Inactive Ingredient Database (IID) – A Predictive Tool for Product Development

Inactive Ingredient:

  • An inactive ingredient is a component of a dosage form, other than the active ingredient, which is inert material and enhances the drug properties acting as a vehicle.
  • Inactive substance may also termed as ‘Excipient’, historically derived from Latin word “Excipere” means ‘to except’.
  • The role of an inactive ingredient is to act as vehicle, to retain attributes like appearance, stability, pharmaceutical, pharmaco-kinetic and dynamic properties of a drug product.

Classification of Inactive Ingredients

According to function of a particular excipient, they are categorized into several classes.

  • Acidifying/Alkalizing
  • Antioxidant
  • Binder
  • Buffer
  • Coloring Agent
  • Diluent
  • Disintegrant
  • Glidant
  • Lubricant
  • Plasticizer
  • Sweetning Agent
  • Tonicity Agent

What is Inactive Ingredient Database?

IID is a collection and aligned set of inactive ingredients, that are present or appeared in FDA approved drug products, allowing industry to access for development of new products.

The first version of database made available in 1987 as hardcopy and an online database came to limelight in 2003.

A snapshot of IID database is depicted below:

 

What is Purpose of IID?

If an excipient is approved in a drug product for a specific route, then FDA will not consider it as new and require minimal investigation studies and less review if it is included in a new product.

How to Read IID database?

IID database provide information about Name, Route, Dosage form, CAS Number, UNII, and Maximum Potency of particular ingredient. The source of information for Route and dosage form are extracted from approved labeling and UNII, CAS number from Substance Registration System and Chemical Abstracts Service respectively.

How to use IID?

IID is a searchable database. Just give any portion of the three-letter string of the above parameters. Results will be appeared alphabetically, which can be sorted by user’s choice based on dosage form, route and potency.

How frequently Database is updated?

As Database provides the information, that aids industry in development and other purposes, FDA updates the database regularly every quarterly, by tenth working day of January, April, July, and October.

What are CAS Number and UNII?

CAS Number:

CAS stands for “Chemical Abstracts Service”. CAS assigns unique numbers to chemical substances and it has no significance as such.

UNII:

UNII stands for “Unique Ingredient Identifier” is a unique alphanumeric code provided by United States Pharmacopiea (USP) and FDA Global Substance Registration System (GSRS) jointly based on molecular structure and description to every substance that has existence.

UNII information is provided as unique identifier in Structured Product Labeling (SPL).

What is Maximum Potency?

The amount or concentration of a drug required to produce half (50%) of that drug’s maximal effect is known as Potency (ED50).

Therefore, with respective to Excipient Maximum potency is the highest amount of ingredient used per unit dose in particular dosage form.

Case Study:

For a drug whose maximum daily dose is 90 mg, the available marketed strengths are 5 mg and 10 mg. Calculate the allowable excipient limits?

Interpretation:

If we consider 90mg as MDD, worst case may be 9 times 10mg and 18 times 5mg dosage form. Let us take an inactive ingredient whose quantitative formula is 50mg and 100mg respectively considering proportional formulation.

So, for 5mg – 50*18 = 900 mg, and 10mg – 100*9 = 900 mg.

Our formulation is allowing a patient to take 900mg of a particular excipient.

When you calculate and compare with IID database, the value should be within the limit specified in IID.

Inference – 50 mg and 100mg of a particular excipient can be used in proposed formulation.

Ambiguity

Apply above case study in practical scenario; it will create a question that for that particular excipient IID database provides multiple grades, route of administration and unit of measurement.

Each grade of ingredient provide different maximum potency for different routes, thus it offer less option for scientists to choose the limits.

Enhancements to the Inactive Ingredient Database

Historically, there is an on-going debate among industry as different grades of same excipient family may exists and each possess unique characteristics probably used in different dosage forms.

As each grade of excipient has unique potency, it is creating a lot of uncertainty among industry or scientists to select appropriate material for development.

Therefore, one can understand that the current terminology in use for route and dosage form are not standardized and leading to ambiguity.

To standardize and harmonize the information to refine it, to understand easily IID database will define standard terms for route, dosage form and unit of measure in the first phase of GDUFA II.

What is the importance of standardization and harmonization?

It will help scientists to compare and select the amount of excipients particular to each route and dosage form precisely based on potency.

MDE vs Potency

MDE and Potency are not linked to each other. Potency is the highest amount of the excipient per dosage unit whereas Maximum Daily Exposure is excipient exposure due to maximum daily dose. Since MDE is superior and provides accurate information over maximum potency, further in future MDE would be display in IID database.

How to justify limit for Different Route or Higher limit listed in IID database?

An applicant may wish to use an excipient in a different route of administration or in higher level than listed in the database provided a sufficient information to determine the safety of the excipient at proposed level or in other route of administration.

To justify the limit the applicant should provide any of the following data:

  1. Complete Pharmacological and toxicological data
  2. Citing reference to any CDER approved product using such limit
  3. FDA Controlled Correspondence response authorizing the use

Role of IID in Marketing Applications

INVESTIGATIONAL NEW DRUGS (INDs)

During IND application agency review for safety and IID may provide evidence of earlier use. If any additional studies conducted with excipients, required to be submitted in IND and are within the scope of review.

NEW DRUG APPLICATIONS (NDAs)/ABBREVIATED NEW DRUG APPLICATIONS (ANDAs)

Applicants must justify the excipient levels by referring IID listing or any of the above data to justifying the use in a different route of administration or in higher level than listed in the database to file or receive the application for review. The technical review includes evaluation of the acceptability of each excipient in the formulation.

Do you want to communicate/Advise FDA about IID?

FDA always welcomes suggestions and inputs from users, specific mailboxes are in place to allow users to communicate with agency.

IID update Mailbox

Anything related to IID database about names, units and request for clarifications can be inquired via email to [email protected]

The inquiries will be assigned to and handle by IID working group in Office of Pharmaceutical Quality.

GSRS Mailbox

Anything related to GSRS database can be inquired via email to [email protected]

Controlled Correspondence

Controlled Correspondence should be submitted to OGD via email to [email protected]

Applicants may submit application-specific questions relating to drug development, including questions about the acceptability of excipient.

Further Reading

  1. https://www.fda.gov/media/128687/download
  2. https://www.fda.gov/media/86660/download

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