New Excipients

Information on existing or new excipients can be described and provided to the FDA in an NDA directly. Alternatively, the manufacturers of excipients may prepare and submit type IV Drug Master Files (DMF) to support the use of an excipient in one or more NDAs. The DMFs are discussed in FDA s regulations under 21 CFR Section 314.420 and the FDA-issued Guidance for Drug Master Files (8). When authorized by the DMF submitter (i.e., the excipient manufacturer) and cross-referenced by an NDA submitter, the FDA reviews the DMF to make determinations on the safety, manufacture, and quality of the excipient use in the new drug that is the subject of the then pending NDA. The DMF becomes active when reviewed in conjunction with the review and approval of an NDA. 

The proper safety evaluation of new excipients has now become an integral part of drug safety evaluation. 

IPEC (1997). Europe Safety Committee The proposed new guidelines for safety evaluation of new excipients. Eur. Pharm. Rev. Nov. 1997 13-20. 

For any new excipients, APIs or drug products (where new does not necessarily mean novel, but new to the receiving site) there are additional testing criteria, e.g. supplier audits, third-party contract laboratory audits, analytical method transfers, sample management/tracking, etc. For those key excipients, where there is on-site historical experience, it still behoves both parties to check whether the local grade/supplier used by the CMO is equivalent to that used by the supplier (Worsham, 2010). There are many examples of differences in excipient physical properties, e.g. particle size, which have been attributed to different excipient sources that could ultimately impact on the performance of those excipients in formulated products (Frattini and Simioni, 1984 Dansereau and Peck, 1987 Phadke et al., 1994 Lin and Peck, 1994). 

The FDA maintains a database of approved excipients Drug Information Electronic Orange Book, http //www.fda.gov/cder/ob/default.htm). Standards and tests for regulatory acceptable excipients are included in the US Pharmacopoeia and National Formulary. Two such tests, dissolution and stability, are included in Exhibit 5.12 for reference. For new excipients to be included in a drug formulation, they have to satisfy one of the following criteria ... 

The extent of revalidation required for formulation changes should be determined on a case-by-case basis. Slight adjustments to the formulation may not require further validation work. This would include an adjustment of the excipient ratios, a change in tablet shape, etc. Specificity and accuracy should be re-evaluated for the inclusion of a new excipient into the formulation (e.g., antioxidants, dyes, preservatives). A change in the formulation such as going from a tablet to a capsule or from a liquid to a solid would mean a significant change to the formulation and complete validation should be performed. 

Erode, G. L. in Vaginal Microbicide Formulations Workshop, Rencher, W. R (Ed), Lippincott-Raven (Philadelphia, PA), Chemical/physical principles in microbiocide formulations with emphasis on hydrophobe modified cationic polysaccharides-a new excipient class, 1998, Chap. 5, pp. 38-50. 

Changes in Components (Excipients) and Composition Changes in the amount or source of drug substance are not addressed by this guidance. Changes in components or composition that have the effect of adding a new excipient or deleting an excipient are dehned at level 3 except as described below ... 

Silverberg and See also point out that often proper planning will allow assessment of an excipient s toxicity in a relatively efficient manner. A less expensive study within a study can be conducted by developing new excipients concurrently with the development of new drugs. Satellite groups of animals receiving an excipient... 

Apte and Katdare (29) aver that new mechanisms in the form of guidelines and procedures are needed to regulate the functionality of new and emerging excipients. In the examples below, the pharmacological effectiveness of a drug can be influenced by the excipient. These new excipients may be antigens, viral vectors, microbial products, or other complex proteins. Their pharmacological activities are not completely independent of their excipient functionality and straddle the line between excipients and APIs. For example, paclitaxel bound to albumin (30) (Abraxane) improves breast cancer therapy. 

The preclinical safety evaluation of a new excipient generally commences after initial in vitro pharmacy work to demonstrate the material s proposed role. Additionally, some in vivo investigations (often a short exposure study in the rodent) may occur, for example, comparing the new proposed material in a drug formulation versus a marketed drug formulation. Enhanced drug exposure and/or a reduced toxicity profile (through the use of lower-dose levels or excipient protection) may be a study end point. 

Additional considerations for topically (dermal, intransal, introral, ophthalmic, rectal or vaginal) or pulmonary adminstered excipients are ocular irritation, sensitisation, oral or parenteral route toxicity studies additional considerations for injectable excipients are an in vitro hemolysis study, measurement of creatinine kinase and protein binding evaluation where appropriate new excipients should also be examined for photosafety. 

Probably to reflect this situation, the FDA has included such studies at an earlier stage than the IPEC guidance. It should be pointed out that if such an assessment showed a potentially new excipient to be teratogenic, it is highly likely that further development (never mind additional reproduction toxicity studies) would not occur. 

Materials that have had prior human use/exposure in food and cosmetics, or from the chemical industry, can be categorized as essentially new excipients. Such previous exposure is likely to be of help for oral and topical use excipient development. Excipients that have had established medicinal product use but are being used by a different dose route and/or chemically modified to enhance their properties are also likely to belong to this category. 

Overall, a wide range of testing considerations are needed for new excipient materials, although the actual package of study types still remains a case-by-case approach. 

On some occasions, a full program of studies may be needed to confirm a risk-benefit situation, whereas in others (e.g., lifesaving therapy), it may be acceptable to have reduced toxicity data (17). Similarly, the extent of studies needed to support the safe use of essentially new excipients, and indeed well-known materials, needs careful consideration based on available knowledge. 

International Pharmaceutical Excipients Council (IPEC). The proposed guidelines for the safety evaluation of new excipients, The IPEC Europe Safety Committee. Eur Pharm Rev 1997. 

Despite widespread agreement that the current system is woefully inadequate in its ability to review new excipients, the regulation of excipients remains mired in the traditional system that relies upon approval of excipients only as components of a drug product, with no true independent review. In this chapter, we discuss the existing regulatory process for excipient review, as well as some potential alternatives to the existing process, some of which have been attempted, without much success, in the past. This article focuses on the regulatory environment in the United States. Where the discussion is applicable to other countries, it will be specifically mentioned in the text. 

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. 

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