systems. Knowing which systems may be needed and properly implementing them can be a big challenge, not only for the initial transition but also as operations continue to scale up.

: What role does your company play in the implementation of automation and/or digitization of bioprocessing?

: We’ve been working with customers to help them build their own facilities of the future, built on a modern distributed control system (DCS). We help them select and install the right solutions and equipment, including innovative technologies like augmented reality and advanced analytics. We also provide training to get employees up to speed on the new equipment and monitoring services to deliver backup support in case of any issues.

: What current technologies and software exist in the industry today that facilitate digitization of the biomanufacturing process?

: A modern DCS, built on an open, unmodified Ethernet, provides smart docking stations and seamless plug-and-play connectivity for mobile equipment. It offers a starting point from which biotech and pharma companies can start connecting their facilities. The modern system offers the same capabilities of a traditional system, with information-enabled functionality designed for scalability. It also offers unified integration from ERP to the shop floor and provides real-time dashboards.

	Visualization is also critical in order to maximize the accuracy and efficiency of a facility. Fixed operator screens or terminals are no longer practical. Instead, workers are more effective when they have tablets or mobile screens that can follow them, and production, throughout the facility. Two visualization technologies that companies can implement today are thin-client technology and augmented reality. Thin-client technology makes mobile visualization possible and helps reduce the risk of error that can accompany mobile equipment. And augmented reality provides a way to bring standard operating procedures directly to the operator, instead of having them look them up.

: What impact does digitization have on workflow, especially the impact on human operators?

: Overall, digitization results in the need for less intervention and policing of workers, since the equipment is all connected.

	1. Biovia, “How Can Biologics Manufacturing Process Improvement Benefit from Integrated Digital Solutions?” Blog, 3dsbiovia.com, June 28, 2016.
	2. US Office of Science and Technology Policy, “Advanced Manufacturing: A Snapshot of Priority Technology Areas Across the Federal Government,” (National Science and Technology Council, Washington, DC, April 2016).


	Vol. 31, No. 7
	July 2019
	Pages: 25–26

	When referring to this article, please cite it as F. Mirasol, “Can Bioprocessing Achieve Digital Transformation?” 

Automation promises to connect biomanufacturing processes more closely, and to bring greater efficiency to the manufacturing floor.

Can Bioprocessing Achieve Digital Transformation?

When it comes to cleaning validation in the biopharmaceutical industry, different biopharmaceutical manufactures face similar challenges. Some common challenges include the ability to have reproducibility when manually cleaning small parts and when using non-clean-in-place (CIP) systems as well as having an effective design in which CIP systems are fully automated.

	Other challenges include a physical build-up of protein on equipment walls that have been cleaned by CIP. This build-up is a process that happens over time when there is no periodic scrub-down of the equipment, allowing for a layer of residue to accumulate in the inner surface of the vessel. In addition, failure of CIP systems over time due to blocked steam traps, poor maintenance, or irregular/erroneous replacement of a steam trap will pose problems for cleaning validation operations (1).

	Because cleaning validation is an important aspect in current good manufacturing practice (cGMP) manufacturing for monoclonal antibodies (mAbs) as well as other biologics, it is important to consider how current practices ensure that cleaning and sterilizing biomanufacturing equipment is conducted properly, and whether differences exist between cleaning and sterilizing equipment used in multimAb product versus single-mAb product manufacture in the same facility.

	To start with, no real differences exist between single-mAb and multimAb product manufacture in regard to cleaning and sanitation/sterilization, industry experts say. Cleaning protocols would be similar in both circumstances. However, it is important to note that there would be no concern with active carry-over in singleproduct facility as there would be in a multi-product facility.

	In the case of AstraZeneca’s Frederick Manufacturing Center in Frederick, MD, for example, the acceptance criteria for sterilization in place (SIP) is based on the European standard EN285 and is non-product specific, according to an AstraZeneca company official.

	“The acceptance criteria for cleaning are non-product specific because sampling assays and each [n]ew [p]roduct [i]ntroduction (NPI) are challenged on a small-scale (i.e., recovery/cleanability), and protein denaturation (i.e., degradation of proteins using in-house chemicals) needs to be demonstrated to verify that the facility is fit. Each program (cleaning/SIP) has on-going monitoring/maintenance program executed annually to verify systems remain in a validated state,”the AstraZeneca official states.

	“Cleaning protocols between a single-mAb and a multi-mAb manufacturing facility would assess the degraded product as an organic impurity in the drug substance of the next batch,” notes Paul Lopolito, senior manager, STERIS Technical Services. “In a multi-mAb product facility, the main difference is having to assess the cross-contamination risk of mAb product process contaminants with the quality attributes of a subsequent, different mAb drug product,” adds Beth Kroeger, manager, STERIS Technical Services.

	“A risk assessment should include an assessment of active degradation rinsability, toxicity, host cell proteins, media, cleaning agent residues, cleaning process capability, and bioburden and bacterial endotoxin,” notes Kroeger.

	In a biomanufacturing facility where multiple mAb therapeutics are produced, it is important to note what types of cleaning validation are necessary, and how often validation must be performed. The AstraZeneca official notes that cleaning validation maintenance is performed annually at the company’s Frederick facility using a matrix approach. “For each NPI, small-scale cleanability/recovery, protein denaturation, and large-scale cleaning verification (matrix approach) are required,” the official states. In addition, establishing if the product is more challenging to clean compared with previous products will determine the requirements for cleaning validation/verification.

	Lopolito points out that a risk assessment should be performed for incoming mAb drug-product toxicity, solubility, degradation product rinsability, media, and buffer constituents compared to the existing validated cleaning procedures for the entire process for the current products. “If this new mAb is not considered worst case, then at least one production run under normal process conditions for cleaning validation or verification should be executed. Provided no significant changes are made to the process, revalidation is generally not required. Continued process verification should be in place to trend quality attributes to establish cleaning process capability and performance control,” he explains. 

	Systems must be in place that help maintain a sterile environment for manufacturing. In terms of cleaning and SIP validation, all equipment, systems, and production parts used for manufacture should be cleaned with a validated cycle prior to use, the AstraZeneca official says. “Cleaning cycles demonstrate that equipment surfaces are clean and free of residues and ensure any leftover product is cleared,” the official states. 

	Kroeger notes, however, that no additional systems are required in a multimAb facility compared to a single-mAb facility “unless the facility is manufacturing products such as antibody-drug-conjugates (ADCs), due to the potential increased toxicity from the small-molecule portion of the ADC, or products other than mAbs/large molecule.”

	Procedural segregation should exist with separate area clearance between products and batches in a multi-mAb facility, Lopolito adds. “Obviously, packed columns and ultrafiltration membranes would be product dedicated, but equipment need not be dedicated once the resin or membranes are removed. Equipment change-over between products is recommended where elastomeric parts are discarded but is not necessary if cleaning validation testing verifies residue removal from the various materials of construction, or they are not considered to have a significant surface area to exceed the maximum allowed carry over limits,” he explains.

	In addition, other procedures, components, and systems that are important to have in place for cleaning validation include automation control, gowning, aseptic practices, changeover requirements, high-efficiency particulate air (HEPA) filtered air, closed systems used for manufacture, positive pressure, isolation valves, external equipment cleaning, room classifications/cleaning, and on-going quality control monitoring, the AstraZeneca official emphasizes.

	Meanwhile, the selection of cleaning agents requires certain criteria. Lopolito points out that cleaning agents should be selected based on performance, rinsability, analytical methods availability, low toxicity, lot traceability, and compatibility with materials of construction.

	Safety is the most important consideration because of toxicity risks, adds the AstraZeneca official. “Do not select cleaning agents that have significant cytotoxicity, allergenicity, or reproductive hazards,” the official asserts. 

	In a multi-mAb manufacturing scenario, residue type is also a key consideration when selecting a cleaning agent because it is necessary to ensure that the cleaning agent degrades the residue of each product, product-by-product, the AstraZeneca official says. “Typically, alkaline cleaning agents are used as they are bactericides and emulsifiers [microbial control and dissolving proteins]. Acidic cleaning agents may be used to remove salt deposits. Cleaning chemicals with surfactants and builders, that are compatible and safe, are preferred,” the official says.

	Innovations in cleaning/sterilization materials are also important to the process. According to Kroeger, there is at least one cleaning agent that is registered as a biocidal agent with disinfectant, biocidal, and biofilm remediation claims. “Detergent performance enhancements including maintenance derouging, antimicrobial effectiveness, and biodegradability are a few of those being developed to support manufacturers’ process optimization and sustainability goals,” she states.

	In addition, a risk-based approach to acknowledge potential failure modes and provide justification on current controls (detection) is in place. It is important to implement this risk-based approach while maintaining the validated state and regulatory requirements, the AstraZeneca official says.

	Biostatistical analysis may also be used to establish control limits (within predetermined acceptance criteria) used for continuous monitoring/trending.

Current practices for cleaning and sterilizing biomanufacturing equipment does not differ much between a multi-product versus single-product setting.