What is IIG limit, how it is useful in formulation?

IIG is abbreviation of  Inactive Ingredient Guide. Now it is used as IID( Inactive Ingredient database or also called as Inactive ingredient guide)but now FDA changed from the old guide to a database many years ago. The limits represent the maximum level of use of an excipient in a dosage form that has been approved by the U.S. FDA in a certain route of administration. It does NOT represent the maximum daily intake, just the amount in one dosage form. If the drug may have only had one dosage form approved per day, then, and only then, would it represent a maximum daily intake. There is no database which currently contains the real maximum daily intake at the FDA. However, they expect that the ANDA sponsor will provide some type of assurance that the maximum daily intake they will be using in their drug is below the highest maximum daily intake that has a prior precedence of use in that route of administration. Obviously, if your daily level of use is below what is listed in the IID for one dosage form, then you should have no problem with your ANDA. However, if your daily level of use would be higher than the max. potency level listed in the IID (or Inactive ingredient guide) then you should see if you may have other drugs that you have already gotten approved with a higher level. If so, you can use that as a reference. If not, then you should send FDA a controlled correspondence and ask them if your daily level of use is below what has previously been approved in the route of administration used for your drug. You can than include this controlled correspondence in your ANDA filing.

The IID limits (Inactive ingredient guide limits)   are simply the level of an excipient that has a precedence of use in a previously approved dosage form for a particular route of administration. Again remember the IID limit is not the daily limit. You can only investigate the daily limit through controlled correspondence and the daily limit is what FDA will need to know is below what has been previously used. If FDA gets back to you and says that your level exceeds the daily precedent level, then you would have to submit detailed safety/toxicology data on the excipient itself along with an argument about why this safety data supports your proposed level of use. It would have to be an argument based on the detailed toxicology data and the ADIs that the data supports for your specific route of administration. This will typically take quite a number of months for them to review.

Remember, the key thing to remember is that the IID or Inactive ingredient guide level is only the amount per dosage form that has been approved. It is NOT the maximum daily intake (MDI)! What FDA really needs you to verify is that your MDI is below what has been used in a previously approved drug for the same route of administration. If your MDI exceeds the IID maximum potency for one dosage form, then you typically would need to submit a Controlled Correspondence to FDA which lists your specific MDI for the specific excipient you are using in your formulation and ask them if this MDI is lower than what has been previously approved. There is no current database that contains this information. FDA will then manually research this and provide an answer to that question that can be used in your filing. It may take a number of months to get an answer so these questions need to be asked early in development not when the dossier is being developed for filing. If the FDA says that your MDI exceeds a prior precedence of use for that excipient, then you would need to submit specific safety information to support the safety of your level of use. Typically, FDA will want more than just summary information on the toxicology. They will ask for a reference to detailed toxicological studies in a DMF or from another source for the particular grade you are using. However, this is not usually realistic since rarely are toxicology studies run on all the different grades within a family of excipients. Therefore, realize that suppliers of excipients will not normally have specific tox studies for the grade you are using but should typically have access to data on the family based on bracket studies. Ultimately, FDA expects the drug sponsor to build a good bridging argument to support the grade you are using in your specific application that is then submitted in your filing that includes a reference to where the existing studies are located (DMFs, literature, etc.). The suppliers can sometimes help but ultimately the drug product sponsor must put this argument together. IPEC-Americas is working with the FDA to try to improve the IID and the processes used related to the MDI precedence issue.

Source: Dave Schoneker (Director  Global regulatory affairs at colorcon

reference

http://www.pharmashastra.com/regulatory/inactive-ingredient-guide/