Developing cell and gene therapies (CGTs), from discovery to commercialization, is highly complex. Further, as this sector continues to mature many process parameters will remain ill-defined. This can make it difficult to forecast budgets for development and manufacturing. There are many reasons why budgeting requires flexibility, from the need to adhere to nuanced regulations, to meeting demanding investor and leadership team timelines.
Here, we have assembled five tips to help maximize the value of your chemistry, manufacturing and controls (CMC) budget and stay on track to meet development milestones.
Tip #1 - Be Realistic About Whether the Process Is Manufacturing-Ready
In the race to the clinic, it is common for CGT developers to underestimate the time required for process development, that in turn, enables a smooth transition to Good Manufacturing Practices (GMP) manufacturing. This failure can have a critical impact on clinical and commercial timelines. However, working with an established contract development and manufacturing organization (CDMO), which has a strong development team and experience with similar projects, can help to develop realistic timelines.
Review Our Checklist and Determine if You’re Manufacturing-Ready
1. Are all consumables GMP-grade?
2. Is the process fully closed?
3. If your process is not fully closed, are open manipulations risk-appropriate?
4. Have you successfully completed a technology transfer?
If you have three positive responses, you are ready for manufacturing!
Tip #2 - Factor in Variability and Contingencies for Materials and Equipment
During the development stage critical decisions about material and equipment are finalized. Your CDMO will help to put in place a sourcing strategy for materials and equipment needed for your process. This includes establishing qualified secondary sources, determining lead times, and eliminating redundancy in the supply chain.
Planning for eventual GMP manufacturing is critical. Early process development should involve discussions with the experts at your chosen CDMO about how to incorporate GMP grade materials. Identifying required GMP grade materials early will allow your CDMO to perform necessary testing and speak with suppliers upfront to determine if they can meet eventual needs when your product reaches the GMP manufacturing stage. Depending on the material, your manufacturing needs can far surpass available stocks.
When it comes to materials and equipment, it is critical to plan ahead. A CDMO will help to de-risk your process through careful forecasting and scheduling.
Tip #3 - Planning for the Regulatory Requirements
Regulations around GMP manufacturing of CGT products can be subject to interpretation. Unfortunately, misunderstanding requirements can lead to delays in progress to the clinic. It is critical to engage with a regulatory expert throughout the development process. A regulatory professional will guide you in discussions with the appropriate government agencies. Input on regulatory affairs will allow you to create a GMP-ready process that is aligned with local regulatory requirements.
Engaging with regulators early can help you make better and more timely decisions. It is easier and more cost-effective to make process changes early. For example, if significant process changes are required to meet regulatory requirements, doing so late in development would require additional preclinical or even clinical comparability data.
Engaging with regulators often throughout the development cycle will ensure that potential issues are identified and addressed prior to any regulatory submission, reducing the risk of delays. For example, you may wish to engage with a regulator during preclinical development to ensure plans are on the right path. You may want to meet with regulators again before completing your first clinical trial application to ensure acceptability of the clinical protocol, finalized manufacturing process, and preclinical data.
It’s also common for companies to engage with their regulators at key milestones, such as the end of early-stage clinical trials or before finalizing late-stage or pivotal studies. Further, if you need to make changes to significant aspects of the product, such as the manufacturing process or target patient population, these are also triggers for engaging with regulators.
Tip #4 - Begin with the End in Mind
It’s important for CGT developers to plan for their manufacturing requirements as early as the preclinical stage of development and “lockdown” their process as soon as possible. The first step is clearly defining end-manufacturing scales and identifying the optimal scaled-down model to use during process development.
Another key early decision will be determining the bio manufacturing modality that is appropriate for achieving the desired scale. For example, is a bioreactor required or can the process be carried out using cell stacks? If a bioreactor is your choice, what system is most amenable to scale-up? Choosing and investing in a modality that will not support commercial manufacturing would be a costly mistake. A good CDMO will help you to avoid this pitfall.
An ongoing discussion with your CDMO about process controls and in-process analytics is an important aspect of ensuring your process is GMP ready. For instance, process controls and analytics used during development will be comprehensive, in order to get the data you need to characterize your process. However, once your process is established, you will have to modify controls and analytics to support manufacturing. Thinking about this during early development will help you to be streamlined and efficient as you transition to the GMP clean room.
Ultimately, process development with GMP compliance in mind, will save time and keep budgets in line.
Tip #5 - Take Advantage of an Experienced CDMO
An experienced CDMO can help guide your therapeutic development journey from process development to GMP manufacture. Even if the technology isn’t familiar to your CDMO, their experience with a wide variety of clients provides broad knowledge to facilitate refinement of the project requirements and budgetary alignment.
A CDMO may provide an initial estimate, but a deeper analysis as they work with a customer may reveal challenges which can increase process development costs. CGT is a nascent industry and as a result, costs are not yet normalized. The benefit of standardization that exists in traditional pharmaceuticals does not apply since each therapy is unique and has variable strategies. A CDMO can provide a representative idea of what the budget and contingencies should be for certain classes of therapies.
A CDMO should take a transparent approach to quoting process development work. They should provide an estimate of timelines, the cost of labour, and materials based on the scope of the work determined in collaboration with a client. A CDMO should also be willing to have an open discussion regarding the risks and assumptions embedded in a development and manufacturing plan. Budgeting for complex CGT products will always require a certain amount of flexibility and an understanding of the inherent risks. A strong partnership with a CDMO can provide stability and ensure product development happens on time and on budget.
To learn more about how CCRM’s CDMO services can support your cell or gene therapy product, please contact email@example.com.