API: If the API can be manufactured in small batches appropriate for pre-IND testing (50 g in this scenario), then importation can proceed using the
21CFR 201.125 exemption. If the API manufacturing processes require a larger batch (for example, 1 kg), then it may be possible for the API CMO to
ship only the 50 g needed for testing (again, under the import exemption) and store the rest until after the IND is in effect.
Drug Product: If the US drug product CMO can process the required 50 g into clinical supplies for pre-IND
testing, then there are no further issues on this front. However, if, for example, the filling equipment
requires a minimum of 500 g of API to run, then there is a significant mismatch. Potential solutions include:
Figure 5.
Impact on
Development Program
• Adding a statement about minimum batch size to the importation paperwork. Please note that
we do not know if this approach will suffice. Communications we have had with FDA on these
matters did not suggest that any exceptions would be made.
• Finding a US-based CMO that can create capsules with only 50 g of API.
• Finding a foreign CMO to create the capsules. Batch size is less important if you can import only
what you need and contract with the CMO to store the excess until the IND is in effect.
• Manufacturing the API and the drug product in the US. Since there is no importation,
batch size is less important.
Identifying, contracting with, and getting a new CMO up-to-speed can be a time-consuming and expensive task.
In some cases, the manufacturing processes may need to be re-engineered to produce appropriate batch sizes.
Impact on Cost and Timelines »
In our scenario a small amount of API is shipped to the US for manufacturing into the test batch to support
the IND submission. This decision impacts the development program in two key ways. First, there’s the cost
of the test batch, which might add an additional $50,000 – $100,000 in manufacturing costs and consume
20 – 200 grams of potentially very valuable and limited API. Second, schedule adjustments will be needed
because the delivery of clinical supplies to the trial sites will be delayed. Until now, the expectation has been
that the drug would be available as soon as the 30-day IND window expired. However, if we consider the
scenario discussed above, the bulk of the API wouldn’t leave China until 2 or 3 days after the IND went into
effect to allow time for the FDA database to be updated. Assuming that the paperwork is correct, it may take
another 5 days for the shipment to arrive, clear customs, and be delivered to the US drug product CMO.
That company now has to make the capsules, perform their quality testing, and ship the product to a
warehouse for distribution to the clinical sites. On average, we estimate that waiting to import the API
until the IND goes into effect will delay the start of patient enrollment by roughly 2 months.
clinipace.com
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