“Toilet Testing”
How Eye Drop Manufacturers Prove Their Preservatives Work
PART 1:
Eye drops should be sterile when you buy them.
The Federal Food Drug & Cosmetic Act has a specific statement about eye drop sterility, found in 21 CFR 200.50(a):
“Informed medical opinion is in agreement that all preparations offered or intended for ophthalmic use, including preparations for cleansing of the eyes, should be sterile.”
This means that the eye drop liquid, the inside of the bottle and the dropper, the outer surface of the dropper and the inner surface of the cap should be sterile when you buy the eye drop. Contamination during manufacturing leads to violations of this law.
PART 2:
Eye drops should stay sterile when you use them.
This is equally critical to eye drop safety. In 21 CFR 200.50(b)(1) the FD&C Act states:
“Liquid ophthalmic preparations packed in multi-dose bottles should contain one or more suitable and harmless substances that will inhibit the growth of microorganisms.”
“Suitable and harmless substance” is FDA-speak for preservative.
The other option under 21 CFR 200.50(b)(2) is to use single-use vials or a bottle with a multi-dose preservative free (MDPF) dropper.
Why does an eye drop in a standard bottle need preservatives? To kill contaminating bacteria that get inside the bottle during ordinary use.
No matter how experienced you are at instilling eye drops, it is impossible to completely avoid contact between the dropper tip and your eyelashes or the skin of your eyelids or fingers. This leads to bacterial contamination of the dropper tip, and thus to contamination of the liquid in the bottle. The preservative’s job is to kill the contaminating bacteria. For a detailed explanation of how eye drops become contaminated see this video.
Over-the-counter eye drop preservatives can be broadly classified into several categories in terms of their chemical structure and likely effectiveness. Read on.
PART 3:
A brief tour of eye drop preservatives
What follows is opinion informed by education and research. Manufacturers with complaints, write c/o The Dry Eye Foundation. Include original data in support of your statements.
Generally reliable preservatives and preservative systems
Note I say “generally” because many other issues such as preservative concentration or eye drop pH, viscosity, and tonicity may affect the kill power of the preservative. Since the FDA does not review or approve OTC eye drops, consumers must take it on faith that these preservatives are getting the job done.
Single ingredient preservatives in the “generally reliable” category include:
benzalkonium chloride (BAK)
sodium perborate (trade names GenAqua and Dequest)
polyquaternium-1 (trade name Polyquad)
Multi-ingredient preservative systems in this category include:
stabilized oxychloro complex (sodium chlorite + sodium chlorate + chlorine dioxide, trade names OcuPure and Purite)
sofZia (sorbitol + borate + zinc)
Using only one ingredient normally found in a preservative system is not guaranteed to work. EzriCare artificial tears (although marketed as preservative-free) contained sodium chlorite, which was insufficient to kill contaminating Pseudomonas bacteria. It is not clear whether the sodium chlorite concentration was too low, or whether sodium chlorite as a standalone preservative is simply not effective.
Specific concerns about the sorbitol / sorbate preservative systems are discussed in more detail later.
Vintage preservatives
Vintage preservatives are not used in prescription drugs in the United States but may still be found in OTC products. Chlorobutanol and alcohol 0.1% are two that come to mind. Benzyl alcohol is used in products manufactured for use in the United Kingdom. These preservatives date from the 1940’s and 1950’s.
Oddly enough, many redness relief drops use the triple-threat combination of benzalkonium chloride, chlorobutanol and alcohol 0.1%. A Japanese company that has been in business since the 1890’s manufactures these products. They just keep adding and never subtracting. Maybe that’s why the products I have tested have a “wow this stings” pH of around 5.5.
There is no modern research on the effectiveness of chlorobutanol or alcohol 0.1% as preservatives, either individually or in combination.
Polyaminopropyl biguanide
Polyaminopropyl biguanide is the standalone preservative for a handful of private label OTC eye drops.
Polyaminopropyl biguanide is one of the disinfectant agents in contact lens cleaners. A disinfectant is a preservative that has a specific job: kill bacteria clinging to your contact lenses after a grueling day at the office.
A quick review of all-in-1 contact lens cleaners on the market shows that many brand name products now contain 2 or 3 preservatives.
Contact lens cleaners include detergents to remove lipid and protein build-up and these detergents are not kind to bacteria or fungus, giving a boost to the germ-killing power of the disinfectant ingredient(s). If you subtract the detergents, the disinfectants may be less effective.
Eye drop manufacturers using polyaminopropyl biguanide as a standalone preservative may have good data to support this decision. Before I use one of these products, I’d like to see it.
Ethylene-diamene-tetra acetic acid
Let’s just call it EDTA.
EDTA is a common eye drop ingredient which acts as a buffer (pH maintainer).
Is EDTA a standalone preservative, or isn’t it? EDTA is effective at killing bacteria in biofilms, where the reported concentrations used range from 4 – 17% (not suitable for contact with your corneas).
EDTA can boost the effect of the primary preservative by weakening the microorganisms’ cell walls but should not be trusted as a standalone. Dr. Berne’s MSM eye drops, which were recalled in August 2023 due to contamination with multiple bacteria as well as fungus, contained EDTA but no other preservative.
Sorbitol / Sorbic acid / Potassium sorbate preservative systems
Alcon’s trademarked preservative sofZia is borate + zinc + sorbitol. This is described as an “oxidative” preservative system that works by stressing out a germ’s metabolism rather than by poking holes in it.
I found sorbitol – which is a sugar alcohol that is used as a food sweetener – to be a peculiar ingredient, but the DailyMed listing for Travatan Z (a glaucoma drop that Alcon spent a ton of money marketing as preserved with nice sofZia, not evil BAK) states sorbitol. So, okay.
Zinc chloride, when combined with a sugar alcohol such as sorbitol, is effective at killing bacteria in biofilms such as the scum that forms on your teeth. The same combination is used to fertilize fruit trees. Don’t drink your Travatan Z, it’s also a laxative.
Sorbitol by itself does nothing, thus the big Z-for-zinc in sofZia.
Although less toxic to the cornea, sofZia is a slow horse compared to BAK. When Travatan Z was approved in 2006, the FDA was primarily concerned that it lowered intraocular pressure as effectively as the already-approved Travatan. The agency appeared indifferent to the possibility that sofZia had zero record of accomplishment as an ophthalmic preservative.
Less happily in 2006, Alcon had to recall Systane Free Liquid Gel, which used sorbitol + borate + zinc as a preservative system. Alcon hastened to make a distinction between this combination and sofZia, as they were reserving the fancy name for pricey prescription drugs. If you ask me, it was all the same. The critical difference – according to Alcon – was that the Systane product contained aminomethylpropanol (as a buffer), which provided a nitrogen food source for mold. Travatan Z does not contain ingredients with nitrogen.
Thus, the effectiveness of Alcon’s “softer” oxidative preservative system was undone by a buffer ingredient that no one considered important.
I mean, who would blame a buffer for overwhelming a preservative, leading to mold growth in an OTC eye drop? It’s like blaming Hello Kitty for mold in your crawlspace.
It is tempting to speculate that Alcon had big plans for sorbitol + zinc + borate and intended to snag a chunk of OTC eye drop revenue by marketing the preservative system, until the humiliation of the Systane recall brought those plans to a crashing halt.
As OTC eye drop manufacturers respond to consumer demand for ‘gently preserved’ drops, more products with an ingredient that starts with sorb are appearing: sorbic acid or potassium sorbate.
Is some confused person trying for sofZia on the cheap? Despite their names, sorbitol and sorbic acid are completely different chemicals – the first is a sugar alcohol, the second is a short-chain fatty acid. Sorbic acid and potassium sorbate are widely used as preservatives in the food industry, including in ready-to-drink beverages. In food they are felt to be mostly useful against molds and yeast, with “selective” effects against bacteria.
Maybe there’s no mistake about using sorbic acid instead of sorbitol: eye drops, bottled soda… a liquid is a liquid.
But this is where the chemistry bites: sorbic acid and potassium sorbate are known as acid preservatives, which means that they are most effective in products – like bottled cola – with a pH around 4.5. They are considered “generally ineffective” above pH 6.0, which is still lower than the pH of a well-buffered OTC lubricating drop.
Out of respect for consumer safety, I hope that reputable manufacturers using sorbic acid-based preservatives individually toilet-test each eye drop they sell.
But nobody is making them do so.
PART 4:
The proof is in the toilet
Dumping an exceptionally large number of particularly nasty bacteria into a nice sterile eye drop is called ‘toilet testing’ in the industry. I heard the term toilet testing from an eye drop manufacturer’s representative at an optometry convention in 2023. I love it and I cannot resist it.
The official (boring) term is antimicrobial effectiveness testing (AET).
Antimicrobial effectiveness testing is the process of ensuring that a drug’s preservative(s) kill contaminating microorganisms – bacteria, yeast and mold – in a reasonable amount of time, and keep them dead.
In my continued voyage through the laws, rules, regulations, policies, and ‘we always do it this ways’ of pharmaceutical manufacturing and marketing I find myself in fresh territory… the United States Pharmacopoeia. Spell pharmacopoeia three times fast. I’ve briefly encountered the USP previously, primarily in relation to ‘USP ingredients.’
USP [51] defines AET for aqueous based products. Eye drops are Category 2: topically used products made with aqueous bases or vehicles. Five individual bottles of a product are inoculated (deliberately contaminated) with the bad-boy bacteria Escherichia coli, Pseudomonas aeruginosa, and Staphylococcus aureus; Candida (yeast); and Aspergillus (mold). The inoculation must result in 100,000 to 1,000,000 individual bacteria / yeast / mold per milliliter of liquid in the bottle.
To pass the AET the preservative(s) must reduce the number of bacteria by 99% (2.0 log units) when tested at 14 days, with sustained 99% reduction through 28 days. For Candida and Aspergillus, the degree of contamination must not increase, which means the killing keeps up with the replicating. Multiple sources for additional technical information can be found by searching “USP 51.”
If you want to geek-out, read this.
Note that passing the AET does not mean that it takes 14 days to kill 99% of the bacteria; ideally death happens much faster. The first test is on day 14. If a small number of particularly tough bacteria escaped the first few days of kill, this gives them a chance to re-proliferate to a detectible level.
The point is that the FDA requires a manufacturer to prove that their preservative(s) eliminate a sizable number of nasty bacteria, yeast and mold inoculated into the eye drop. Most of us don’t have these microorganisms on our facial skin or hands* or would not inoculate such a substantial number into our eye drop bottles during regular use. So, passing the AET is super-over-kill.
Preservative(s) do not work – or fail – in isolation, as we saw with Systane Free Liquid Gel. It is not the preservative that is being tested, it is the product that is being tested for resistance to contamination.
The toilet test is how manufacturers prove that their eye drop products are adequately preserved.
*First wash your hands, then use your eyedrops. Yes, soap.
PART 5:
This is my skeptical face
Over-the-counter eye drop manufacturers have gotten on the preservative free / “mild preservative” bandwagon, due to consumer demand.
A properly packaged preservative free product is safe, if there was no contamination during manufacture. Proper packaging means either single-use vials or a bottle with a MDPF dropper. If there was contamination during manufacture, a MDPF dropper will not save you because its job is to keep bacteria from getting in. It still lets the contaminated eye drop out.
A properly preserved product is safe. The problem is that here at the Dry Eye Foundation, we keep finding eye drops that do not appear to be properly preserved.
PART 6:
What this means to you
First – Preservatives have two jobs.
21 CFR 200.50(b) job: protect against contamination during use.
Post EzriCare job: last line of defense against contamination during manufacture.
Second – No credit for partial right answers.
EDTA does not function as a standalone preservative, although it can increase the effect of other preservatives. Do not use a product in a standard bottle that is “preserved” only with EDTA.
Sodium chlorite is one of three ingredients in stabilized oxychloro complex. Never forget EzriCare artificial tears. If an eye drop’s only preservative is sodium chlorite (even with EDTA), it is a “use at your own risk” product.
Sorbic acid and potassium sorbate are primarily food preservatives which do not work well at typical eye drop pH and are better at killing yeast and molds than bacteria. An eye drop that is preserved with sorbic acid or potassium sorbate is a “use at your own risk” product.
Third – You can do so much better.
Alcohol 0.1%, benzyl alcohol, chlorobutanol, and polyaminopropyl biguanide have no business in a modern dry eye drop.
Fourth – It is not the preservative that must past the toilet test, it’s the product.
An effective preservative in eye drop A may not be effective in eye drop B.
Since everything about OTC eye drop manufacturing is on the honor system patients must never assume that manufacturers have toilet tested their products.
Shop smart. Don’t push your luck. If you want to avoid BAK and don’t like any drops with modern preservatives such as Purite or Polyquad, consider name-brand products in MDPF bottles or snap-top vials.
- Sandra Brown M.D.