Understanding FDA's Draft Guidance: Composition Statements Of Ingredients In Labeling In NDAs And ANDAs
By Sravan Kumar Chadalavada, Freyr Solutions
Presentation of a drug product’s composition and the corresponding details of the ingredients in the product labels is important. Sometimes, it is difficult to represent the information accurately and logically, as we need to adhere to the complex regulatory requirements of the health authority. At the same time, we need to make sure that the ingredient statements in labels are consistent with the other components of the drug application. This has been a pain point for pharmaceutical manufacturers for a long time, as it may lead to a greater number of review cycles before drug approval if the information is not consistent in the labels and other drug application components.
In April 2024, the U.S. FDA provided draft guidance1 to address this and make the drug application and approval process easier. In this article, I will discuss the guidance and how it helps drug companies.
Why Is This Guidance Important And Much Needed?
- Health authority regulations require NDAs and ANDAs to include full details of a drug product’s components, including a list of all ingredients — active and inactive — along with their quantities and roles.
- Errors or inconsistencies in presenting these details can affect the efficiency of FDA review and derail the approval process, which in turn affects manufacturers in terms of time and money.
- In the FDA's review process and experience, inconsistencies were observed in how ingredient compositions were represented in the drug application components and the statements present on drug labels.
- The data present in the various application components must be similar and consistent.
FDA Guidance Points Of Note
1. Consistency Between the NDA and ANDA Applications
- The statement of ingredients in the label must be consistent with the composition statement of 3.2.P.1 of the eCTD.
- Include in the labeling, both qualitatively and quantitatively, all the names of the active and inactive ingredients. This includes, for example, the hydration state, pH adjusting function, etc.
- Present any inactive ingredient used in making a solution in actual amounts rather than just mentioning the solution.
- Do not round the amounts presented on the label, in accordance with the information in the application components.
2. Consistency in Compositions Identified Within the Same Application
- Ensure that the labeling captures all the information of the ingredients statement and is consistent throughout the application. For example, the ingredients statement is present in either the batch formula or the master formula. All these should be captured in the labeling and must be consistent.
- Applicants should clearly identify the components of inactive ingredients.
- Capture the actual concentration of the inactive ingredient present in the drug, and not the concentration used in manufacturing.
- Be consistent with units of measurement throughout the labels and other components of the application. And the same units of measurement must be used, wherever appropriate.
- In the composition statement, list the nominal amounts for inactive ingredients. If a range is more appropriate than a nominal amount or concentration, then provide proper justification.
3. Information on Inactive Ingredient Function, Hydration State, and Amount
- List with clarity the primary function of the inactive ingredient.
- Use accurate and consistent nomenclature, such as established names.
The application holder of an approved NDA and ANDA should submit an updated composition statement and the corresponding statement of ingredients in labeling when applicable, consistent with the recommendations in this guidance, in an appropriate submission after approval.
Key Insights
Ensuring Consistency Between Submission and Labeling
A central theme of the guidance is the requirement for qualitative (Q1) and quantitative (Q2) alignment between the composition statement submitted in Section 3.2.P.1 of the electronic common technical document (eCTD) and the drug's labeling, particularly the Description section. Discrepancies between internal documentation (e.g., batch records) and external labeling remain a major source of regulatory delay.
Precision in Identifying Inactive Ingredients
Applicants are expected to provide exact and consistent nomenclature, including hydration state, grade, and source. Where multiple forms of an excipient exist (e.g., hypromellose variants), precise identification is crucial. The guidance recommends referencing the Global Substance Registration System (GSRS) for standardized terminology and including United States Pharmacopeia–National Formulary (USP–NF) titles where applicable.
Defining Function and Amount of Excipients
The FDA emphasizes the importance of clear functional descriptions for each excipient. Rather than using mechanistic or ambiguous terms such as “acidifying agent,” applicants should specify roles like “pH adjuster” or “solubilizing agent.” Similarly, only actual concentrations used in manufacturing — not prepared quantities — should be listed. When excipients are added in variable amounts, the term q.s. (quantum satis) must be appropriately used, supported by rationale.
Standardizing Units and Calculations
Uniformity in units of measurement is mandatory. Applicants should consistently apply w/w, w/v, or v/v conventions and ensure the declared percentages are meaningful and justified. Any conversions between units should include calculation methodology and relevant excipient properties (e.g., density).
Labeling Requirements and Compliance
For nonoral dosage forms, labeling must include a full list of inactive ingredients and their quantities, except for certain agents like isotonicity adjusters, which may be referenced by function. All ingredients should appear in alphabetical order, matching the composition statement precisely.
Addressing Formulation Variability and Updates
Applicants using multiple manufacturing sites or processes must submit a comprehensive parent composition statement that encompasses all possible ingredient variations. Post-approval changes — such as color adjustments or minor edits — must be clearly documented, with substantive changes submitted via appropriate regulatory pathways rather than annual reports.
Mitigating Review Delays
The guidance identifies frequent issues encountered in NDA and ANDA assessments, including inconsistent batch documentation, incomplete ingredient identification, and unaligned labeling. Adhering closely to these recommendations can significantly reduce assessment cycles and regulatory feedback loops.
Conclusion
This draft guidance reflects the FDA’s increasing focus on transparency, traceability, and harmonization in pharmaceutical submissions. It underscores the need for meticulous documentation and precision in all components of a drug’s regulatory profile. Proactive compliance with these recommendations will not only enhance the quality of submissions but also facilitate a smoother review and approval process.
References
About The Author:
Sravan Kumar Chadalavada is a pharmaceutical professional at Freyr Solutions with over 13 years of experience in medicinal product labeling. In his current role as manager of the Labelling Center of Excellence (CoE), he leads initiatives in global labeling management, labeling automation strategy, and client engagement. His expertise spans regulatory labeling requirements across the U.S. FDA, EU, and the rest of the world