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FORMULATION AND DEVELOPMENT


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as substances other than the active pharmaceutical ingredient (API) that have been appropriately evaluated for safety and are intentionally included in a drug delivery system.2


Excipients are components


of the drug product intentionally added to enable the delivery, ease of manufacture, and stabilization of the API in a formulation. Excipients are listed in the IID,3


which provides information on


previously accepted excipient levels and routes of administration in drug products approved by FDA. There is no independent regulatory approval process for excipients outside of an FDA drug product review. This leads to challenges associated with the introduction of new excipients in drug development and into USP-NF.


Challenges and Opportunities in Development of New Excipient Monographs in NF


The attendees at the USP Excipient Workshop discussed the growing need for new excipients to support innovative drug development, particularly in the realm of new delivery systems and stable novel dosage forms. Unlike new chemical entities which provide breakthrough therapies in the API world, discovery and manufacturing of a new chemical entity is almost never a feature of a new excipient. There are many ways to create a new excipient. FDA may consider any substance not listed in IID to be a new excipient, and as discussed below, inconsistent nomenclature can make an excipient already listed in IID appear to be new. A new excipient can alternatively be obtained from excipients having a prior and repeated history of use by, for example, co-processing a combination of established excipients, and thus creating a new modification of the physical form or a new variation of the excipient composition. Such modifications often raise the question as to whether either a new USP excipient monograph should be developed or an existing monograph should be modified.4 There is an opportunity for new excipients to meet the ever-increasing challenges drug development scientists and engineers face in the delivery of an active pharmaceutical ingredient (API) and manufacture of a drug product. However, amid concerns about FDA acceptance of a new excipient, pharmaceutical manufacturers stay within the boundaries for excipient levels and routes of administration listed in the IID.5,6


This conundrum cannot be addressed without considering


a new excipient’s safety profile. For excipients that are currently listed in the IID, the USP website (www.usp.org) contains a list of priority missing monographs for development, with input requested from sponsor(s) and a donor recognition program.7-9 excipients are described by Moreton10


Classes of new to include:


• new chemical material; • co-processing of existing material;


• new semi-synthetic derivatives or new chemistry (e.g. degree of substitution) of existing materials;


34 | | May/June 2016


• excipients used in food (e.g. Generally Recognized As Safe (GRAS) database listed materials) and animals, now proposed for pharmaceuticals;


• excipients for new route of administration;


• new botanical source or manufacturing process for existing materials;


• new physical grades.


Challenges identified by USP include prioritizing monographs that need updating, defining meaningful specifications and obtaining procedures and acceptance criteria from sponsors to support a new route of administration. USP welcomes opportunities to work together with FDA and excipient users and manufacturers to expedite the development of monographs. USP will also work independently with the European Pharmacopoeia (EP) and Japanese Pharmacopoeia (JP) in development of harmonized monographs for new excipients.


Understanding USP’s Role with Excipients Used in Biologics


In particular, the topic of new excipients for biologic dosage forms has drawn more attention recently because of the unique challenges involved in formulating and stabilizing drug substances exhibiting higher-order chemical structure that is necessary for activity. Owing to poor stability, release and absorption via the gastrointestinal tract for biologic drug substances and biologics, they are most commonly delivered parenterally as sterile products. The latter are often produced using non-sterile excipients. Thus, it is desirable to control the microbiological quality of excipients at a level compatible with the biologic manufacturing process. However, the retention of structural integrity of a biologic drug substance could conceivably be affected by the composition of excipients or by excipient impurities. Questions for discussion at the workshop included:1) Should USP have lower limits on bioburden in specifications for all parenteral use, aiming to minimize the potential for excipients to contribute to higher endotoxin levels?; and 2) Should USP develop monographs or a general chapter(s) to help in the selection of the excipient best suited for parenteral use? Stakeholder collaborations can stimulate additional avenues to both update and harmonize excipients used in injectable biologics.


FDA’s Inactive Ingredient Database


The USP Excipient Workshop discussed tha FDA’s Federal Register Notice regarding the enhancement of the utility and usability of the IID to help the agency identify and ultimately establish best practices and issue a technical guide or draft guidance. At the workshop, attendees discussed the current challenges with the IID and the importance of avoiding contradictory nomenclature for excipients.11


USP has a long-standing legal role in establishing the names of drugs, including excipients, under Section 502(e)(3) of the Federal Food, Drug and Cosmetic Act. Under this provision, the established


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