Excipients Step into the Spotlight - Pharmaceutical Technology

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Excipients Step into the Spotlight
Industry and regulatory experts discuss excipient testing, regulatory expectations, supply-chain challenges, and pricing in this Speakers Roundtable. This article contains bonus online material and podcasts.


Pharmaceutical Technology
Volume 6, Issue 34, pp. 38-42

Novelty finds its way

PharmTech: IPEC recently completed a pilot program involving a novel excipient safety evaluation procedure to promote regulatory acceptance of new excipient usage outside of the new drug application (NDA) process. BASF's Solutol HS 15, a new solubilizing excipient, went through the process and was ultimately published as an official monograph in USPNF (see PharmTech's November 2009 issue for the full story). Why are novel excipients so necessary today and why is industry reluctant to use them?

Carter: Because the approval of an excipient for use in a drug product occurs in the FDA review and approval of a finished drug product, pharmaceutical companies tend to stick with excipients that have already been approved in other drugs to limit the chance of delaying the approval process. The result is that new drug products that could benefit from the functionality of new excipients end up being formulated with old technology and the patients are deprived the benefit of advancements in science that could deliver better medicines. IPEC recognized this problem and our safety committee developed a process for novel excipient review whereby an independent group of recognized experts could review the manufacturing and safety data provided by an excipient company and make a recommendation as to the safe use of the excipient. This information can then be submitted along with the panel's review as part of the manufacturer's application. While the evaluation process is not an official approval, a favorable review using a process similar to that used by an FDA reviewer provides confidence to the pharmaceutical company that the excipient will not cause a delay of the drug approval process, thus encouraging the use of novel excipients to make better medicines.

PharmTech: What role did USP play in this pilot?

Sheehan: BASF collaborated with USP in the development of this compendia monograph (Polyoxyl 15 Hydroxystearate NF, the USP-NF official title for Solutol HS 15). One of the major challenges at that time was that Solutol HS 15 was not used in an approved dosage form in the US and as a result was not listed in the FDA's /CDER /Inactive Ingredients database (IID). There is no independent approval or evaluation procedure for new excipients used in an approved dosage form in the US because they are evaluated only in the context of an NDA or biologic license application (BLA). FDA only permits the use of an excipient in an FDA approved dosage form marketed in the US. Once the drug product is approved by FDA, the excipient is listed in the IID and usually followed by the development of the compendia monograph standard. The IID listing includes the name of the excipient, the dosage form, and the amount per dosage unit. Drug product names are not mentioned in the IID database. Solutol HS 15 was considered novel or new as it had no prior use in a human drug product approved in the US. The term, "new excipient" is defined by FDA's 2005 industry, Non-clinical Studies for the Safety Evaluation of Pharmaceutical Excipients as follows:

"In this guidance, the phrase new excipients means any inactive ingredients that are intentionally added to therapeutic and diagnostic products, but that: (1) we believe are not intended to exert therapeutic effects at the intended dosage, although they may act to improve product delivery (e.g., enhance absorption or control release of the drug substance); and (2) are not fully qualified by existing safety data with respect to the currently proposed level of exposure, duration of exposure, or route of administration."

The term, "novel excipient" is also defined in FDA's 2004 guidance, Drug Product, Chemistry, Manufacturing and Controls Information:

"Novel excipients are excipients used for the first time in a human drug product in the United States or by a new route of administration. Any novel excipient should be identified and its specification included in this section of the application (P.4.6)."

As a result, new drug product manufacturers are reluctant to risk drug approval with the use of new excipients because it adds additional risk to the drug application process; the entire application could be rejected if the excipient is considered unsafe.

The IPEC-Americas Novel Excipient Safety Review Procedure required BASF to submit a safety evaluation package to an independent toxicology consulting firm for novel excipient evaluation. BASF also submitted the independent safety evaluation report and all components to FDA through the IPEC –Americas safety committee chair. BASF informed USP about Solutol HS 15 safety evaluation by FDA under the IPEC-Americas Novel Excipient Safety Evaluation Procedure Program and their plan to submit a new monograph proposal. USP subsequently collaborated with FDA resulting in the publication of the draft monograph in the USP Pharmacopeial Forum (PF) Jan.– Feb. 2009 edition, followed by publication of the monograph in USP 33-NF 28 Reissue (official Oct. 1, 2010).

Recently, USP has expanded the USP Pending Monograph process to include excipients. Excipients that satisfy the Pending Monograph requirements listed on the USP website qualify for this approach. Requirements include submission of a drug master file (DMF) for an article to FDA. The purpose of pending monographs is to have an official USP-NF monograph ready as soon as possible after FDA grants final product approval (with associated excipients(s)). To this end, the pending monographs approach lets monograph development begin before FDA's approval process is complete, resulting in an official USP-NF monograph more rapidly than would be possible if monograph development started only after final FDA approval. Pending monographs are considered authorized rather than official text because they are approved by the USP Council of Experts, but are not part of an official compendium of the U.S. (USP or NF). For more information on the Pending Monograph approach and the USP-NF standards setting process, visit the USP websites: http://www.usp.org/standards/pending/ or http://www.usp.org/USPNF/submitMonograph/.

PharmTech: Since the pilot, what feedback has BASF received in terms of clients willing to use a novel excipient that hasn't appeared in an NDA?

Velagaleti: First-time use of a novel excipient in a drug product is very critical due to understandable apprehension by customers if not previously used in a FDA-approved drug (as noted, FDA does not approve or reject excipients). Under IPEC's Novel Excipient Safety Evaluation program and discussions on this program with FDA, the agency as we understand from IPEC has agreed to to look at only one novel excipient ahead of time, before being used in a drug product (before appearing in an NDA). Even though Solutol HS 15 has gone through the IPEC program, FDA will review it again within an NDA. Hopefully, because of this review and the submission of the BASF toxicology DMF to FDA subsequent to the agency review under this program, the Solutol HS 15 safety review in the context of a drug application may move faster. More importantly, the agency review enabled BASF to request from USP an official monograph, which USP published. This has made it easier for us and the program should open door for more novel excipients to enter the market.

PharmTech: Based on this pilot, is FDA becoming more open to the use of new excipients in pharmaceuticals outside of the NDA process?

Motta: It is not FDA's intent to preclude industry from developing new technologies that have been proven to improve the quality of the drugs offered to consumers. As a matter of fact, in 2005, the agency published a guidance for industry, Non-Clinical Studies for the Safety Evaluation of Pharmaceutical Excipients to provide guidance regarding developing safety profiles to support use of new excipients as drug components.


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