This is no time to talk about time. We don’t have the time!
-Deanna Troi, “Star Trek: First Contact”
Timelines are one of the major topics during biotech product development, whether that is performed in-house or via contract with a CDMO. While most scientists working in biotech came into the field to do research and to help find new products to help patients, there is undeniably the capitalist aspect to the business as well. Getting a new product approved and onto the market before a competitor is critical to getting market share, meeting clinical timepoints is critical to continued venture capital funding, and of course ensuring that the product has enough commercial years while still on-patent is required to ensure the ROI needed for it to be successful. There are hundreds of articles and discussions about those aspects of biotech product development timelines, so instead of rehashing that information this post will discuss the hidden holdup of materials supply and how it impacts timelines.
12 months to GMP! Are you sure?
Several CDMO’s advertise “12 months from contract signing to GMP production,” and it certainly seems like the unofficial new standard for startups bringing their first molecule to the clinic. This sounds great on paper, and many clients don’t see a problem with it at first, thinking that they’re looking at 9 months of development and then 3 months for the transfer and GMP production. That sounds reasonable, right?
It would be….except for the lead times of GMP materials.
Biotech processes are complex and include specialty materials from multiple vendors. While vendor lead times have improved significantly over the long lead times experienced during the pandemic, they are often a minimum of 4 months and can be as long as 12 months. Vendors are constantly working to improve their own manufacturing and storage capabilities, as they’d prefer to not have to tell their customers about long lead times, but they are also running businesses and won’t plan to lose money on stock that may not be used just to cut lead times down by a few weeks. There are also external factors that impact vendor production times, such as storms hitting production facilities, which may change lead times.
Simpler items that see consistent demand, like sterile filters, often have lower lead times than items that are more complex or see lower demand, like chromatography resins. Some items even have compound lead times, such as a prepacked column which has a 16-week lead time for the column packing but also a 12-week lead time to get the resin, resulting in a 28-week total lead time after ordering before the column arrives at the facility.
Items arriving at the facility is also not the end of the lead time, because then they must be inspected by Quality, entered into the GMP system, and released for GMP use. This process usually takes a few days to a few weeks, depending on the item and whether it’s been used at that facility before. Introducing a brand new product or supplier into a GMP facility is a big undertaking, and often requires additional time and resources before it’s available for use.
Where does that leave process development?
Assuming a six-month lead time to get the GMP materials onsite and ready for use, that means the bill of materials and both upstream and downstream processes have to be locked a full six months prior to product thaw for GMP. This is half of the promised 12-month timeline at a minimum, and sometimes process lock is required nine months ahead of time, which cuts it down to just 3 months between contract signing and process lock.
Process development does not start at the CDMO the day the contract is signed by the client, or even the day that the molecule is transferred internally at an R&D company. The scientists have to be allocated to the project by management, the project management team has to be set up, any new materials have to be ordered, and time on the existing bioreactor controllers and chromatography systems has to be planned out. No lab is sitting empty waiting for the next project, ready to start immediately, so actual experimental work is likely not starting until the beginning of month two.
What does this timeline tell us? There are only 3-6 months allotted for process development, and one of those months is taken up by project start-up and preparation, resulting in just 2-5 months for all of process development to occur!
This may be sufficient if the product is a typical mAb that is well behaved, but if it’s a new or atypical modality, the chances of getting everything developed into a robust enough process to survive scaleup to clinical production are much lower. Keep in mind that if this is a brand new molecule, this may be including cell line development, clone selection, master cell bank generation, bioreactor development, chromatography and filtration development, and analytical development of multiple assays – a large body of work that is just not going to be done (or probably not done well) in only 2-5 months.
Treat Process Lock as the End of Development
When planning out a new project, the process lock date should be considered the end of development for upstream and downstream. These teams plus the analytical team may continue some work after that date, and even produce tox or formulation study material, but no major process changes can be made without pushing out the GMP production timeline. Once the process lock to GMP thaw time period is known, then a true timeline can be built that allows sufficient time for process development to do their work to produce a robust process that meets the regulatory guidelines for a successful IND.
Contract signing to GMP initiation in twelve months isn’t impossible, and it has been done in many locations for many companies. But it’s not always guaranteed, and often the process development team is blamed for holding up the timeline when in fact it’s the early process lock due to long materials lead times that is the real difficulty in meeting the desired timeline. Always check on materials lead times, especially for new items, before finalizing a timeline to ensure that the process has the best opportunity for success.
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