New and Improved! Now with Tromethamine!

Pulling a fast one with a new ingredient?

While the FDA and CDC are discussing vaccination for children ages 5-11, I have been hearing community concerns about the addition of tromethamine and tromethamine hydrochloride to the Pfizer-BioNTech COVID‑19 vaccine. It is completely valid to have concerns over what may feel like somebody trying to "pull a fast one" on us; fortunately, it's nothing to be concerned about and is actually a good thing.

First of All, What is Tromethamine?

Tromethamine, along with tromethamine hydrochloride, (known collectively as "Tris") is an acid stabilizer and buffer. What that means is that it is an alkaline substance (like baking soda) that protects other substances by reducing overall acidity; this protection is important while freezing the vaccines (Sek, 2012). Tris is a commonly used ingredient in medications; examples include the topical acne product Tazorac Gel (Allergan, 2011), the oral cholesterol-lowering drug atorvastatin (Sandoz, 2009), the under-the-skin injectable Humalog U‑200 insulin (Eli Lilly, 2019), and the intravenous anti-seizure medicine Cerebyx (Pfizer, 2013). Tris is also an ingredient in the Moderna COVID‑19 vaccine (Moderna, 2021).

What Tromethamine is Not

Most of the negative claims that I am seeing about Tris are in relation to drugs called Toradol (ketorolac tromethamine) and Tham Solution (tromethamine injection). People take adverse events reported from those drugs and incorrectly assume that they apply to Tris used in the vaccines. Tris is not Toradol. Tris is not Tham Solution.

Let's handle the claims connected to Toradol first. Toradol is a potent, prescription-only medication that is used to treat severe pain and inflammation; in fact, it cannot be taken for more than five consecutive days because of its potency and the possibility of organ damage (Roche, 2013; Hospira, 2015). That sounds pretty scary! The good news, though, is that this has ABSOLUTELY NOTHING to do with the vaccines OR Tris. This is because, despite "tromethamine" being in the name "ketorolac tromethamine," Tris itself is not an ingredient in Toradol. In reality, a molecule of ketorolac (C₁₅H₁₃NO₃) has been chemically bonded with a molecule of tromethamine (C₄H₁₁NO₃), creating a completely new molecule called ketorolac tromethamine (C₁₉H₂₄N₂O₆) (National Center for Biotechnology Information [NCBI], 2021a; NCBI, 2021b; NCBI, 2021c). Recognizing the lack of a comma between "ketorolac" and "tromethamine" is very important! Think about it like water - hydrogen gas and oxygen gas are both violently explosive on their own, but they form water when chemically bonded (2H₂ + O₂ → 2H₂O), which is pretty much the opposite of explosive. With this knowledge in hand, any adverse events caused by Toradol cannot be attributed solely to tromethamine (or ketorolac, for that matter). For this reason, it is my professional opinion that any negative claims regarding the vaccines that cite Toradol should be completely ignored by anybody without a PhD in pharmacology.

Now we can examine Tham Solution. Tham Solution is a medication used to treat certain cardiac emergencies (Hospira, 2006). On its surface, negative claims regarding the vaccines that cite Tham Solution seem much more plausible since Tham Solution actually does contain tromethamine. Here's the deal, though: the amount of tromethamine matters. A single dose of the vaccine for children ages 5-11 contains 0.15 mg of Tris (Pfizer, 2021b). A single dose of Tham Solution, on the other hand, contains 10,000 to 15,000 mg of Tris (Hospira, 2006). That's right, there is literally 100,000 times more Tris in Tham Solution than the vaccine. The amount of Tris in the vaccine would be useless in a cardiac emergency, and the amount of Tris in a dose of Tham Solution would be impossible to fit in a syringe of the vaccine.

I liken the comparison of the amount of Tris in the vaccine and the amount of Tris in Tham Solution to vitamin A. Consuming a low-to-moderate dose of vitamin A is helpful in preventing skin cancer (Moon et al., 1997), while a larger dose of the same vitamin A can cause your liver to fail, your skin to fall off, and could potentially kill you (Rodahl & Moore, 1943). See how the amount matters? So please, be extremely skeptical about negative claims regarding the vaccines that cite Tham Solution.

Pick a Color, Any Color

Pfizer and BioNTech have been working on a new formulation of their COVID‑19 vaccine. This new formulation uses the same mRNA and lipid nanoparticles, but the salts have been removed, the amount of sucrose has been increased, and Tris has been added; it is being referred to as the "gray cap" formula (Pfizer, 2021c; Pfizer, 2021d). The vials that the original Pfizer-BioNTech formulation comes in have purple caps (plastic lids) on them. Likewise, the Moderna vaccine comes in vials with red caps and the Johnson & Johnson/Janssen vaccine comes in vials with blue caps.

The "purple cap" version of Pfizer-BioNTech's COVID‑19 vaccine for individuals ages 12 and up, whether the label says "Pfizer-BioNTech COVID‑19 vaccine" or "Comirnaty" (more on that name confusion is available in my earlier post, "The Road to Comirnaty: FDA, EUA, BLA, OMG!"), has very strict temperature requirements; it also must be diluted (like juice concentrate) by the person administering the vaccine before it can be used (Pfizer, 2021a; Pfizer, 2021d). On the other hand, the Moderna vaccine can be kept in a regular freezer on its coldest setting for long-term storage or a regular refrigerator for around a month, the Johnson & Johnson/Janssen vaccine simply needs to be stored in a regular refrigerator, and neither of those two need to be diluted ahead of time (Janssen, 2021; Moderna, 2021). Pfizer-BioNTech's "gray cap" version is more in line with the Moderna vaccine's temperature requirements; it also no longer needs dilution before use (Pfizer, 2021c), bringing it in line with both of the other vaccines. These modifications will improve product availability, simplify the administration process, and reduce opportunities for human errors.

But What About the Children!?

Okay. The little ones can have their own vial color: orange!

Seriously, though, the vaccine for children ages 5-11 gets its own vial cap color. It basically follows the formula of the "gray cap" version with all of its ingredients set at exactly one-third the amount of its grown-up counterpart's ingredients; the only other difference is that it does need to be diluted (Pfizer, 2021b; Pfizer, 2021c). A safety study of 2,268 children ages 5-11 was conducted using this vaccine and it was found to be safe (Pfizer, 2021b).

Let's Share Recipes!

For those of you who want to look through the differences between formulations, I took the time to sort through each one's respective documentation and organized it into a single convenient table. Information about each individual ingredient can be found in my earlier post, "Answering 'What's in the Vaccine?'" (hint: information on tromethamine and tromethamine hydrochloride is in the Moderna section).

Ingredient	Purpose	Purple Cap	Orange Cap	Gray Cap
nucleoside-modified mRNA (BNT162b2)	Main Ingredient	30 mcg	10 mcg	30 mcg
ALC-0315¹	Lipid Nanoparticle	0.43 mg	0.14 mg	0.43 mg
ALC-0159²	Lipid Nanoparticle	0.05 mg	0.02 mg	0.05 mg
DSPC³	Lipid Nanoparticle	0.09 mg	0.03 mg	0.09 mg
cholesterol	Lipid Nanoparticle	0.2 mg	0.06 mg	0.2 mg
sucrose	Sugar (Stabilizer)	6 mg	10.3 mg	31 mg
sodium chloride (from dilutant)	Salt (from dilutant)	2.16 mg	0.9 mg	×
sodium chloride	Salt (Stabilizer)	0.36 mg	×	×
potassium chloride	Salt (Stabilizer)	0.01 mg	×	×
monobasic potassium phosphate	Salt (Stabilizer)	0.01 mg	×	×
dibasic sodium phosphate dihydrate	Salt (Stabilizer)	0.07 mg	×	×
tromethamine	Acid Stabilizer (Base)	×	0.02 mg	0.06 mg
tromethamine hydrochloride	Acid Stabilizer (Base)	×	0.13 mg	0.4 mg
¹ Compound name: ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate) ² Compound name: 2[(polyethylene glycol)-2000]-N,N-ditetradecylacetamide ³ Compound name: 1,2-distearoyl-sn-glycero-3-phosphocholine (Pfizer, 2021a; Pfizer, 2021b; Pfizer, 2021c; Pfizer, 2021d)

My Educated Guess...

I don't work in the vaccine division of Pfizer or BioNTech, so I don't know exactly what they're thinking/planning, but my educated prediction as a registered nurse is that they will eliminate the "purple cap" formula, and quite possibly the "orange cap" formula, and move everything over to the "gray cap" formula - with instructions to use either a 10 mcg dose or a 30 mcg dose that is determined by the recipient's age. Right now, the branded product Comirnaty uses the "purple cap" formula, but since they only changed the inactive ingredients and nothing that affects the recipient of the vaccine, the work involved in getting it switched over to the "gray cap" formula shouldn't be that big of an undertaking for Pfizer and BioNTech. A move like this would streamline their manufacturing process and allow them to distribute their vaccine to more regions that are currently underserved. But that's all speculation.