Many, if not most, 505(b)(2) submissions represent a change to an approved drug, usually involving a formulation change. Understandably, the focus of sponsors is often primarily on supporting the safety and efficacy of the active ingredient(s). However, the safety of the inactive ingredients (excipients) needs to be supported as well. Choice of excipients can therefore have a significant impact on the ability to streamline a drug development program.
Often we hear from clients, “The excipients are not an issue. Everything we’re using is GRAS.” Now, “GRAS” stands for Generally Recognized as Safe. With an acronym like that, it’s tempting to think that selecting excipients that are GRAS should do the trick. But GRAS status is not sufficient to meet the regulatory requirements to demonstrate safety of an excipient in a drug product, and sponsors are often surprised when the Agency requests additional (and sometimes substantial) nonclinical or even clinical data to support the safety of the proposed product formulation.
Why isn’t “GRAS” status sufficient? To understand that, let’s review what “GRAS” is, and what it isn’t.
GRAS and Drugs
As it applies to drugs, “GRAS” refers to drugs that were approved between 1938 and 1962 on the basis of safety alone. These are the drugs that underwent the Drug Efficacy Study Implementation (DESI) reviews by the National Academy of Sciences/National Research Council – i.e., the DESI drugs with which many readers of this blog may be familiar. Drugs that were found to be efficacious in a DESI review were awarded “GRASE” status, or Generally Recognized as Safe and Effective (sometimes referred to as GRAE/GRAS) for the specific condition(s) of use studied.
Importantly, drugs that were not determined to be GRASE – either because they just didn’t work or there was insufficient evidence of efficacy – did not retain “GRAS” as a marketing status. Most of these drugs were officially pulled from the market and left to languish in 21 CFR §310.545 (although some can be found as unlawfully marketed, unapproved drugs). A lucky few remain legally marketed while the awaiting Agency completion of the DESI review process or finalization of an over-the-counter (OTC) monograph (OTC monographs also utilize the “GRASE” designation).
Notice that “GRAS” and “GRASE” as used above refer only to active ingredients – not to excipients.
The GRAS List
The current use of “GRAS” applies to food additives. This is where the infamous “GRAS List” comes into play. Nice reviews on this topic can be found on the FDA website or 62 FR 18938. Briefly, in 1958 the Food Additives Amendment to the Federal Food, Drug, and Cosmetic Act defined any substance intentionally added to food as a “food additive” and stipulated that these substances were subject to pre-market approval by FDA unless the use of the substance was “GRAS.” Initially, recognition by “qualified experts” or experience based on common use in food was sufficient evidence that a substance was GRAS, and the FDA published the first “GRAS list” in the Code of Federal Regulations (CFR).
However, many substances that the food industry considered GRAS were not included in the 1958 list, and manufacturers requested opinion letters from FDA. In these letters, FDA rendered informal opinions regarding GRAS status. This process was deemed insufficient to ensure safety, and in 1972 FDA initiated a comprehensive study of substances presumed to be GRAS, to be conducted by the Life Sciences Research Office (LSRO) of the Federation of American Societies for Experimental Biology (FASEB). The LSRO selected qualified scientists (known as the Select Committee on GRAS Substances [SCOGS]) to conduct these studies. When a study was completed, the Agency reviewed the SCOGS report and, if merited, issued a final rule affirming GRAS status based on the findings. At the same time, the Agency reviewed GRAS Affirmation Petitions from industry for substances that were not part of the FDA review; final rules on the GRAS status for these substances were also issued. The current GRAS list can be found at 21 CFR §182, §184, and §186.
The GRAS Notification Process
Eventually the GRAS Affirmation process became too burdensome for the Agency’s limited resources, and was replaced by the current GRAS Notification process in 1997. In the current process, industry submits a GRAS Notice along with supporting data, but the Agency does not affirm or deny GRAS status. Rather, FDA responds to the notifier by letter stating either that it does not question the basis for the notifier’s GRAS determination, or that the notice does not provide a sufficient basis for a GRAS determination.2 GRAS Notices are published on the FDA website, but neither of these responses qualifies as an actual “finding.”
Importantly, GRAS applies to a specific use for the substance in question, not to the substance itself. The intended use(s) for substances are included in the GRAS list or GRAS Notice. While there may be similarity in the “intended use” – for example, guar gum is used as an emulsifier and thickener in both foods and drugs – the dose, frequency of administration, duration of administration, and route of administration often differ between the food use and the use of a proposed drug product. The Agency has cited these differences as a primary reason why GRAS status is insufficient to establish excipient safety in a proposed drug product.
- GRAS is no longer used for drugs, but when it was, it applied only to the active ingredient.
- GRAS is currently used only for food additives, and is a mixture of Agency GRAS affirmations (the GRAS list) and informal notices that carry little to no regulatory weight in the drug arena.
- GRAS applies to a food additive substance only in the context of its intended food use, and there are often significant differences between the food and drug uses, especially in potential exposure to a substance.
- GRAS status or the existence of a GRAS Notification does not guarantee that a substance has sufficient information to support its use in a potential drug product. The Agency has, in some cases, determined that a GRAS substance is, in fact, a novel excipient.
Where Do I Start?
So, if GRAS status does not provide the necessary support, how do sponsors select excipients that will meet their needs while streamlining a development program? A good place to start is FDA’s Inactive Ingredient Database (IID). The IID provides information on excipients in FDA-approved drug products. Once an excipient has appeared in an approved drug product for a particular route of administration, it is not considered “new” and may require less extensive support in a future drug product. For many potential drug products, this may be all the support that is needed.
Additional support may be needed if the route of administration is not listed in the IID (the list is not always up-to-date), the listed potency is less than that in the sponsor’s proposed product, the overall exposure to the substance from the sponsor’s product will be higher than that from the approved product (something that cannot be gleaned from the IID), or if the sponsor’s product will be used in a different patient population (also not obvious from the information in the IID). This support can come from many sources, so sponsors should not always assume that they will need to conduct additional studies. Premier Consulting can assess the information available to support your formulation, and can help you determine if further studies will be needed, identify the studies will get you the information you need while minimizing cost and time, and, if needed, assist with reformulation strategies.
For an assessment of whether your product is appropriate for approval via the 505(b)(2) pathway or to learn more about ways Premier Consulting’s multi-disciplinary team can help you create an optimized development plan to get your product approved, read more here or contact us.
Karen Seta-Aust, PhD
Associate Director of Research Services
 The process was implemented even though the proposed rule has not yet been finalized. See “About the GRAS Notification Program,” http://www.fda.gov/Food/IngredientsPackagingLabeling/GRAS/ucm2006851.htm.
 See “Inactive Ingredient Search for Approved Drug Products: Frequently Asked Questions,” http://www.fda.gov/Drugs/InformationOnDrugs/ucm080123.htm.