Exploring Successful Cell and Gene Therapy Development

Cell and gene therapies and regenerative medicines (CGT&RMs) offer remarkable promise for treating various medical conditions. Accordingly, the sector is booming, with pharmaceutical and biotechnology companies across the globe seeking new regions in which to expand their CGT&RM portfolios. Among the many countries working to facilitate expedited CGT&RM product development, manufacture, and commercialization, Japan has become a go-to location, offering an attractive patient population, advanced technological capabilities, and accelerated approval pathways. However, developing and manufacturing CGT&RMs is no easy task. It is expensive and can involve considerable hurdles. Doing so in a foreign country (such as Japan) can be even more difficult, especially if you lack knowledge of regional regulations and processes. So, how should companies go about manufacturing and commercializing their CGT&RMs in Japan, and how can they maximize their chances of success? In this guide, you’ll discover: • Options available to foreign pharmaceutical and biotech companies for CGT&RM manufacture in Japan • The benefits of working with a Japan-based CDMO • Key capabilities to look for in a success-enabling Japan-based CDMO partner Introduction 03 IntroductionWhat are the options for developing and manufacturing CGT&RMs in Japan? When it comes to developing, manufacturing, and commercializing a CGT&RM product in Japan, foreign pharma and biotech companies have several options to choose from. Each option has several notable advantages and disadvantages, so companies must ensure they evaluate each carefully — choosing the wrong option could drastically impact your chances of success. Broadly, companies have three major options available to them: • Building CGT&RM development and manufacturing facilities in Japan • Developing and manufacturing a CG&RM product locally before shipping to Japan • Partnering with a Japan-based contract development and manufacturing organization (CDMO) Below we provide an overview of each option, detailing the relative advantages and disadvantages you should keep in mind. 04 What are the options for developing and manufacturing CGT&RMs in Japan?1. Going solo: building your own infrastructure in Japan The first option involves a company outside of Japan building their own facilities for product development and manufacture in the region. Broadly, this option proceeds via the following steps: Conduct an initial business & feasibility assessment to identify and evaluate suitable locations, and build a business case Create a legal entity in Japan Set up your facility, including recruiting and training staff, procuring equipment, and validation Review and select appropriate construction vendors and build a facility Secure authorization as a manufacturer 1 2 4 3 5 Advantages The primary advantage of building your own infrastructure in Japan is that you will not need to manage complex technology transfer to an external company in a foreign country. This is important, as technology transfer is already challenging, especially when it comes to CGT&RMs: CGT&RM manufacture involves highly complex processes that can be difficult to scale up/out and standardize, and CGT&RM manufacturers must contend with inherently variable starting materials. Moreover, several aspects of CGT&RM manufacture involve manual work, since efforts for more widespread automation are still in progress. That means personnel will need to be carefully trained on unique and complex processes that have a high risk of error and where meticulous organization is critical for success. Managing technology transfer to an external company in a foreign country compounds these issues, as it will likely involve or require different program governance, infrastructure, systems, and communication approaches. Companies that build their own facilities in Japan, therefore, can sidestep the additional potential risks, timelines delays, and costs that technology transfer to an external foreign company can entail. Owning your own infrastructure can also give you more control over your manufacturing timelines and may even be more cost-effective than other approaches over the long-term (although there are also significant cost-related downsides to this approach — as discussed in the next section). Having your manufacturing infrastructure in the same country as patients also significantly simplifies logistics for the distribution of manufactured products (which is particularly beneficial for autologous CGT&RMs). Finally, building your own facilities in Japan enables you to establish a strong footprint in Japan, making subsequent portfolio expansion in Japan smoother and easier. Japan’s regulatory workflow for building and maintaining CGT&RM manufacturing facilities 05 What are the options for developing and manufacturing CGT&RMs in Japan?Disadvantages While managing technology transfer inhouse (rather than to an external company) is a significant advantage, opting to build manufacturing infrastructure in Japan has major drawbacks. First, building such infrastructure requires very large upfront costs. Such a significant investment means that building CGT&RM manufacturing facilities often only makes sense if a company has a long-term portfolio vision for Japan, with multiple therapies in the pipeline. Moreover, building and then maintaining manufacturing infrastructure in a foreign country is complex, time intensive, and requires smooth global management. Ultimately, this means that building infrastructure in Japan is typically only suitable for large pharmaceutical or biotech organizations: smaller firms often don’t have the required capital, capacity, human resources, or know-how to succeed. Companies building their own facilities in Japan also need to carefully manage regulatory and legal obligations. For instance, companies must understand and adhere to Japan’s workflow for building and maintaining manufacturing facilities, including becoming an authorized manufacturer following inspection from regulatory authorities, and passing unannounced periodical audits. Extensive experience is required for success, with companies often needing to hire local regulatory experts. Regulatory experts in Japan, however, are scarce and highly sought after, making recruitment competitive and costly. Finally, companies that choose to build facilities in Japan will need to effectively navigate vast language and cultural differences. This often entails hiring Japan-based pharmaceutical employees that can speak fluent English to smoothly interact with regulatory authorities, local governments, suppliers, regional colleagues, and global company headquarters. 06 What are the options for developing and manufacturing CGT&RMs in Japan?SUMMARY: Building your own manufacturing infrastructure in Japan Advantages • No need to manage complex CGT&RM technology transfer to an external company in a foreign country • Can provide more control over manufacturing timelines • May be more cost-effective over the long term • Having manufacturing facilities in the same country as patients can simplify logistics, which is especially beneficial for autologous therapies Disadvantages • Large upfront costs and ongoing resource and knowledge requirements mean this option is often only suitable for large companies with a multi-therapy pipeline • Demands understanding of complex regulatory requirements related to constructing and maintaining a Japanese manufacturing facility • Must navigate language and cultural differences for effective regional and global collaboration and smooth facility operations 07 What are the options for developing and manufacturing CGT&RMs in Japan?2. Developing and manufacturing locally before shipping to Japan Another option open to CGT&RM companies is to develop and manufacture their product locally using their own manufacturing facilities (or by partnering with a local CDMO) before shipping the product to Japan. Advantages Local manufacturing has several advantages, and for the right therapeutic modality (see disadvantages below for more detail), could be an ideal option. As with option 1, companies choosing to produce their therapies locally in their own facilities can avoid the difficulties of complex technology transfer. (Even if a company uses a local CDMO, technology transfer is still likely to be easier than with transfer to a foreign facility.) Furthermore, this approach enables centralized control of manufacturing, enabling better insight into and control over the manufacturing process, and embedding greater ability to adapt to market changes. Companies opting for local manufacturing also won’t need to commit to a huge upfront investment for building foreign infrastructure. And, they can avoid the regulatory, language, and cultural hurdles of building, running, and maintaining a foreign manufacturing facility, too. 08 What are the options for developing and manufacturing CGT&RMs in Japan?Disadvantages Manufacturing CGT&RMs locally before shipping to Japan has several limitations that make it difficult in many scenarios. Most importantly, due to the requirement for long-distance shipping, this approach only works for therapies that have a sufficiently long shelf-life or that can be cryopreserved or lyophilized. For the same reason, option 2 is challenging and risky when it comes to autologous therapies. Unlike allogenic products, autologous therapies require cells to be extracted from the patient, transported to a manufacturing site, modified, and processed, and then transported back to the patient. The entire process must be rapid and managed under very carefully controlled environmental conditions and with full chain of identity and custody. But the distance between regions such as the United States or Europe and Japan mean this can be prohibitively complex and expensive. (That said, it may be feasible for autologous therapy companies operating in countries closer to Japan (e.g., Korea or Taiwan), but the process would still be difficult and could compromise product quality.) What’s more, even when a company’s products are suitable for long-distance shipping (i.e., allogenic products (or, less commonly, autologous products) that have sufficient shelf-life or can be cryopreserved or lyophilized), they must still contend with several hurdles. For instance, companies (or their local CDMO partners) will need to adjust their products to follow Japanese regulations, which may involve altering specifications, ingredients, and analytical methods, and requires a deep understanding of Japan’s regulatory requirements. Managing long-distance transport of fragile products is also challenging and resourceintensive, especially as rigorous control and monitoring of shipping conditions, such as temperature, is required. Finally, companies will need to be familiar with and adhere to laws for the export of biological materials, as well as comply with Japanese import laws. While import laws in Japan are similar to other major geographies, such as the US and Europe, this adds another potentially timeintensive consideration for those not directly manufacturing their products in Japan. Logistics complexity of an autologous cell therapy (BioProcess International, 2015) 1. Kit production 8. Administration kit protocol 1. Kit production 2. Collection and pack- out 7. Clinical investigator 2. Collection and pack- out 3. Transit 6. Transit 3. Transit 4. Receipt and inventory 5. Distribution 5. Storage and monitoring 4. Storage and monitoring 2. Transit 6. Transit 3. Receipt and inventory 1. Product acquisition Cell therapy manufacturing 09 What are the options for developing and manufacturing CGT&RMs in Japan?SUMMARY: Manufacturing locally before shipping to Japan Advantages • No need to manage complex CGT&RM technology transfer to foreign country • No large upfront investment to build foreign manufacturing infrastructure • Avoids the regulatory, language, and cultural hurdles of building, running, and maintaining a manufacturing facility in a foreign country Disadvantages • Can be risky for autologous therapies due to difficulty of quality control during shipment • Must manage complicated and costly long-distance shipping while ensuring rigorous control of environmental conditions throughout transport • May need to alter products to meet Japanese regulatory requirements • Must consider and adhere to strict import and export laws regarding biological materials 10 What are the options for developing and manufacturing CGT&RMs in Japan?3. Partnering with a Japan-based CDMO The final option for companies looking to expand their CGT&RM portfolio into Japan is to partner with a Japan-based CDMO to manufacture their therapy in the region. Advantages As with option 2, companies that partner with a Japanbased CDMO won’t need to commit to a huge upfront investment for building out and maintaining foreign manufacturing infrastructure. They also won’t need to grapple with the regulations associated with building and maintaining such facilities. And, if they partner with a CDMO fluent in several languages including English, they can ensure smooth communications with internal and external stakeholders, and sidestep the need to navigate complex cultural differences. Finally, companies that partner with Japan-based CDMOs can reap the logistical benefits of having manufacturing infrastructure close to patients. But that’s not all. Working with a Japan-based CDMO has several additional advantages over option 2. Given manufacturing facilities will be located within Japan, long-distance product transportation won’t be needed, meaning this approach is suitable for both autologous and allogeneic CGT&RM products. Working with a Japan-based CDMO also offers companies the flexibility to develop and manufacture just one product — you don’t need to have a pipeline of several potential products which would be required to justify the expense and complexity of building your own Japanese manufacturing infrastructure. Importantly, owing to the size of Japan, a single CDMO could be sufficient to serve the entire region, unlike other regions such as the US, where you might need several facilities (on both the east and west coast, for example) to adequately serve patients. Working with a Japan-based CDMOs is therefore comparatively simpler in terms of management and logistics. Key considerations While working with a Japan-based CDMO outcompetes other manufacturing options on several fronts, companies must be aware of a few potential challenges when it comes to choosing this option. Most importantly, the success of this approach depends heavily on your choice of CDMO, as not all CDMOs were created equal. They vary extensively in expertise, experience, and technological know-how in ways that can mean the difference between program success and failure. And, with so many variables and processes to consider, it can be difficult to know what capabilities to look for. 11 What are the options for developing and manufacturing CGT&RMs in Japan?SUMMARY: Partnering with a Japan-based CDMO for CGT&RM manufacture Advantages • No large upfront investment to build and maintain foreign manufacturing infrastructure • Avoids complexities of building, running, and maintaining a manufacturing facility in a foreign country • Suitable for both autologous and allogenic products • Offers the flexibility to develop just one product (rather than requiring a multi-product pipeline to justify building your own infrastructure) • Having manufacturing facilities in the same country as patients can simplify logistics, which is especially beneficial for autologous therapies • A single CDMO could be sufficient to serve the entirety of Japan Considerations • Success depends heavily on CDMO choice • Capabilities of Japan-based CDMOs varies significantly, and knowing what to look for can be difficult 12 What are the options for developing and manufacturing CGT&RMs in Japan?Partnering with a Japan-based CDMO offers several advantages over alternative approaches to developing and manufacturing CGT&RMs in Japan. But, as noted in the previous chapter, the chances of success depend heavily on the experience and capabilities of the CDMO partner. So, what should foreign pharmaceutical and biotech companies look for in an ideal, Japanbased CDMO? Deep regulatory know-how and expertise Japan’s regulatory environment has the potential to significantly accelerate the delivery of CGT&RMs to market. In fact, it’s one of the key benefits attracting pharma and biotech companies to Japan for CGT&RM portfolio expansion (read more about the regulatory benefits of Japan in our recent eBook). However, at the same time, Japan’s unique regulatory landscape is one of the most common obstacles faced by inexperienced companies. To ensure foreign companies aren’t caught off guard by this new landscape, they must source deep regulatory expertise as early as possible, ensuring they can grasp regulatory expectations quickly, and better plan a risk-mitigating development strategy. They also need to engage with Japan’s regulatory authorities early and frequently. Such early consultation can also bring to light important financial privileges, helping developers avoid unnecessary costs. Accordingly, it is vital that a Japanese CDMO partner has broad and deep regulatory knowledge, as well as established relationships with regulatory bodies. This is one of the most important capabilities to look for when selecting a Japanese CDMO partner. What to look for in a success- enabling Japan-based CDMO 13 What to look for in a success-enabling Japan-based CDMOCGT&RM-specific manufacturing and technology transfer expertise CGT&RMs pose unique challenges when it comes to clinical manufacture, owing to their intrinsically sensitive and varied starting materials, and complex, non-standardized, manual processes. Accordingly, creating repeatable, scalable, compliant processes is no easy feat, and transferring these processes to a foreign organization such as a CDMO can be difficult. Without the right expertise and capabilities to hand, companies can waste time and resources creating a CGT&RM manufacturing process that can’t scale while remaining compliant, and technology transfer can be unnecessarily complicated and issue prone. Your chosen CDMO should therefore have extensive experience in working with a broad range of starting materials (cell types and vectors), efficient manufacturing process development, and smooth technology transfer. Even in the commercial stage, CGT&RMs can pose challenges, particularly when it comes to stable product supply. For example, minimizing the risk of Out-ofSpecification (OOS) products is much more difficult in CGT&RMs (especially in autologous products) compared to other modalities. Continuous improvement of manufacturing methods and specifications is vital. But this demands deep understanding of the relevant regulations as well as experience in commercial CGT&RM manufacturing. Companies seeking an effective CDMO partner should also therefore ensure that their selected CDMO can offer this know-how and experience. 14 What to look for in a success-enabling Japan-based CDMOA strong track record of bringing CGT&RM products to market Many of the capabilities of a success enabling CDMO hinge on extensive experience of manufacturing and commercializing CGT&RMs in Japan. By partnering with a CDMO that has trodden the path to CGT&RM manufacturing success many times, companies not only get a partner that has the right capabilities, knowledge, and network for success for a multitude of potential scenarios, but also access to a wealth of insights into how to maximize efficiencies and capitalize on opportunities at every step of the process. It’s no surprise then that companies looking to maximize chances of success in Japan should seek a CDMO that has already brought several CGT&RMs to market. Strong collaboration with logistics companies As already noted, cell-based CGT&RMs are highly sensitive to exogenous factors such as temperature. In the case of autologous cell-based therapies, manufacturers must also guarantee rapid delivery to the point of care while ensuring a secure and meticulous chain of identity and chain of custody. This means careful, efficient management of logistics is essential to ensure the right environment is always maintained. Fail to get this right and you could compromise the efficacy