Outsourcing Clinical Supplies Manufacturing | Page 4

Now, when examining a shipment of clinical supplies, FDA field offices can use EES to search and verify the status of an API, its manufacturer, whether it has been referenced in a valid NDA, or whether it is the subject of a valid IND. This last part is key: FDA is saying that you must have an IND “in effect” before importing API/drug product into the US. It’s not a new law; it’s an admittedly valid reinterpretation of 21CFR Parts 312 and 201 that now can be enforced using EES. An IND is considered in effect only when the FDA has no further questions or no questions at all once the 30-day review period has passed. Clearly, waiting to ship the API/drug product until the IND is in effect can result in significant costs and clinical program delays if the sponsor fails to properly plan for the extended timeline. Advanced planning is required, and working with a knowledgeable customs broker in addition to an experienced quality and regulatory group is highly recommended. Note that, based on our experience with numerous clients engaged in early phase drug development, many ports of entry have yet to adopt/enforce this requirement. As of January 2013, we are only aware of import refusals under this requirement for materials entering the US through Chicago. We expect it will not be long until the other ports are using EES and this application of the regulations to refuse clinical supplies in advance of an effective IND. Figure 4. Resolving the “Catch-22” Submitting an IND without Clinical Supplies: A “Catch-22” » There is, however, an additional wrinkle. In the last few years the CMC (Chemistry, Manufacturing, and Controls) reviewers at FDA have begun to require that the Certificate of Analysis (COA) for the clinical batch be included in the IND rather than just providing a commitment to submit the COA prior to patient dosing. In effect, you can’t get an IND without testing the API/drug product, and you can’t the API/drug product into the country without an IND. Theoretically, this “catch-22” can be resolved by importing only a limited quantity of API/drug product to complete release testing and put some samples on stability. This research exemption and the required labeling are detailed in 21CFR 201.125,7 which precludes the importation of excess drug that could, at any point, be turned into supplies for human use. For illustration, let’s take a typical scenario: ▶ Synthetic small molecule API manufactured in China ▶ US drug product manufacturer to create powder in capsule clinical supplies (ie, the formulation is literally just API in the capsule) ▶ IND not yet submitted ▶ API needed for pre-IND testing = 50 g. clinipace.com 3