If you’re developing an injectable or ophthalmic drug product, one of the earliest and most consequential formulation decisions you’ll make is which excipients to use. The wrong choice can create formulation stability problems and trigger regulatory questions that complicate your CMC package or require additional toxicology studies.
Two concepts sit at the center of the excipient decision: compendial excipients and the FDA Inactive Ingredient Database. Understanding both, and understanding how they relate to each other, will make you a more informed partner in your own formulation development program.
Kevin Sill, PhD
President & Co-Founder
Callan Pharma Services
What Are Compendial Excipients?
A compendial excipient is any inactive ingredient that appears in an official pharmacopeial compendium. The most referenced is the United States Pharmacopeia–National Formulary (USP–NF), followed by the European Pharmacopoeia (Ph. Eur.) and the Japanese Pharmacopoeia (JP). The Chinese Pharmacopoeia (ChP) has recently undergone a significant transformation and is now much more aligned with international standards, increasing its utility in global manufacturing considerations. The 2025 edition, effective October 1, 2025, explicitly aligns chemical drug standards with USP and Ph. Eur. requirements and incorporates ICH Q4B harmonized testing methods, making ChP monographs increasingly relevant for programs with global development plans or Chinese manufacturing partnerships.
When an excipient has a compendial monograph, it means there is a defined, publicly available standard for what that material should be. A pharmaceutical manufacturer sourcing a compendial excipient can test it against that monograph and confirm it meets the specification. That traceability is important, as it gives regulators confidence that the inactive ingredient in your drug product is what you say it is, made to a consistent standard.
It is important to note that a compendial-listed excipient does not automatically mean that it is safe for every route of administration or at every concentration. Compendial status establishes identity and quality. It does not establish safety for your specific application at your specific dose.
What Is the FDA Inactive Ingredient Database?
The FDA Inactive Ingredient Database (IID) is a publicly available database maintained by the FDA that lists inactive ingredients that have been used in previously approved drug products in the United States. For each excipient, the IID records the route of administration, the maximum approved amount, and the dosage form in which it has been used.
The IID is not a list of excipients that are approved for use. That framing is a common misconception. The FDA does not formally approve excipients in isolation. What the IID captures is historical precedent: these are the inactive ingredients that the FDA has already reviewed and accepted as part of a drug product approval for a given route of administration. That history matters, because it means the safety of the excipient at that concentration and for that route has already been evaluated through the NDA or ANDA review process.
For a drug developer, the IID is one of the most practical tools available in early formulation work. An excipient that appears on the IID for your route of administration, at a maximum approved amount at or above your target concentration, comes with a body of regulatory precedent behind it. That precedent significantly reduces the documentation burden in your IND and simplifies your CMC justification.
An excipient that does not appear on the IID, or that appears only for a different route of administration or at a lower concentration than you need, is not off limits, but may require additional testing or justification for use.
How Callan Uses the IID in Formulation Development
At Callan, the IID functions as a hierarchy that guides excipient selection from the earliest stages of formulation work. We work through that hierarchy systematically before recommending any excipient for a client program. The logic is straightforward: the further an excipient sits from established regulatory precedent, the more work is required to justify its use, and the more risk it introduces into your development program.
Here is how that hierarchy works in practice.
First priority: IID-listed excipients for your specific route of administration.
The starting point is always the IID for your intended route, whether that is intravenous, subcutaneous, intravitreal, topical ophthalmic, or another parenteral or ophthalmic route. Excipients listed on the IID for your route at concentrations at or below the maximum approved amount carry the strongest regulatory precedent. When we design a formulation screening panel, we begin here. If we can build a formulation that meets your target formulation profile using only IID-listed excipients at or below established levels, that is almost always the preferred outcome. It keeps your regulatory path as clean as possible.
Second priority: IID-listed excipients for closely related routes of administration.
Not every excipient you might need will have precedent for your exact route. In those cases, we look to the IID for closely related routes. If you are developing a subcutaneous injectable, an excipient with IID precedent for intramuscular injection is a reasonable next step. The tissue exposure and physiological environment are similar enough that the existing precedent provides meaningful support, even if it is not a direct match. We apply the same logic for ophthalmic routes: an excipient established for topical ophthalmic use may be a reasonable starting point for an intravitreal application, though the concentration requirements and safety considerations differ and additional justification will be needed.
Third priority: Compendial excipients with precedent for other routes of administration.
If the IID does not offer useful precedent for your route or closely related routes, the next step is compendial excipients that are established for other routes of administration. A USP–NF monograph provides identity and quality standards, and approval for any route of administration demonstrates that the FDA has reviewed the excipient in a pharmaceutical context. The regulatory justification required increases at this step. You will need to explain why you are using an excipient without direct precedent for your route, and you may need additional safety data to support that use. But you are still working with materials that have a known identity, established quality standards, and some regulatory history.
For programs with international development plans or Chinese manufacturing partnerships, compendial excipients listed in the ChP warrant consideration at this stage as well. As ChP monographs continue to align with USP and Ph. Eur. standards, an excipient with ChP precedent increasingly carries weight in a global regulatory argument.
Last resort: Novel excipients.
A novel excipient is any inactive ingredient that has no prior approval in a drug product in the United States. Using a novel excipient in an IND-stage program is entirely possible, but it comes with significant regulatory burden. The FDA requires that novel excipients be treated essentially as new drug substances, with full safety characterization, toxicology data, and a detailed CMC justification. The phrase we use at Callan is “enabling technology.” If the target formulation profile cannot be achieved through careful consideration of compendial excipients and technique, then, and only then, should formulations containing novel excipients be evaluated.
How This Connects to Your Formulation Feasibility Study
If you have read our post on formulation feasibility studies, you will recognize this hierarchy as the framework behind the excipient row in our Target Formulation Profile table, which distinguishes between excipients at or below IID levels and those above IID levels. That distinction reflects the regulatory and development risk described here. When Callan designs a formulation screening panel for a feasibility study, the IID hierarchy determines which excipients we evaluate and in what order. Our goal is always to find a formulation that meets your target product profile using excipients with the strongest available regulatory precedent. If that is not possible, we want to know that at the feasibility stage, not after you have built a development program around an approach that will require extensive additional justification downstream.
Getting Started
Excipient selection is one of the earliest decisions in formulation development and one of the most consequential. Getting it right from the start protects your regulatory path, simplifies your CMC package, and reduces the risk of expensive reformulation later.
If you are not sure where your compound sits relative to the IID for your intended route, or if you are trying to understand what excipient options are available for your program, reach out for an introductory call. We can give you a quick read on the landscape before any formal engagement begins.
Frequently Asked Questions
Is the FDA IID a list of approved excipients?
No, and this is one of the most common misconceptions in early formulation work. The FDA does not formally approve excipients in isolation. The IID captures historical precedent: these are the inactive ingredients the FDA has already reviewed and accepted as part of an NDA or ANDA approval for a specific route of administration. An excipient listed on the IID has regulatory history behind it. An excipient not on the IID is not prohibited, but it requires additional justification.
What is a compendial excipient?
A compendial excipient is any inactive ingredient that appears in an official pharmacopeial compendium such as the USP–NF, European Pharmacopoeia, Japanese Pharmacopoeia, or Chinese Pharmacopoeia. Compendial status means there is a defined, publicly available standard for the material’s identity and quality. It does not establish that the excipient is safe for every route of administration or at every concentration.
Does compendial status mean an excipient is safe to use in my injectable formulation?
Not automatically. Compendial status establishes identity and quality standards for a material. It does not establish safety for your specific route of administration, concentration, or patient population. An excipient may have a well-established USP monograph and still require additional safety justification if it lacks IID precedent for your intended route or if your target concentration exceeds the maximum approved amount listed in the IID.
What is a novel excipient and what does it take to use one in an IND?
A novel excipient is any inactive ingredient with no prior approval in a US drug product. Using one in an IND-stage program is possible, but the FDA requires it to be treated essentially as a new drug substance, with full safety characterization, toxicology data, and a detailed CMC justification. At Callan, we refer to novel excipients as enabling technology: they are worth pursuing only when the target formulation profile cannot be achieved through careful selection of compendial excipients and formulation technique.
How do I justify using an excipient that is not listed on the IID for my route of administration?
The strength of your justification depends on how far the excipient sits from direct IID precedent. An excipient with IID precedent for a closely related route, such as intramuscular precedent for a subcutaneous program, requires a relatively straightforward scientific rationale. A compendial excipient with no IID precedent for any parenteral route requires more extensive justification, potentially including additional safety data. A novel excipient requires the most comprehensive package. In all cases, the justification should be built into your CMC documentation from the start, not added after a regulatory question arises.
