Yesterday, FDA released draft guidance on the use of the Inactive Ingredient Database (IID) in drug development. The guidance is one step FDA is taking to address feedback from the generics industry that IID enhancements are needed to help sponsors make the right formulation decisions.
What is the IID?
The IID is an FDA database of drug product components extracted from approved drug product formulations. This database lists the maximum quantity of excipients (inactive substances generally used as a carrier of the API) per unit dose.
Why is it wrong to assume all excipients listed in IID are safe?
Safety of an active pharmaceutical ingredient (API) or excipient is a function of the exposure: the amount, duration and tissue to which the material is exposed. The IID does not contain the maximum daily exposure, maximum daily intake, or specify which product(s) the data come from. This information, with the exception of sterile injectable and some liquids and creams, is generally considered proprietary to the sponsor.
Without this data, a toxicology review is needed for every excipient in a proposed product to bridge the gaps and connect excipient quantities to formulations.
What studies are needed to test safety?
If the excipients in the new drug product are listed in the IID for the given route of exposure, and the amounts in the new drug product are at or below IID maximum potency levels, additional nonclinical qualification of the excipients is typically not required.
Nonclinical testing will likely be needed to qualify the excipient if it is:
- not listed in the IID
- listed but not for the new route of exposure, or
- proposed to be dosed at levels higher than the maximum potency level in the IID
In addition, nonclinical studies may be needed if there were any unexpected or potential interactions between the excipients, degradants, and/or impurities. The nonclinical testing can range from including appropriate control groups in any new toxicity studies to a full nonclinical program to qualify the safety of the excipient, as outlined in FDA’s excipient guidance.
What’s ahead for the IID?
FDA has agreed to complete enhancements to IID by October 1, 2020 to provide maximum daily intake and maximum daily exposure information for each route of administration for which data is available. The Agency will make updates on an ongoing basis, with a quarterly notice of updates to help users identify changes made.