Excipients in New Drugs

NDA applicants are required to submit a list of all excipients (as well as other drug components), used in the manufacture of a proposed new drug. Additionally, the applicant must provide sufficient information to establish that the use of each excipient is safe for its intended use, at its intended quantity. This information includes safety data, a statement of the composition, specifications, and any analytical methods used for the excipient. When a USP/NF monograph exists for an excipient, the applicant may state that the excipient in the drug will comply with the standards in the monograph instead of providing composition, specification, and analytical method information. The required safety information includes 

In the absence of existing human exposure data or other review of the excipient, FDA recommends in its guidance on Pharmaceutical Excipients (2) that the excipient be evaluated using a battery of standard nonclinical tests (7). Which tests are appropriate depends upon the likely patient exposure given the intended use of the drug if approved. Table 1 provides a summary of the necessary tests. This test paradigm will likely be considered as setting the standard for data requirements for any new excipients, whether or not approved by the FDA in an NDA or ANDA, or reviewed by some future alternative review/approval mechanism. 

All the tests above, as appropriate. Additional tests will depend on the route of administration, and may include a sensitization study, and an ocular irritation study. Other studies may be required depending on the data gathered from the completed studies 

Abbreviation. ICH, International Conference on Harmonisation. Source From Ref. 8. 

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Established excipients are those with a history of use in drug formulations and thus are known to the regulators. Indeed, many appear in pharmacopeias and can be referenced as such in new drug applications in which they occur in the formulation. Thus, in theory, preclinical testing should not be needed. However, there is a common misconception that once an excipient is used in an approved product, it is automatically assumed to be safe for use in any product thereafter that involves the same route of administration and level of exposure (17). In reality, even in such cases, the level of toxicity information may need to be brought up to current... 

Even for established excipients, regulators will look carefully at their presence in new drug formulations because they are not necessarily inert materials and some have well-established activity and/or toxicity. Clinically relevant adverse reactions are known for well-known excipients and the subject is covered elsewhere in the published literature (2,20,75-81). Findings tend to be uncommon compared to the overall prevalence of adverse drug reactions and often involve hypersensitivity reactions that are not likely to be predicted by conventional toxicity studies. 

The evaluation as a food additive or GRAS substance may provide relevant safety information to support the use of a proposed new excipient in a drug product. The evaluation of a new excipient that is to be used orally as a food additive and that is evaluated independent of the drug product approval process may serve as a review of the safety of the excipient by a recognized regulatory authority. 

After the excipient has seen extensive utilization in multiple marketed products, the regulatory system has a process for review of the data resulting in possible inclusion of the monograph in the Japanese Pharmacopoeia (JP). The JP defines the mandatory standards for substances used in a pharmaceutical product. Inclusion in the JP establishes precedent status for the excipient and this notation permits use of the material in new drug products under defined conditions without the need to submit extensive supporting data. 

Impurity (1) Any component of the new drug substance that is not the chemical entity defined as the new drug substance. (2) Any component of the drug product that is not the chemical entity defined as the drug substance or excipients in the drug product. 

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