1. The Inactive Ingredient Database (IID): Purpose and Utility 

The Inactive Ingredient Database (IID) is a crucial resource for drug development, particularly for generic drugs. 

• Definition and Scope: The IID provides information on excipients (inactive ingredients) present in FDA-approved drug products, including ANDAs (Abbreviated New Drug Applications) and NDAs (New Drug Applications). However, it does not include excipients from approved BLAs (Biologics License Applications) or OTC (Over-the-Counter) products. 

• Significance: If an excipient has been used in an approved drug product for a specific route of administration, it is generally not considered "new" and may require less extensive review for subsequent drug products. This can significantly aid drug development. 

• Search and Data Points: The IID can be searched online by excipient name or downloaded as an Excel file. Records include information on: 

• Route of administration (e.g., oral) 

• Dosage form (e.g., extended-release capsules, lozenges, powder) 

• CAS (Chemical Abstract Service) number 

• UNII (Unique Ingredient Identifier) code 

• Maximum Potency Per Unit 

• Maximum Daily Exposure (MDE) values (increasingly populated, especially for oral products). 

2. Limitations of the IID 

Despite its utility, the IID has significant limitations that applicants must be aware of. 

• Lack of Exposure Model Information:  

• The database currently does not provide information regarding the different exposure models for example it does not have information regarding safety in pediatric populations e.g., acute versus chronic. 

• Insufficient for Full FDA Compliance: The presence of an excipient in the IID at a particular level does not automatically satisfy all FDA requirements. Additional information may be requested during filing or review stages. Therefore the inclusion of an exipient at a level described in the ID does not necessarily satisfy all the FDA requirement You may be asked to provide additional information um at the filing or review stage. 

• Information Blackout for IID Mailbox: The IID mailbox can assist with listing errors or clarifications but cannot answer application-specific questions, disclose proprietary information (e.g., specific NDA/ANDA formulations), or confirm the acceptability of proposed excipient levels. 

3. Excipient Safety Justification: The Nonclinical Perspective 

• Role of Excipients: Inactive ingredients are intentionally added but should not exert a therapeutic effect. Generic drug formulations can use different excipients than the Reference Listed Product (RLD), with exceptions for parenteral, ophthalmic, and otic uses, which "should have a same exient." 

• Generic Drug Safety Evaluation: Since generic drugs do not undergo clinical safety trials, applicants must identify and characterise differences in excipients compared to the RLD and provide data demonstrating that these differences do not affect safety and efficacy. 

• Key Approach: "Similar Context of Use": The cornerstone of OGD's excipient safety evaluation is the "similar context of use," encompassing route of administration, duration of use, and patient population. 

• Context of Use Analysis: Reviewers compare the context of use in the generic drug product with that in the IID. Discrepancies necessitate additional toxicological information. 

• Common Misconception: MDE Alone is Insufficient: A frequent mistake by applicants is assuming that a proposed Maximum Daily Exposure (MDE) level is justified simply because it does not exceed an IID listing for the proposed route. This is often rejected if the context of use does not match, particularly for duration of use and patient population. 

• Example: A generic product for chronic pediatric use cannot be justified by an IID listing for acute adult use. This creates a "safety gap." 

• Addressing Safety Gaps with Nonclinical Data: When the context of use does not match, nonclinical toxicity data can be leveraged: 

• Chronic Use: Chronic and subchronic toxicity studies or carcinogenicity data. 

• Pediatric Use: Developmental and reproductive toxicity (DART) studies. 

• Proposing Higher MDEs: Applicants can propose an MDE higher than that listed in the IID, but this requires justification, such as repeat-dose toxicity information to ensure a sufficient margin of exposure, or clinical information demonstrating safe prior human use at the proposed level. One can still you can proposed a higher MD than listed IID uh but you need to provide the justification such as the repeat those toxicity information.  

4. Specific Challenges and Justification Strategies 

The presentation details strategies for specific types of excipients and common scenarios. 

• Polymer Excipients (Different Grades): Polymers are complex macromolecules. If the exact polymer grade isn't in the IID, applicants can leverage information from "related grades" if the differences are minor (e.g., molecular weight, chain length, viscosity). 

• Regulatory review involves two steps: 

1. Comparing physical-chemical properties of the new and related grades. 

2. Evaluating if they share similar structure and toxicological profiles to extrapolate safety. 

• Case Study 2 illustrated acceptance of a new polymer grade based on "weight of evidence approach from the prior use of clinical safety use and then nonclinical toxicity safe data of the related grade of the polymer." 

• Flavouring Agents Not in IID: For flavouring agents not found in the IID, applicants should: 

• Provide safety data for individual ingredients within the flavour (genotoxicity, general toxicity). 

• Include a quantitative breakdown of ingredients with CAS numbers and CFR citations or a right-to-reference statement for the flavour's Drug Master File (DMF). 

• Data Gaps and Regulatory Actions: If OGD identifies data gaps during safety review, nonclinical information may be requested. If concerns persist, applicants may be advised to reformulate or pursue a 505(b)(2) application (which allows reliance on existing safety/efficacy findings for a new drug). 

5. Case Studies Illustrating "Context of Use" Importance 

Two case studies underscore the critical role of "context of use" in safety justification. 

• Case Study 1: Oral Product, Chronic Use in Pediatric and Adult Populations:  

• Problem: Applicant referenced a high IID MDE (640 mg/day) for an excipient, but this IID listing was only for acute adult use, while the proposed product was for chronic use in both pediatric and adult populations. 

• Initial Outcome: Agency may recommend reducing the excipient level or providing safety justification for chronic pediatric use. 

• Resolution: Applicant can provide publicly available developmental toxicity studies, which supported the proposed MDE for pediatric use, leading to acceptance. The MDE for pediatrics is typically half that for adults. 

• Applicant may then propose MDE 80 mg with the justification using the publicly available developmental toxicity study and the proposed MDE may be acceptable for use of pediatric population. 

• Case Study 2: Oral Product, Chronic Use in Adults with Different Polymer Grade: 

• Problem: Proposed polymer grade (2,000) not exactly listed in IID, though other grades of the same polymer family were. 

• Justification: Applicant can provide critical chemical property and impurity specification information for their new polymer grade. 

• Reg. Evaluation: Confirmed similarity to known safe related grades, review of literature (general toxicity, absorption), and submitting toxicity profile of small impurities/degradants. 

• Outcome: May be acceptable based on a "weight of evidence" approach from prior clinical safety use and nonclinical toxicity data of related polymer grades. 

6. Summary and Recommendations 

• IID as Justification: The IID is valuable for justification if an excipient has been previously used in a similar context of use (route, duration, patient population). 

• Addressing Context of Use Differences: If there are differences, a nonclinical toxicology reviewer will assess excipient safety using nonclinical information. 

• Applicant Actions: Applicants must provide information that characterises their excipient and supports its safety for the proposed context of use. 

• Controlled Correspondence: Seeking advice via controlled correspondence can "facilitate the review and reduce the review cycle."