If there were a bar where all of the hip drug product formulators hung out at the end of a hard day of formulating, two things would be certain, the beers on tap would be from breweries like Avery, Greenflash, and Dogfish Head rather than Coors, Miller, and Anheuser Busch, and all of the jokes would be about discovery guys. We formulators would pick on the discovery guys in part because deep down inside we realize they are smarter than us and get more dates than we do and in part because they make our lives miserable, and they think that DMSO is a formulation. Just as likely in this bar is that no one would dare challenge out loud the sanctity of our bible, the FDA Inactive Ingredients Guide, for fear of being beaten up out back by a bunch of hooligan formulation zealots.
Just in case there are any discovery guys reading this, the Inactive Ingredients Guide (http://www.accessdata.fda.gov/scripts/cder/iig/index.cfm) is a list of (supposedly) all excipients used in marketed drug products listed by route of administration and level in the formulation. For a long time this was a pdf document that hadn’t been revised since 1996, but more recently, the Agency has maintained it as a searchable database that is presumably updated as new drug products are approved. We rely on it to know what has been safely done already so that we don’t come up with a formula that provides great solubility, stability, and bioavailability but does irreparable damage to the patient. And just as importantly, we rely on it so that when our boss or sponsor asks us if that excipient is precedented, we can point to the list and say “there it is; FDA said it’s okay.”
While the Inactive Ingredients Guide is certainly a useful reference, and we can be grateful to the Agency for providing it to us, there are a number of pitfalls with relying on it too heavily, and without trying to pick a fight, I want to point some of these out:
• First and foremost, the guide is only a list of excipients that have been used and not a list of excipients that are allowed in a particular type of dosage form. If an excipient is not on the list, it may mean that it is harmful, but it more likely means that no one has had the guts to venture off The List and use it. For example, anyone who has ever worked in inhalation can tell you, sometimes rather emphatically, that phosphate buffer cannot be used in nebulizer formulations, but I have yet to find anyone who can tell me why not. Even the pulmonary division at CDER may be unclear on this point, as I have seen phosphate buffered saline used as a nebulized placebo in some FDA-approved clinical trials.
• Just as importantly, the fact that an excipient is on the list for a particular route of administration does not necessarily mean that it is safe. Paclitaxel has been formulated with high levels of the PEGylated surfactants, Cremophor EL and Polysorbate 80, both of which are known to cause anaphylaxis in susceptible humans and in pretty much all dogs. The FDA accepted these formulations because they were the only thing that worked for a drug that isn’t used unless it is the only thing that works. It doesn’t mean you can go crazy with the Cremophor in an injectable formulation of ibuprofen.
• Even if a drug is on the list for a particular route of delivery, the details of administration never seem to match the target at hand. Looking up an excipient in the database is just the first step in assessing whether it is precedented. One need next dig out package inserts for the actual drug products it is used in and determine whether the level of the excipient and the site, rate, and duration of administration as well as the dosing frequency and period of dosing are sufficiently similar to the intended use at hand. Since the names of the drug products are not listed (or even hinted at) in the database, this is best done by searching the name of the excipient and the route of administration on a package insert-providing website such as http://RxList.com or http://Drugs.com. If you are doing anything more complicated than a bolus injection or an IR tablet, don’t count on finding an exact match to what you want to do.
• Since the list includes only approved products and since it takes so long to get a product approved, the fact that an excipient is not on the list does not mean that it has not undergone extensive clinical testing and been found to be safe. Only a few years ago many of our clients shied away from using hydroxypropyl-beta-cyclodextrin (HPBCD) even in Phase 1 formulations since the only two cyclodextrin-based formulations on the list used the sulfobutyl ether (Captisol®). The four HPBCD-containing products currently on the list would likely have been through most or all of their Phase 3 trials at the time.
• Contrary to what some may believe, the database is not complete. When performing the abovementioned searches on package insert websites I almost always come up with a few drug products that are not included on the FDA list.
• Another more trivial concern with using the database is that you really need to be sure that you know the correct name of whatever you are looking for. For example, if you do a search on ethanol, you will come up with a relatively short list of ethanolamides and ethanolamines but nothing that would taste good in your punchbowl. You need to search on alcohol if you want to know where the strong stuff is.
What are the disadvantages of using an excipient that is not precedented? From the regulatory perspective, the FDA is only interested in whether the overall drug product is safe and efficacious and well enough controlled to be consistent from batch to batch. They are not the ones telling us we can only use what is on their list. Nonetheless, besides pleasing your boss, there are some distinct advantages to sticking to what is tried and true:
• The prior use of an excipient in a similar formulation amounts to a clinical history, just as a drug that has been used before has a clinical history that it allows it to slide through on an ANDA or 505.b.2. Every drug product is its own entity and is judged on its own merits regardless of what excipients it contains, but having a precedent substantially reduces the risk of an unanticipated problem and makes for easier writing in the Pharmaceutical Development section of an NDA.
• The fact that an excipient has been used for the same route of delivery in an approved product means that there is a Drug Master File on it as well as a supply that is appropriate for the use. A little carnauba wax might be just the thing to brighten up your injectable formulation, but you might be hard pressed to find an endotoxin-tested grade.
The main reason we formulators have such a hard time getting dates is that we are inherently boring people. While the discovery guys are creating spanking new molecules for novel targets, we are stuck in our dingy labs searching the shelves for those same old bottles of HPMC or PEG or lactose. We tend to blame our conservative ways, directly or indirectly, on the FDA, but it is really not they who are holding us back. In most cases it makes sense to stick to what we know, but I wonder how often safer or otherwise better formulations have been overlooked simply because they were not sufficiently similar to what had been done before.
As some final advice for my fellow formulators:
1. Never forget that all those sexy discovery, pre-clin, and clinical people are useless without us.
2. As to the title of this piece, I would certainly not advise you to try bacon fat as an excipient, especially if you are trying to reformulate Lipitor, but if there were a demonstrated safety or efficacy advantage and you had a well-controlled supply, there is no legal reason you could not throw in a bit.
3. If you are thinking about a novel excipient, be bold and stand your ground. Don’t let anyone tell you that you can’t use it just because it is not on some list. Go ahead and throw in a sodium rather than a potassium salt or a sulfate rather than a chloride. Be the first on your block to put whatever crazy new thing Gattefosse comes up with into an injectable. Use phosphate in a nebulizer or black pepper extract in a nasal spray. Whatever you put in, I promise I will find a way to use it too. Once you get it on The List.
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