The FDA recently announced it has made corrections, updates, and additions of a backlog of formulations to the Inactive Ingredient Database (IID), an important modification for drug developers and development. The previous state of the IID had become an issue as excipient suppliers recommend the use of new excipients to meet the challenges of new formulations and delivery mechanisms.  However, even after these excipients had been approved in drug product formulations and supportive data should be available, it was not accessible to sponsors as supportive safety data.  Too much time was spent re-creating data packages on “nearly novel excipients” for industry and reviewing those packages for the agency when this information existed and excipient vendors should be able to point to it within the IID.

What Is the IID?

The IID is a FDA database of drug product components extracted from approved drug product formulations. This database provides insight into the quantity of excipients currently in formulations on a mg/unit in solids or % wt/wt (or %wt/vol) in solutions, creams and sterile injectables.

What the IID Is Not

The IID is not a formulation guide for source of composition information on approved dosages. This information, with the exception of sterile injectable and some liquids and creams, is generally considered proprietary to the sponsor. You will not be able to connect component/excipient quantities to formulations from this database alone.

What Is New in the IID?

The FDA presented its progress at the 2016 AAPS meeting in Denver, Susan Zuk, acting branch chief of the Regulations, Guidance and Standards division of the Office of Pharmaceutical Quality (OPQ) stated that the backlog of nearly 4000 formulations since 2005 has been almost completely caught up along with correcting errors and standardizing the units and naming nomenclature where possible.  They acknowledged the support from the International Pharmaceutical Excipient Council (IPEC) and multiple sponsors sending comments to the email IIDUpdate@fda.hhs.gov for the help provided with the corrections and improvements of this data base.  IPECamericas.org is a great resource for information, where some valuable white papers on terminology, excipients, and quality are available to non-members.

How to Use the IID:

With all of this new data, drug sponsors should re-look at the IID while developing submission packages. This typically is discussed in module 3. With 4000 formulations and X-fold pieces of data from 2005, a sponsor has many choices on what to include in an application and could be making decisions on missing or erroneous data. Finding an excipient in the IID is still a challenge, but may be helped by downloading an excel copy and searching by the unique identifier (UNII) or the name used in the United States Pharmacopeia (USP).

A word of caution when working in the USP -single monographs may cover a wide range of grades and multiple sources of the component. The Chemical Abstracts (CAS) number is also searchable and will cover a wide range of compounds with the same molecular formula. Often there will be a series of seemingly the same compounds in a wide variety of dosage forms with various stated levels. This information will need to be interpreted per the unit dose and the maximum daily dose of your drug product. By looking to literature searches and published pre-clinical and clinical data to fill gaps, the maximum daily dose (MDD) greater than the identified IID quantity can be extrapolated. Also note that there are now entries that state NA, which may mean they cannot validate what level was present in the original approved drug product.

Improvements in the IID benefit all drug developers and reviews, but it is not necessarily the complete information for safety claims in a new drug application (NDA). 505(b)(2) applications often rely heavily on the drug substance safety data proven by the original application. The safety and suitability of the drug product must still be demonstrated. There will continue to be challenges in interpreting the information from the IID (provided as mg/unit or w/w % of a topical), correlating the component total quantity to be dosed at the greatest labeled use with the maximum daily dose (MDD) for the formulation of each component and understanding the delivery mechanisms / targeted absorption matters in interpreting the IID.

In closing:

The FDA recognizes that there is still room for improvement to the IID, and has provided email links to send your questions and/or corrections to them:

• Corrections and question about the IID: IIDUpdate@fda.hhs.gov
• Corrections and questions about preferred names: fda-srs@fda.hhs.gov
• Questions about excipients in generic product development: GenericDrugs@fda.hhs.gov

The joint efforts for the IID from users will make it the closest thing to “Wikipedia” you will find on a FDA website.

With an in-house CMC team of experts, Premier Consulting can provide guidance through safety data and recommend the appropriate use of IID data. Contact us to learn more.