Excipients and Inactive Ingredients in Drugs & Drug Safety

In our world of drug safety and PV, we don’t think much about inactive ingredients and excipients found in drug products. In fact, we don’t even know which ones are in the drugs we take, make, sell and prescribe, and we may not even be sure where to find out where they are.

Yet, there is nothing to preclude an adverse event (AE) or even a serious AE to occur due to an excipient or other additive.

What are they?

In theory, these additive ingredients are inactive. What does “inactive” mean? According to the FDA: “21 CFR 210.3(b)(7), an active ingredient is any component of a drug product intended to furnish pharmacological activity or other direct effect in the diagnosis, cure, mitigation, treatment, or prevention of disease, or to affect the structure or any function of the body of humans or other animals. Active ingredients include those components of the product that may undergo chemical change during the manufacture of the drug product and be present in the drug product in a modified form intended to furnish the specified activity or effect.”

Some inactive ingredients can be active in some circumstances. Alcohol is both an active and inactive ingredient.

There is an FDA database called the “Inactive Ingredient Database” that is updated quarterly. There is also a Q&A page. A search on “talc” shows over 50 uses in oral and sublingual/buccal tablets, chewing gum, capsules (hard and soft gelatin), granules, syrups, elixirs, suspensions, film coated tablets, controlled release products, orally disintegrating products, shampoo, lotion, ointment, powder (perhaps the only non-surprising use) and more.

First, what kind of additions to the active moiety are there? Here’s the basic list (See: wikpedia.org for a brief review):

• Antiadherents: These chemicals reduce the undesired adhesion/sticking between substances in the manufacturing process.
• Binders: These help hold the ingredients together. They may be saccharides (disaccharides like sucrose, polysaccharides like starch or cellulose, or sugar alcohols like sorbitol), protein (e.g. gelatin) or polymers (PEG).
• Coatings: On the outside of the tablet. They may be hydroxypropyl methyl cellulose or shellac (!). Some tablets have enteric coatings to delay release to more distal parts of the digestive tract. Capsules usually are coated with gelatin.
• Disintegrants: These chemicals disband and dissolve when wet and allow the tablet to break up in the gut releasing the active ingredient.
• Fillers: AKA bulking agents or diluents. These add volume to drugs delivered in very small amounts (e.g. mcg) in tablets or capsules.
• Flavors: A spoon full of sugar helps the medicine go down. Well, sometimes that’s not enough and there are flavorings that can be added such as mint, cherry, peach, vanilla etc. Most people would say, however, that these flavorings rarely resemble the true flavorings found in nature…
• Colors: Used for marketing, appearance and to make identification easier in some cases.
• Lubicants: Prevent clumping during manufacture. They include talc(!), silica and others.
• Glidants: Also used to reduce friction in manufacturing.
• Sorbents: Used for moisture proofing to prevent absorption of liquid or gas in the product.
• Preservatives: Includes antioxidants, vitamins, selenium, amino acids, parabens.
• Sweeteners: To make the product “tastier” especially those that stay in the mouth a longer time such as antacids or syrups.

The WHO also has a nice slide presentation on inactive ingredients.

Where to find the excipients:

For a particular product, look in the approved labeling. For example, from the US labeling for Clarinex (desloratridine) syrup: CLARINEX Syrup is a clear orange colored liquid containing 0.5 mg/1 mL desloratadine. The syrup contains the following inactive ingredients: propylene glycol USP, sorbitol solution USP, citric acid (anhydrous) USP, sodium citrate dihydrate USP, sodium benzoate NF, disodium edetate USP, purified water USP. It also contains granulated sugar, natural and artificial flavor for bubble gum and FD&C Yellow #6 dye. (dailymed.nlm.nih.gov).

Note that the quantities in the final product are not listed. It is entirely possible that small amounts of these “inactive” chemicals are quite active in higher doses. This has been described with lactose, which is often used. In small amounts this is usually harmless; in higher doses those with significant lactose intolerance may experience GI effects including diarrhea, gurgling, malaise, etc…

One also cannot assume dose proportionality of excipients. It is not always the case that twice as much of the excipient is used in the 400 mg tablet as in the 200 mg tablet.

Can the excipients and additives cause adverse events?

Yes they can. Some will be allergic reactions. Chemicals such as sulfites, benzoates, aspartame, saccharin, oleic acid, benzyl alcohol, lactose, soya lecithin, propylene glycol, and sorbitan trioleate have been reported to cause allergic reactions. (See: www.drugs.com/inactive/. This site also has an excellent alphabetical list of inactive ingredients).

The most serious case of excipient-induced AEs occurred in the US in the 1930s when diethylene glycol was used in a sulfonamide. This is similar to anti-freeze and some 100 people died from its ingestion. This was used to make a liquid version of the drug. It was tested for flavor, appearance and fragrance but not toxicity. This produced a major scandal and helped push Congress to pass the Food, Drug and Cosmetic Act of 1938. Tragically this chemical is still being used in various places around the world and has resulted in toxicity and deaths in a dozen other places around the world as late as 2008. (See https://en.wikipedia.org/wiki/Diethylene_glycol#Epidemiology)

Picking Up AEs due to Excipients

It is quite difficult to pick up AEs due to excipients for lots of reasons. As noted above, most of us in the PV world don’t think about them at all. We don’t quite know where to find them. The inactives may vary from formulation to formulation, from country to country, or from time to time as manufacturers change formulations or vendors. The same formulation may be used in different factories around the world which source from different suppliers. The manufacturing groups usually don’t tell the PV group. In large companies making thousands or tens of thousands of formulations around the world, it is very difficult to track this.

Also as noted above, we don’t know how much of each additive is in a tablet or capsule or liquid.

There is a very very low level of suspicion in prescribers, consumers and the pharma world. This is usually justified as it is unlikely that significant AEs that occur are due to an excipient. We also have no idea if there are drug-excipient interactions. Carrying this through to clinical trials, it is entirely possible that some of the AEs reported with placebos (which by definition have no active ingredients) are due to the excipients. Obviously, AEs are reported with placebo products in clinical trials and the EMA requires expedited reporting of certain SAEs with all study products (the study drug in question, comparators and placebos).

What to do in Drug Safety?

About the only advice one can give here is along the lines of the following:

• Try to sensitize the manufacturing/regulatory departments in your company to inform drug safety about major or significant formulation changes regarding excipients. How to define this is problematic. It is not worth getting every formulation change though if there are hundreds or more products.
• Have a look at your products’ formulations. If you find some unusual additives (e.g. alcohol), put this on a watch list for AEs with that product that might conceivably be due to the additive.
• If clusters of AEs occur from the same region or lot number which are clearly out of the ordinary, think of manufacturing issues (GMP issues) and formulation/excipient change.
• For outliers or really extraordinary or “wacky” unexpected AEs (particularly SAEs) look for the unusual cause including excipient issues. This is one of those times to consider violating the old saying “When you hear hoofbeats, don’t think of zebras”.
• Follow, of course, all reporting requirements, laws and regulations. Even if you should find that the AE may be due to an excipient this is reportable under IND and NDA regulations and the equivalent requirements in the EU and elsewhere.
• Some governments are starting to question whether “generally recognized as safe” for drug and food additives are so safe. We may begin to see some changes here.

Tags: adverse events, drug safety, FDA, inactive drugs, Pharmacovigilance