The use of inactive ingredients is as dated as the beginning of formulated drugs. Experts now agree that “excipients are neither inert nor inactive substances and depending upon their chemical nature and host factors may produce a variety of undesirable reactions.”¹ The good thing is, the regulatory authority that is primarily responsible for the safety of inactive ingredients used in pharmaceutical products intended for the U.S. market has been actively working on ways to improve the availability of information related to inactive ingredients.

As part of the Food and Drug Administration’s (FDA) mandate, it not only reviews the safety and efficacy of drug products, it also ensures that the inactive ingredients used in the formulations are also safe. A new inactive ingredient, commonly referred to as an excipient, will receive careful review related to its safety. If the FDA has approved an excipient as part of approved drug products for a route of administration, generally it is no longer considered new. Therefore, the excipient may go through less extensive review when the same excipient is used in a new drug product. To make things more efficient and useful for the FDA and the industry, the FDA has been making this review status available for some time in the form of guidance and more recently in the form of a database. This article summarizes the key takeaways from the most recent draft guidance² on the topic with some historical background of the struggle with inactive ingredients.

Background
An article containing 773 ingredients prepared by the FDA in 1982 for use as inactive ingredients was the earliest list of inactive ingredients.³ In 1985, the American Academy of Pediatrics’ Committee on Drugs published an article on “Inactive” Ingredients in Pharmaceutical Products.⁴ The Committee stated that because of the large number of inactive ingredients and their frequency of use, practicing physicians had become concerned about their possible physiologic effects. “The increasing number of reports of adverse effects associated with pharmaceutical excipients has led to professional and consumer organizations formally requesting the FDA to require complete disclosure on the product label of all substances contained in pharmaceuticals.”⁵ The article discussed the problems encountered with inactive ingredients and highlighted the specific excipients such as benzyl alcohol, propylene glycol, lactose, coloring agents, sulfites and saccharin.

In 1987, the FDA prepared and published a list of inactive ingredients in paper format and called it the inactive ingredient guide (IIG).⁶ The list contained inactive ingredients and the amounts that have previously been reviewed and approved by the FDA for a dosage form and/or particular route of administration. Over time, the list continued to grow as more inactive ingredients and additional details were added. The FDA released the online version of the inactive ingredient database (IID) in 2003.⁷ Since its release, both industry professionals and the FDA have been using the database. The IID database indicates the maximum potency of a specific excipient based on the route of administration and dosage form. In this fashion, formulators can use the IID database to evaluate the use of potential excipients in their drug product without needing to generate additional safety information. Similarly, when the FDA receives a new drug application (NDA) or an abbreviated new drug application (ANDA), it refers to the IID to see if the proposed excipients in drug product formulations are acceptable or require additional documentation related to safety.⁸

However, inactive ingredients continued to be an issue for both the industry and the FDA. In October 2010, the FDA implemented the Substance Registration System (SRS) which had a significant impact on the IID. Concerns were raised regarding how it is managed, and the information utilized for NDA and ANDA drug product reviews. By 2011, the International Pharmaceutical Excipients Council of the Americas (IPEC) had been contacted by a number of both member and non-member companies around the world concerning issues related to changes in the FDA policies on how the IID was to be referenced to determine the acceptable levels of specific grades of excipients.⁹ IPEC requested and met with the FDA on December 9, 2011, to convey the industry concerns and understand the FDA’s needs. Since then, IPEC and the FDA have met frequently to facilitate the appropriate use of IID listing information.

In October 2013, the FDA published a draft Guidance for Industry titled “ANDA Submissions - Refuse-to-Receive Standards.”¹⁰ The guidance suggested that an excipient is considered justified, for receipt purposes, if the proposed level is at or below the amount indicated in the IID for the corresponding route of administration of the test drug product. If an applicant uses an excipient at a level that is higher than what is listed in the IID, a few options are available. First, an applicant can submit complete pharmacology/toxicology information to support the excipient. Second, cite specific examples of a CDER-approved drug product that contains the inactive ingredient at or above the proposed level of use for the appropriate route of administration. Alternatively, the applicant can submit a Controlled Correspondence requesting an evaluation of the proposed level of use before submission of the ANDA. The final guidance was issued on September 2014.¹¹ As the generic drug industry was facing new challenges in drug development, the FDA indicated that it had developed a prototype IID database to improve the IID. The enhanced database includes the Maximum Daily Intake (MDI) of excipients in addition to the potency per unit used in the current IID.¹²

In April 2015, IPEC published a position paper on FDA’s Inactive Ingredient Database.¹³ In it, IPEC articulated its position on the current state of the IID and FDA’s use of the data in the IID to determine acceptance of ANDAs. IPEC stated that “pharmaceutical companies have encountered longer review cycles, unnecessary requests for additional safety studies/information and/or Refuse to Receive letters from the Agency.”¹⁴ IPEC recommended that the FDA “institute policies based on sound science and risk for using IID information in the evaluation of ANDA applications.”¹⁵

With the authorization of GDUFA II, the FDA published a commitment letter regarding its performance goals and program enhancements for fiscal years 2018-2022.¹⁶ The commitment letter included the following goals for the IID: “By October 1, 2020, FDA will complete enhancements to the IID so users can perform electronic queries to obtain accurate Maximum Daily Intake and Maximum Daily Exposure information for each route of administration for which data is available FDA will update the IID on an ongoing basis and post quarterly notice of updates made. Such notices will include each change made and, for each change, the information replaced.”¹⁷ As a first step toward that goal, the FDA published the draft guidance, “Using the Inactive Ingredient Database,” in July 2019.¹⁸ 

The Draft Guidance: Using the Inactive Ingredient Database
The guidance describes how the industry can use the IID to evaluate excipient levels that are safe for use in new formulations. It describes the structure, nomenclature, maximum potency levels, and units of measure used in the IID. The FDA enters all drug formulations into the Agency’s internal master database as part of the application record. On the other hand, the FDA creates the IID based on a subset of information from the internal master database and makes it publicly available. The IID lists the largest value of an excipient for each route of administration and dosage form available from the FDA’s master database. However, IID does not reveal the formulation or identify the product. This value appears as the maximum potency listed for the excipient for that route of administration and dosage form. At times, the FDA removes entries from the IID if the Agency has reason to question the safety of excipients, or to correct information. The removal usually happens when drug products are reformulated or withdrawn from sale for safety reasons that implicate the excipients. The implication is that an excipient may remain on the database if the corresponding drug product is reformulated or withdrawn from sale, not for safety reasons or the safety issue is not due to the excipient. If someone needed to look up previously published versions of the IID for an ingredient, archival files from 2009 to present, can be downloaded through the IID web page.

The IID displays the preferred term for the excipient as it appears in Global Substance Registration System (GSRS) to promote consistency in nomenclature in the IID. Most entries in the IID are distinguished with a unique ingredient identifier (UNII), which is generated by GSRS. The UNII also facilitates Structured Product Labeling (SPL), which includes UNIIs for all excipients. The guidance defines the maximum potency as the highest level of the excipient per dosage unit in each dosage form in which it is used. The FDA provided an example in the guidance to illustrate the difference between the maximum potency and maximum daily exposure (MDE). Since the units of measure differ for different dosage forms, the FDA attempted to clarify the unit of measure for various dosage forms. For example, maximum potency for solid oral dosage forms is listed as weight. Liquid oral dosage forms are listed as weight per volume and topical products are listed in percentage weight/weight or weight/volume. Finally, parenteral dosage forms are listed as percentage weight per volume.

Although applicants of Investigational New Drug Applications (INDs), NDAs, and ANDAs review the IID to help justify the levels of excipients in their formulations, INDs and NDAs usually include nonclinical or clinical studies conducted with the excipients or proposed studies may provide safety data. Generally, excipients proposed for a generic drug are first reviewed by the FDA when the ANDA is assessed during filing review. For ANDA filings, applicants can refer to the appropriate level of the excipient listed in the current IID. If the applicant is proposing a level higher than that is listed in the IID, a justification supporting the safety of the excipient at the proposed level may get the application accepted for filing. When referencing an IID listing that differs from the proposed excipient in nomenclature, molecular weight, viscosity, or grade, applicants should justify citing the IID listing as the basis for the excipient and its proposed level of use. However, the multidisciplinary review of the safety of the excipients proposed is done during the technical review of the application. If a reference to the IID and any additional information submitted by the applicant is not satisfactory, the FDA may request safety information. However, one should keep in mind that when an excipient requires clinical investigations to establish the safety of the excipient, that drug product would not be permitted in an ANDA.

The guidance also discusses the options available for the industry to communicate with the FDA. Other than contacting the FDA via email to fda-gsrs@fda.hhs.gov for UNII related requests or to iidupdate@fda.hhs.gov for IID listings, reports of errors, or clarifications, applicants may submit application-specific questions about the acceptability of excipient levels, to the Agency as a Controlled Correspondence. The industry has been using this as the primary mode of communication regarding inactive ingredients. The FDA has provided helpful and detailed information on various topics that are covered under the scope of controlled correspondence in the guidance for industry on Controlled Correspondence.²⁰ Unfortunately, the Controlled Correspondences are processed in accordance with current GDUFA timelines that are not helpful for the fast pace of generic drug development and the responses are not always specific for legal or confidentiality reasons.

What to Expect
As expected, this guidance does not provide much more in terms of what is coming down the pike. The FDA has been providing bits and pieces of hints in terms of what to expect. In phase I of this enhancement initiative, new data standards such as the route of administration (ROA), dosage form (DF) and units of measure (UOM) will be applied.²¹ Once the unit of measures (UOM) are standardized within the database, numeric potency values can be accurately compared for each excipient by ROA and DF combination. The advantage of converting to SPL terminology is evident as there are fewer terms for ROA and DF.  One other benefit for frequent users of the database is a change log that identifies changes made in each publication.

One thing is for sure, by October 2020, the IID will include the MDE of excipients for which it is available. Note that only MDE, rather than maximum potency for those excipients, will be listed, if available. What is not clear is that in the absence of an MDE, will maximum potency still be listed? The user-friendly IID interface may not provide all the answers right away, but at a minimum, we will be able to obtain the MDE in a matter of a few clicks for most excipients. 

References

1. Kumar, A., “Adverse effects of pharmaceutical excipients”, Lippincott, Williams and Wilkins, Adverse Drug Reaction Bulletin, October 2003, No. 222
2. U.S. Food and Drug Administration, “Using the Inactive Ingredient Database – Guidance for Industry”, Draft Guidance, July 2019
3. Brown, J.L., “Incomplete labeling of pharmaceuticals: A list of “inactive” ingredients”, N Engl J Med, 1983, 309(7):439-441
4. American Academy of Pediatrics – Committee on Drugs, “‘Inactive’ Ingredients in Pharmaceutical Products”, Pediatrics, 1985, 76: 635-643
5. Id
6. U.S. Food and Drug Administration, “Using the Inactive Ingredient Database – Guidance for Industry”, Draft Guidance, July 2019
7. Id.
8. Id.
9. The International Pharmaceutical Excipients Council of Americas, – “Inactive Ingredient Database Issues with ANDAs: Backgrounder Document”, IPEC – FDA OGD Meeting, December 9, 2011
10. U.S Food and Drug Administration, “Guidance for Industry – ANDA Submissions - Refuse-to-Receive Standards”, Draft Guidance, October 2013
11. U.S Food and Drug Administration, “Guidance for Industry – ANDA Submissions – Refuse-to-Receive Standards”, September 2014
12. Naiqi, Y., “Inactive Ingredient Database – FDA Update”, The USP Excipients Stakeholder Forum, June 18, 2014
13. The International Pharmaceutical Excipients Council of Americas, “IPEC-Americas Publishes Position Paper on FDA Inactive Ingredient Database”, April 22, 2015
14. Id
15. Id
16. U.S. Food and Drug Administration, “GDUFA II Commitment Letter: GDUFA Reauthorization Performance Goals and Program Enhancements Fiscal Years 2018-2022”, May 12, 2016
17. Id.
18. U.S. Food and Drug Administration, “Using the Inactive Ingredient Database – Guidance for Industry”, Draft Guidance, July 2019
19. Id
20. U.S. Food and Drug Administration, “Controlled Correspondence Related to Generic Drug Development – Guidance for Industry”, September 2015
21. U.S. Food and Drug Administration, Most Recent Changes to the IID Database, Current as of 05/06/2019

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Sharif Ahmed
Lachman Consultants Services

Sharif Ahmed is a Principal Consultant in the Regulatory Practice at Lachman Consultants with nearly 30 years of progressive responsibilities in the pharmaceutical industry who is knowledgeable of the product approval processes of U.S. FDA and Health Canada.