Many industry experts rate planning for manufacturing needs at every stage of development as a critical component of success for cell and advanced therapy (CAT) companies. They note that considerations related to manufacturing, including making capacity decisions too early or late, using off-the-shelf versus custom components, and managing product variability, can have a significant impact on costs and development timelines. In some cases, they can put entire companies at risk.

To explore these issues further, we invited three leading experts in CAT manufacturing planning and technology to offer their insights:

Brian Hanrahan (Invetech): First and foremost, if you don’t think about manufacturing and scalability early, it can limit your ability to get to commercial scale. There are now more options than ever in terms of technology, but you need good internal and external guidance to make the right choices at the right time.

Dieter Hauwaerts (Celyad): The biggest mistake I see is companies that do not have a carefully thought out plan in place early on. Many companies also estimate their scale needs imprecisely and sometimes overdo it by scaling up too fast, or underestimate the work required to deliver beyond clinical scale volumes.

Richard Grant (Invetech): In CAT research, manufacturing is manual at first, and many researchers are too risk- and change-averse. They continue to focus on manual operations for too long. Eventually this will become cumbersome and increase the risk of contamination. CAT companies need to be prepared to change a manufacturing process whenever it is necessary or advantageous. The next five years will be a critical time in CAT technology with many important advances. And they should have the process locked in before changes become too risky and expensive.

Hanrahan (Invetech): It is important for CAT companies to recognize early on that to the regulatory agencies the manufacturing process is the product, especially in the absence of clear characterization (e.g., potency assays and mechanism of action). Ultimately, if you do not have a sense of where you are trying to get to at commercial scale, it can be very difficult to get there.

Hauwaerts (Celyad): You have to plan for all your potential manufacturing changes and you need to consider every option. It is essential to remember that there is no one path forward that works for every company and every cell therapy product.

Grant (Invetech): You need to look at every step in your manufacturing process right from the beginning and identify those that are most variable. And very early in the development cycle you need to think about the timeline and technology to address potential problems. How can you make processes consistent? How can you adapt them to a closed manufacturing system? These decisions will often be based on the most complex steps in the manufacturing process. But you have to plan for changes in processes that present a risk of variation in the cells and also the “skilled steps” or complex manipulations that are handled manually initially. In cases where manual processes do not affect quality, you may be able to delay decisions on automation. It is ok to continue to use manual operations as long as they do not increase risks or costs.

Hanrahan (Invetech): Multiple factors associated with manufacturing can lead to delays and additional costs. In some cases, challenges in manufacturing can completely derail a clinical program. CAT companies need clear guidance from internal teams and experienced consultants on decisions related to technology and automation at every stage.

Grant (Invetech): In the pre-investigational new drug (IND) stages researchers are focused on safety and demonstrating mechanism of action. They need to see if the product works and does no harm. At this stage, it is generally too early for a comprehensive manufacturing assessment.

Hauwaerts (Celyad): In pre-clinical development, major investments and decisions related to manufacturing are usually not priorities. Testing is done in-house or in animal facilities. Production processes do not yet need to be fully outlined or standardized. At this stage, it remains more important to easily adapt these processes as necessary.

Hanrahan (Invetech): It is usually the transition from pre-clinical to clinical trials that will drive the first decisions related to automation.

Hauwaerts (Celyad): By the time the IND is filed and companies start treating in humans, they must be able to describe all manufacturing processes and materials in sufficient detail. In addition, development cycles in the clinic for CAT companies can be fast, so companies often need to develop manufacturing quickly. Into Phase I and definitely by Phase II, CAT companies need to make definitive choices related to manufacturing. To be able to do so, they also need a clear view about their indication, the size of their target patient population, and the way the product will be used in the hospital environment.

Grant (Invetech): By Phase I, companies should consider development of a manufacturing planning document that presents an initial outline of the path forward to full capacity. This should identify all of the production processes and the technologies available to execute them. The plan should also indicate where investments in equipment will be necessary in the development timeline.

Hauwaerts (Celyad): By Phase II, feedback from regulators related to manufacturing is key, and this is where they tend to get very involved. Initially their feedback is on safety, focusing on issues such as viral banks, raw materials and sera. At later stages, feedback tends to focus on product potency and consistency/variability. Guidelines and standards for advanced therapy medicinal products (ATMPs) are out there, and regulators do expect CAT companies to adhere to them. Regulators are well educated, and know what is achievable in manufacturing and testing, but they look to the CAT companies to come up with the solutions for their specific products.

Grant (Invetech): Phase II is when CAT companies really have to lock in and invest in their manufacturing process. They need to move toward commercial scale even though they don’t need to be 100 percent there yet.

Hanrahan (Invetech): By Phase III companies need to be using the technologies they will be using in commercial production. At this stage, particularly for autologous therapies, the patient numbers are not sufficiently large and therefore a fully integrated and automated solution is not necessarily required. However, CAT companies do need to be able to clearly validate that the key processes are consistently the same.

Grant (Invetech): Differences in manufacturing in allogeneic versus autologous therapies are significant but fairly straightforward. With autologous therapies, you need to plan to replicate the process for individualized batches to meet demand. With allogeneic therapies, you need to assess what your batch size will be and whether you can consistently produce in those quantities.

Hanrahan (Invetech): The first step with allogeneic therapies is to confirm whether you can make big batches. A later but critical consideration is whether commercial stage production procedures are commercially viable. With autologous therapies, once you confirm a reliable and consistent production process, you need to demonstrate that you can replicate it to meet demand at every stage. From cell collection through clean up, manipulation and production, you also need to consider opportunities to optimize use of equipment through integration of multiple production processes.

Hauwaerts (Celyad): With autologous, you replicate your production technology as needed. With allogeneic, the goals and challenges are mainly related to the size of your equipment and production facility – you need bigger equipment to produce more products. One common planning mistake CAT companies can make is investing too much too soon; they overestimate production needs and develop non-scalable or larger facilities than they need.

Hauwaerts (Celyad): Decisions to move from OTS to custom equipment can be tough. OTS is usually more affordable, but it’s only a good option if you don’t have to accommodate its limitations too much. Most companies use OTS early on, and tweak it as they advance their development programs. We have seen instances where OTS technology has supported CAT companies very well far into the clinical development program.

Grant (Invetech): In many cases, especially early in the development cycle, OTS equipment can be adapted for many needs in cell therapy manufacturing. But they are self-limiting. They typically can’t run in a full factory set-up, may add unacceptable costs or overhead, and they can’t do everything. So it’s rarely a long-term solution. Take for example a dendritic cell based cancer immunotherapy with amplified RNA as the antigen teaching the patient’s immune system to attack the metastatic tumors (Argos Therapeutics). In this case, the number of complex cell based processes, and the requirement for days of incubation, as well as the complexity of the PCR based RNA manufacturing process demanded a custom solution.

Hanrahan (Invetech): When it comes to OTS versus custom, it often does not need to be fully one or the other. CAT companies can often prioritize by using some OTS technology for processes that are not critical and adding customization to support those that are more critical and complex. In these cases, an integrated solution where OTS and customized or configured equipment are matched and connected together can provide a closed manufacturing solution.

Grant (Invetech): One great advantage today is that more cGMP-ready equipment is becoming available some with flexible user interfaces to perform more cell therapy manufacturing functions such as cell selection and cell washing. We are seeing a trend to instrumentation and cGMP manufacturing technology that is modular and suitable for integration. This is allowing OTS equipment to reach new levels of configuration enabling better and cheaper cGMP manufacturing options.

Hauwaerts (Celyad): Regarding planning related to single use systems, it’s a good idea to begin planning in Phase I and make firm decisions by Phase II. You should postpone decisions as long as possible, because single use systems represent big and ongoing capital investments. But in most cases, decisions related to single use systems will be driven by the timing planning for a company’s manufacturing facility, because it can have a significant impact on facility footprint and workflow.

Grant (Invetech): In their early days, most CAT companies have scientists on staff but they do not have engineers or regulatory teams in place to support many essential manufacturing decisions. By the time they are planning for early-stage clinical research, CAT companies should prepare a comprehensive gap analysis to identify proficiencies and needs related to manufacturing. To do this, they often have to reach out to consultants who have relevant experience in building a manufacturing plan. It is also important that these consultants have scientists with cell processing experience, in addition to their other technical skills, to ensure that the solutions proposed suit the manufacturing process.

Hauwaerts (Celyad): CAT companies should identify consultants early on to support planning for manufacturing. But it’s important to note that very few consultants have experience in both early- and late-stage manufacturing requirements. In most cases, companies engage separate consulting partners for each stage in the planning and build out process. In early stages, the primary consideration for consultants is that they are familiar with a company’s science. In later stages, consultants need to be more familiar with larger scale manufacturing that can support commercialization and can achieve target levels of purity and consistency. CAT is still in its early years, and so there are not many consultants who have worked extensively with late-stage companies. It may be necessary to find consultants with relevant late-stage experience in other areas such as biotechnology or regenerative medicine that is transferable.

Hanrahan (Invetech): Phase II/early Phase III is the key point where companies need to be engaged with consultants who can help them develop a final detailed plan for scalability. They can help you through the range of decisions necessary to transition to an appropriately customized and automated closed system. At this stage, a production process should be well established and vetted. We have worked with a number of CAT companies at these stages, helping to select the appropriate equipment for integration into their manufacturing process. In cases where there’s no current solution available in the market, we have invented suitable solutions to enable closed cGMP manufacturing.

Hauwaerts (Celyad): CAT companies also need the necessary internal resources in place to plan for manufacturing and scalability – you cannot just outsource everything. This applies to the development and manufacturing groups, but also other teams like regulatory and clinical development must plan for durable knowledge integration.

Hauwaerts (Celyad): One of the first and most important things to look for in working with an outside partner on manufacturing is the strength and flexibility of your own internal team. While being very strict on the key quality attributes, they should also be willing to consider new ideas. They cannot be overly rigid or protective when it comes to the manufacturing process. They must be able to assess and embrace change. The stronger your team is, the more you will get out of any partnership.

Grant (Invetech): You’ll want to look at any service provider’s relevant experience and ask pointed questions. Do they understand cell processing? Have they had experience helping companies navigate through all phases of clinical development and product manufacturing? Are they familiar with and can they access, connect, control and configure any custom equipment and automation solutions you may need? They need to be able to draw out and understand the cell science and translate the process requirements into an engineering specification.

Hanrahan (Invetech): You should note whether consultants have helped clients reach late stage production requirements, as well as plan for commercial production. A strong relationship between all the internal stakeholders is also imperative to keeping the process moving forward efficiently.

Grant (Invetech): CAT companies should look for a partner with a rigorous process in place to guide and manage the relationship at a scientific, engineering, and business level.

Hauwaerts (Celyad): The most important thing CAT companies can do to streamline development and reach manufacturing goals is to be well organized internally. R&D, clinical, regulatory and manufacturing teams must work together well. And all internal stakeholders must be honest and clear in their guidance to external support teams, especially related to problems and challenges. You need to have agreement on deliverables and timelines. In manufacturing and scalability planning, problems most often arise when teams are not properly aligned.

Hanrahan (Invetech): The great news for CAT companies is that there are more manufacturing options becoming available. With more choices, there is a greater likelihood of identifying good and affordable manufacturing solutions that can be assembled and configured for their processes. A good partner can help you identify and apply the right technology for your needs, and/or develop solutions for any gaps identified.

Grant (Invetech): CAT companies should be comforted by the fact that if you access the right resources and follow good guidance with great internal alignment, the process works. You can address most challenges and if you act early the risk of serious downstream problems will be very low. Your path to success can be very clear.