Introduction:

For many people, pets are a major part of everyday life. They become part of their households and are like family, but like children, none of them come with true owner’s manuals. Sure, there are many books on the subject, but who do you trust? And who has the time to read all that stuff? What happens if or when they become sick or injured and need medication?

As a somewhat reticent parent of a very large Weimaraner (OK, my husband and daughter bought him without my knowledge), I was forced to learn rather quickly about the ins and outs of pet ownership. Still, he arrived, and we needed to determine what’s best for this 99-pound dufus, who amazingly survived eating an entire box of oatmeal raisin cookies. It wasn’t pretty, but that story is reserved for an antidote CE.

At the University of Connecticut School of Pharmacy, advanced compounding students are trained in some veterinary compounding, but most pharmacy schools do not teach it. This is a bit upsetting since people spend millions of dollars on pets every year. An estimated 65.1 million households are home to dogs and another 46.5 million households have cats in the U.S. With pet ownership comes the responsibility of caring for them. The average cost of veterinary care for a dog is $730 per year, with cats averaging $253 per year. In 2022, Americans spent $136.8 billion dollars on their pets.¹

Increasingly, pharmacy staff need to know some basics about companion animals and their health issues. Pet owners can request a paper prescription from the veterinarian and fill it at community pharmacies. The American Veterinary Medical Association (AVMA) incorporated prescription guidelines into their 1991 bylaws. It states that “a veterinarian shall honor a client's request for a prescription or veterinary feed directive in lieu of dispensing but may charge a fee for this service.”² What do you do when a pet owner brings a prescription to your pharmacy?

People’s perceptions about feeding human food to dogs and cats are surprising. An old wives’ tale, passed from generation to generation, tells us that dogs can eat just about anything, including bones. Most of us now know that sharp bone shards can penetrate the soft tissues at the back of the throat, they can lodge in the esophagus, or they can pierce the intestines. It is also possible for a piece of bone to lodge in the trachea (windpipe), interfering with a dog’s ability to breathe.³ The controversy still continues today, but no pet owner wants their pet to have broken teeth, mouth injuries, or intestinal blockages if they can avoid it. If cooked bones are out, what else is bad for them? Certain foods create a risk for most pets, so compounders must not use these items as ingredients in their compounds. Table 1 contains a list of some human foods that should be avoided in pets.

Table 1. Human Foods That Should Not Be Given to Pets⁴

 

Food Item	Type of Pet	Toxicity/Reasoning
Alcohol	Dogs, cats, chickens, rabbits	Alcohol poisoning
Tobacco	Dogs, cats	Nicotine
Onions, chives, garlic (Allium family)	Dogs, cats, chickens,  rabbits	Sulfates, disulfides
Avocado	Dogs, cats, chickens, horses, cows, pet birds	Persin
Salt	Dogs, cats, chickens	Fluid imbalance
Spicy foods	Dogs	G.I. upset
Grapes, raisins	Dogs, cats, rabbits	Kidney failure
Caffeine	Dogs, cats, rabbits	Methylxanthines
Chocolate	Dogs, cats, horses, rabbits	Theobromine and caffeine
Citrus fruits	Cats, chickens	Citric Acid, essential oils
Cinnamon	Dogs, cats	Mouth and throat irritant
Nutmeg	Dogs, cats	Myristicin
Macadamia nuts	Dogs, cats	Toxicity unknown
Mushrooms	Dogs, cats	Mycotoxins
Green tomatoes, raw potatoes	Dogs, cats, chickens, horses, rabbits	Solanine
Raw bread dough, raw yeast, bread	Dogs, cats, horses, rabbits	G.I. upset, bloating, empty calories
Rhubarb	Chickens, rabbits
Dairy items, ice cream	Dogs, cats, chickens, horses, rabbits	High sugar, high fat, lactose intolerance. Adult cats become lactose intolerant
Sugar free gum and sugar free candy	Dogs, cats	Xylitol
Seeds and Pits	Dogs, cats, chickens, horses, rabbits	Cyanide
Turkey skin, chicken skin, ham	Dogs, cats, rabbits	High fat content, can cause acute pancreatitis
Marijuana	Dogs, cats, horses, rabbits	Tetrahydrocannabinol (THC)

 

Items like alcohol, tobacco, caffeine, and chocolate make sense. Alcohol and tobacco affect dogs and cats as they do humans, but our pets are much smaller, so it takes significantly less alcohol or tobacco to cause catastrophic events such as breathing problems, vomiting, diarrhea, coma, or even death. Dogs are curious, and a tobacco or marijuana “cigarette” on the ground might be pretty tasty. The average tobacco cigarette contains 10 to 12 milligrams of nicotine. A toxic dose of nicotine for a pet is 0.5 to 1 milligram per pound, and a 4-milligram dose per pound can be lethal.⁵ Doing some quick math, consuming as little as three or four cigarettes could be fatal to a 10-pound dog.

Vaping has become extremely popular, which has caused an increase in nicotine poisonings. An average 6 mL, 5% nicotine e-cigarette can contain up to 300 mg of nicotine. Pets can be subjected to nicotine poisoning by secondhand smoke, through spillage on skin, and by drinking the vaping liquid. Consider this: a 40-pound dog would only need to be exposed to a 1 mL dose for it to become poisoned.⁵ Nicotine is not the only toxin in e-cigarettes. They also contain volatile organic compounds, heavy metals (e.g., cadmium, copper, lead, nickel, tin) and they contain propylene glycol. All of these components are harmful to pets.

Those other “cigarettes” can be pretty tasty too. Marijuana use is on the rise in the U.S. since it is now legal in more than 21 states, and for the first time, it has now made its way onto the list of the top 10 items that cause pet poisonings. The two major components of marijuana are cannabidiol (CBD) and delta-9-tetrahydrocannabinol (THC). CBD is nontoxic to animals, whereas THC is the psychoactive ingredient that is extremely toxic. CBD is widely advertised for human and pet use, but consumers must read labels carefully. Most CBD products are not entirely pure. They contain small amounts of THC.⁶

Although secondhand smoke and consuming raw marijuana leaves can be toxic, the most reported intoxications come from pets eating infused edibles. Edibles like brownies, cookies or gummies are made with concentrated THC infused oils or THC-infused butter. They tend to be a more significant threat since most edibles also contain chocolate or xylitol.⁷  If pets exhibit any symptoms, they should be taken to a veterinarian. THC poisoning closely mimics the signs of antifreeze poisoning which is fatal and an antidote needs to be given as quickly as possible.^6,7

Symptoms of marijuana intoxication can become visible within 30 to 60 minutes after ingestion. Pets may stumble and cross their feet, walking as if they were drunk, they may have enlarged pupils, become lethargic and flinch in reaction to sudden movements. Pets with severe cases of intoxication may vomit, have tremors, shake uncontrollably and in extreme cases become comatose. Roughly 50% of dogs develop urinary incontinence and dribble urine uncontrollably (which might make the drug less popular if this happened in humans).⁷

Some medications contain significant amounts of alcohol. If unsecured, a dog or cat could consume them. Certain formulations of diphenhydramine (Benadryl, Sominex), guaifenesin with codeine (Cheracol Plus), dextromethorphan, guaifenesin, pseudoephedrine combinations (Dimetane, Robitussin, Triaminic, Vicks), hydrocodone and pseudoephedrine combinations (Novahistine), and certain multivitamin liquids (Geritol) contain alcohol. Some remedies can contain up to 25% alcohol, which can harm pets (and children).⁸  Alcohol is sweet tasting to dogs, so they will not stop drinking it until it is all gone.

Caffeine and chocolate ingestion should also be taken seriously. Caffeine contains methylxanthines, which can cause bronchodilatory and stimulatory effects in humans. In animals, they can also cause vomiting, diarrhea, hyperactivity, seizures, and cardiac arrhythmias. Chocolate, derived from the roasted seeds of Theobroma cacao, contains methylxanthine, theobromine, and caffeine. The theobromine content in chocolate is three to ten times that of caffeine. Cats do not have taste buds that can detect sweetness, but dogs do have a sweet tooth and love the taste of chocolate. One ounce (28 grams) of chocolate could be a lethal dose in a small dog. Theobromine has a half-life of two to three hours in humans, but it is longer in dogs. The half-life of theobromine in dogs is 17.5 hours.^9,10 The SIDEBAR provides more information about chocolate toxicity in dogs.

 

How Much Chocolate is Too Much?^10,11

Different cocoa beans and chocolate products contain various amounts of methylxanthines. Compounders and veterinary care providers must consider the dog or cat’s weight and the amount of chocolate consumed.

Methylxanthine doses of 15 mg/kg (7.5 mg per pound) or less should not harm a dog. This is equivalent to one square of dark chocolate for a 3 kg (6 lb.) dog or seven squares of chocolate for a 15 kg (33lb.) dog. One square of chocolate is approximately 6 grams (0.21 oz). This formula calculates the dose consumed:

Theobromine dose = concentration in type of chocolate x amount eaten/weight

Caffeine dose = concentration in type of chocolate x amount eaten/weight

Theobromine + caffeine = Total methylxanthines

The caffeine and theobromine amounts in the specific type of chocolate may be on the label, and the Table¹⁰ below provides some information about common products. However, in emergencies, healthcare providers can use calculators on the Internet that performs this calculation quickly and efficiently. This is not to say that cats never get into chocolate and get sick. There are also cat chocolate toxicity calculators online in case of emergency.

Methylxanthines in Chocolate ¹⁰

Product	Methylxanthines per 1 gram chocolate	mg methylxanthines /ounce of chocolate
Dry cocoa powder	28.5 mg	800 mg
Unsweetened bakers chocolate	16 mg	450 mg
Milk Chocolate bar	2.3 mg	64 mg
Dark Chocolate bar	5.7 mg	150- 160 mg
Cocoa bean hulls (mulch)	9.1 mg	225 mg
White chocolate	Negligible

 

Excess salt (sodium chloride) can cause fluid imbalances which could lead to seizures and spicy foods can cause painful vomiting, diarrhea, or stomach ulcers. Dogs, cats, and even birds are very sensitive to salt, so pet owners and compounders should be aware of common items that contain large amounts of salt. For example, sea water, baking soda, homemade play dough, and driveway deicer all contain high concentrations of salt. Sodium chloride poisonings in dogs are most often caused by pet owners who use salt to induce vomiting after the dog has ingested a different toxin. It is important to consult with a veterinarian or pet helpline before administering any type of antidote.¹²

Even seemingly harmless spices can be harmful. Cinnamon can cause mouth irritations and nutmeg, which contains myristicin, can cause hallucinations in smaller animals. Mushrooms contain mycotoxins which can also cause hallucinations, diarrhea, vomiting, or kidney failure and in extreme cases, liver failure.⁴

Although more toxic to cats than dogs, onions, chives, garlic,  and all members of the allium family of herbs contain sulfoxides and disulfides, and an oxidant called n-propyl disulfide. These can cause a fatal anemia, called oxidative hemolysis, which affects dogs, cats, rabbits and chicken. Signs of anemia may take several days to appear.^4,17,18  If a dog is fed a little garlic once in a while it should not be a problem but avoid giving pets garlic supplements. It was once believed that garlic supplements given to dogs could help to repel fleas and ticks, but this has now been proven to be ineffective.¹³

Other problematic vegetables include green tomatoes, raw potatoes, and avocado. The tomato plant’s green parts, its stems and leaves, and raw potatoes contain solanine. Solanine is poisonous, even to humans. It has pesticide-like properties and is part of the plant’s natural defenses. Solanine can be found in green potatoes and potato tubers (eyes).¹⁴ It is also found in other members of the nightshade family (e.g., eggplant skin).

Avocado is only slightly dangerous to dogs and cats, but extremely dangerous to birds and large animals such as cows, goats, sheep and horses. The bark, leaves, skin, pits and fruit of the avocado contain persin, which is a fungicidal toxin. Persin is an oil soluble compound that seeps into the fruit from the large seed inside. It is similar in structure to a fatty acid, and is harmless to humans, but toxic to most animals. Symptoms of persin toxicity range from edema and mastitis to respiratory distress and heart failure.^15,16

Chickens, which are increasingly popular in back yards, are sensitive to many food items. They should not be fed most human foods, but especially avoid feeding them citrus fruits, uncooked rice and uncooked dried beans, fruit seeds and pits, tomato leaves, green potatoes, and rhubarb.¹⁷ Rhubarb’s high oxalic acid content binds to minerals and can form kidney stones. Although high in calcium and phosphorus, certain dried beans are acidic and contain hemagglutinin. Hemagglutinins bind to receptors on red blood cells to initiate viral attachment and infection.

Rabbits, guinea pigs, and most herbivores have similar dietary restrictions. Fruit seeds and pits contain small amounts of cyanide, which can be a concern to smaller animals. Cabbage, cauliflower, other gassy vegetables and iceberg lettuce must be avoided. Iceberg lettuce contains lactucarium. Lactucarium (also called lettuce opium), a milky fluid excreted near the base of the lettuce plant, has sedative properties. Rabbits and other herbivores should stick to darker greens.¹⁸

Factors That Influence Toxicity

Each species of animal reacts to toxins differently due to variations in absorption, metabolism, or elimination. The dose of toxin per body weight is a major concern. Other factors include the animal’s age, size, nutritional status, stress level, and overall health. For example, most young animals do not have a fully developed system of metabolism, which may cause a toxin to remain in their system longer, causing more harm. Horses, rabbits, and small rodents do not have the ability to vomit, which means that they may be poisoned at a lower dose.¹⁹

One must also consider the chemical nature of a food, drug or poison that is consumed. If the drug or toxin dissolves in water easily, it will spread throughout the body easier. If there are substances added to an active ingredient, such as a binding agent or outer coating, or if it is a sustained release product, it will affect absorption.¹⁹ Overall, pharmacists should become familiar with species specific toxins and the factors that affect the risk of toxicity. Animals absorb, distribute, metabolize, and eliminate medications and toxins differently from humans, and the interspecies differences are also notable. See the SIDEBAR for a list of the top ten toxic items.

 

ASPCA: The Official Top 10 Toxins of 2022²⁰

Each year, the Animal Poison Control Center of America (ASPCA) compiles a yearly list of toxic items. They received 335,136 pet poisoning calls in 2022 and have tabulated the results as follows:

1. Over the Counter Medications. Ibuprofen and acetaminophen are the most common.
2. Food items. Protein bars, xylitol, grapes and raisins top the list.
3. Human prescription medications
4. ASPCA received approximately five calls per hour regarding chocolate.
5. Plants
6. Household chemicals. Disinfecting wipes top the list.
7. Veterinary products
8. Rodenticides
9. Insecticides. Ant baits are an example.
10. Recreational drugs. Edible THC products are the most common.

 

Evolution has influenced species-specific diets. Dogs have evolved to become opportunistic gorgers, while cats are very picky. A dog will eat every bit of chocolate once he starts, which is the reason why dog poisonings are more common. Cat poisonings are less common and are usually the result of intentional harm by human beings.

Pause and Ponder: Have you tried to give a dog a tablet or capsule? Did you wrap it in some meat or cheese? How did you get a cat to take his dose?

When to Compound

Pharmacists should consider compounding veterinary products under three conditions:

1. When a commercial product is unavailable. This could be due to drug recalls, drug shortages, or because a commercial product has yet to be developed. In some cases, rapid changes in disease state management create an urgent need for medication.
2. When an approved drug needs to be modified. This would include an increase or decrease in dosage due to a lack of appropriate dosage size, or a lack of formulation for a desired route, for example, making a dilution, adding flavoring, or changing the form of the drug. A popular compounding task is changing a tablet into a suspension.
3. When the likelihood of nonadherence is high. Owners’ adherence is greater when they can administer one combination product instead of two or three. For example, combining two injectable vaccines or allergy medications into one syringe for ease of use would be helpful to the pet owner. Of course, it is also more beneficial to the animal, since it will minimize harm and stress, which will lead to a better prognosis. Our students have recently formulated a compound of ketoconazole, gentamicin sulfate, and mometasone furoate all in one for a dog with an external ear bacterial yeast infection.

Dogs and cats can be very particular, and their sense of smell will give that medication away every time. This means that compounding must be creative. The most popular forms of medications for veterinary consideration include capsules, transdermal medications, flavored liquids, tablets, chews, or treats. Oral formulations can be difficult to give, but devices such as droppers, mechanical pill injectors, oral syringes, and oral pastes and gels can mask medications. Pill pockets—soft, flexible treats—can be molded around a tablet or capsule. Medicated oral pastes and gels, when placed on a cat’s paw, are an ingenious way for the cat to lick his medicine up. Compounders make a variety of products from hairball pastes and pectin gels, used for diarrhea, to dental licks and probiotic powders which are placed on a cat’s fur.

Human compounding caters to the customer, and the same is true for pets. Tuna or salmon flavoring attracts cats; beef or chicken flavoring may fool dogs; and birds love seeds. Other ingredients can be rather generic. Compounders can choose from a myriad of thickeners, sweeteners, and preservatives. Choosing the correct excipient could be crucial.

Pause and Ponder: Take another look at the list of forbidden foods. Which items on your pharmacy compounding shelf could be harmful to pets?

Ingredients for veterinary compounding

In human compounding we tend to lean toward avocado or grapeseed oil to soothe and treat the skin, which are lighter than other oils. We use alcohol, propylene glycol, polysorbate 80 (Tween 80), and essential oils in compounds and peanut butter quite often for dog treats. These may not be the best choices in some veterinary situations. Let’s look at what is safe and what should not be used for pets.

Sweeteners

Sugar substitutes are game changers for people who have diabetes or are on low calorie diets. Xylitol is a current human favorite, occuring naturally in small amounts in berries, cauliflower, corn, mushrooms, oats, plums, and pumpkins. In industrial production, the purest form is extracted from raw biomass materials such as hard and soft wood, and especially from the birch tree. More economical processing uses hydrolyzed, purified agricultural corn, wheat, and rice waste. Economists expect xylitol production to become a $1.4 billion industry by 2025.²¹ Why the increase in popularity? Xylitol contains two-thirds of the calories of sucrose and has a mild increased saliva effect. Unfortunately, xylitol is extremely toxic to dogs.

When dogs consume xylitol, it is quickly released into the bloodstream, causing an immediate and potent release of insulin from the pancreas. This leads to severe hypoglycemia, with onset that can occur anywhere from 10 to 60 minutes after ingestion. Without treatment, the dog may develop liver failure, have seizures, or become comatose.²²

Products that contain xylitol are ubiquitous. It’s found in foods such as barbeque sauce, candy, gum, jam, ketchup, low calorie maple syrup, and peanut butter (meaning that compounders who use peanut butter need to check labels carefully; xylitol may be listed as 1,4-anhydro-d-xylitol, anhydroxylitol, birch bark extract, birch sugar, D-xylitol, Xylite, xylitylglucoside, or zylatol). In fact, sugar-free gum is the most common source of xylitol poisoning in dogs. For example, one piece of gum or one breath mint can be fatal to a 10-pound dog. The Pet Poison Helpline responded to 5,846 xylitol poisoning cases in 2020.²²

Xylitol can also be found in many pharmaceuticals and personal care products: cough syrup, deodorant, digestive aids, gummy vitamins, laxatives, mouthwash, nasal sprays, shampoo, skin care products, sleep supplements, toothpaste, and especially orally dissolving tablets. Small traces of xylitol can even be found in prescription medications.²² Gabapentin tablets and capsules do not contain xylitol, but gabapentin oral solution contains xylitol. The side bar discusses one xylitol poisoning case.

 

SIDE BAR: POOR MIMI²³

In 2020, Mimi, a pet poodle passed away after receiving gabapentin. The veterinarian prescribed gabapentin oral solution, for ease of use and medication adherence for Mimi’s seizures. The owner administered the dose and Mimi’s seizures increased, so the owner called the veterinarian, who increased the dose of medication to be given. Within 24 hours Mimi was gone.

How could this happen?

Many veterinarians are unfamiliar with the added ingredients in human formulations. Also, drug manufacturers may change sweeteners without notice. A retail pharmacist filled her prescription for gabapentin oral solution with the commercially available product, which contained xylitol.  When the dogs owners went to the pharmacy to investigate, they found several factors which caused the problem.

• They were told that the pharmacist did not know that the solution contained xylitol and he was also unaware that xylitol was harmful to dogs.
• The pharmacy had no drug utilization reviews processes in place for veterinary drugs.
• The existing built-in computer software was not programmed to issue alerts for xylitol or other veterinary toxins.
• The pharmacy did not have a veterinary drug reference book, for example, Plumbs Veterinary Medicine, or a veterinary drug formulary. Unfortunately, the majority of state boards of pharmacy do not require pharmacies to carry a veterinary drug reference book.

Pharmacists and pharmacy technicians need to be aware of additives in human drug formulations that can be harmful to pets. Mimi’s death could have been avoided.²³

 

Many other sugar substitutes are considered safe to use in veterinary compounding. Erythritol, a sugar used mainly in keto desserts and baked goods, is safe in small amounts. Stevia and aspartame are also considered safe to use, although pets may experience stomach aches or slight diarrhea. Saccharin (Sweet-n-Low), sucralose (Splenda), or monk fruit, a newer sweetener, are all considered safe in pets.²⁴ Dogs have more of a sweet tooth than cats, but in general, sweeteners should be kept to a minimum.

Flavors

Using an optimal flavor profile helps mask the active ingredient’s taste and will promote animal adherence. Compounders should use only flavorings that are intended for compounding use. They shouldn’t use meat-flavored bouillon cubes or bouillon powders for compounding since they contain high amounts of salt, onion powder, and other harmful spices. Table 2 lists common flavorings and the species that find them enjoyable.

 

Table 2. Common Flavorings for Pets²⁵

Animal	Flavor	Reasoning
Birds	Banana, grape, orange, raspberry, tangerine, tutti-fruiti, piña colada	Birds prefer sweet and fruity flavors
Dogs	Bacon, beef, liver, chicken, turkey, cheese, peanut butter, molasses, caramel, anise, marshmallow, raspberry, strawberry, honey	Dogs prefer meats and sweets
Cats	Fish, liver, tuna, cod liver oil, sardines, mackerel, salmon, beef, chicken, cheese, bacon, molasses, peanut butter, butterscotch, marshmallow	Cats do not like very much sweetness but hate bitterness
Gerbil	Banana cream, orange, peach, tangerine, tutti-fruiti	Gerbils like sweet and fruity flavors
Iguana	Banana, cantaloupe, kiwi, orange, tangerine, watermelon, other melons	Iguanas and most reptiles rely on their sense of smell more than taste, so it must smell good
Rabbits	Banana cream, carrot, celery, lettuce, parsley, pineapple, vanilla, butternut	Find their favorite vegetable or fruit and use it
Poultry	Cantaloupe, corn, meal, milk, vanilla, butternut, watermelon	Research is ongoing to determine the sense of taste in chickens.

 

Preservatives and Additives

The Food and Drug Administration (FDA) maintains a list of additives generally recognized as safe (GRAS) for use in pet foods. Manufacturers must submit food additives used in their pet foods for FDA review, which if approved, are added to the GRAS list.²⁶

Still, many excipients should not be used for veterinary compounding ^27,28,31

• Butylated hydroxyanisole (BHA)
• Butylated hydroxytoluene (BHT)
• Ethoxyquin
• Propylene glycol
• Polysorbate 80 (Tween 80)

BHA and BHT are preservatives that are added to oils and rendered fats in certain pet foods and treats. They have been found to be carcinogens and can cause liver and kidney damage in rats, but the FDA has cleared them for use in small amounts in pet foods and treats. Ethoxyquin, a preservative, is used as a hardening agent. It is also used in pesticides and rubber and is illegal for human use, yet the FDA has ruled the additive “may be safely used in animal feeds” when used according to regulations.²⁷ Which is the best preservative to use? The answer is to stick to more natural preservatives. Vitamin C and E are great choices, as are lemon, except for use in cats and chickens, and honey. Honey is packed with vitamins A, B, C, D, E, and K and also contains potassium, calcium, magnesium, copper, and antioxidants. Giving a pet a small amount of honey can even help to build immunity from some allergens, such as pollen.²⁹

Propylene glycol is a controversial excipient used as a humectant, or moisturizing agent, in many pharmaceutical formulations. Propylene glycol is derived from ethylene glycol, which is antifreeze’s main component. Small amounts may be used in dog formulations, but it is extremely toxic to cats. Extended exposure to propylene glycol over several years has been shown to cause seizures and possible blood disorders in both dogs and cats.²⁸ Cats may develop Heinz body hemolytic anemia, which can lead to death.

Cats and dogs are also extremely reactive to essential oils. Popular essential oils (e.g., eucalyptus oil, peppermint oil, tea tree oil) can be found in some natural flea repellents, perfumes, and aromatherapy products. These are safe to use in humans and can be found in many topical preparations; using these oils in topical preparations for dogs or especially cats (since they are continual groomers), can be harmful. Signs of toxicity are lethargy, depression, ataxia, tremors, seizures, or death.³⁰

Polysorbate 80 (Tween 80) is a surfactant used in soaps and as a lubricant in eye drops. It is also used as an excipient quite often to stabilize aqueous formulations of lipophilic drugs for vaccines and for parenteral administration. Many Chinese herbal injectable medications contain high amounts of polysorbate 80. When dogs are given intravenous (IV) medications that contain high levels of polysorbate 80, for example vitamin K, it causes systemic histamine release, which causes allergic reactions and tachycardia and may lead to an anaphylactic reaction.³¹

Corn syrup is a cheap humectant, sweetener, and flavoring agent all-in-one, but it can be addictive to dogs and can increase blood sugar significantly. A vegetable-based glycerin, such as coconut glycerin is a better choice.³²

Food dyes and colorants should be used sparingly when compounding. Blue dye #2, red #40, yellow #5 and #6 can cause hypersensitivity or allergic reactions in some pets. Also, caramel color 4-methylimidazole (4-MIE) is under investigation as a possible carcinogen in pets.³² In actuality, pets do not care about the color of the compound. Artificial coloring only appeals to the pet owner.

 

When to Call a Professional

When should pet owners or concerned pharmacy staff call a professional for a suspected pet poisoning? The sooner the better. The first call should be to the pet’s veterinarian, but national hotlines are also available for emergencies 24/7 for a fee.

• ASPCA Animal Poison Control

https://www.aspca.org/pet-care/animal-poison-control

888-426-4435

Free access to website

$95.00 fee for hotline service

*90% of the fee is covered with ASPCA insurance

 

• Pet Poison Helpline

http://www.petpoisonhelpline.com

855-746-7661

Free access to website. $85.00 fee for hotline service

 

General Recommendations for Compounding

Under the Federal Food, Drug, and Cosmetic Act (FD&C Act), the FDA permits compounding of animal drugs when the source of the active ingredient is a finished FDA-approved drug, and not a bulk drug substance (BDS), unless certain exceptions, described below, are followed. A “bulk drug substance” is a substance used to make a drug that becomes an active ingredient in the drug’s finished dosage form.³³ Most pharmacists would recognize that as an active pharmaceutical ingredient (API).

A commercially available drug may not always be available or appropriate for veterinary use. For example, an FDA-approved drug may have excipients or preservatives that are unsuitable for pets, the dose may be too large, or the flavoring may be unacceptable. In this case, the FDA has acknowledged the need for certain bulk drug substances. On April 14, 2022, the FDA released the Guidance for Industry (GFI #256), entitled “Compounding Animal Drugs from Bulk Drug Substances” which became effective in April 2023.The FDA has also created approved BDS lists for use in veterinary preparations.³⁵  Separate BDS lists exist for non-food producing animals, for food producing animals, for veterinary office stock drugs, and certain wildlife species.³⁶ GFI #256 allows pharmacies to purchase and use bulk drug substances from FDA-registered suppliers if a certificate of analysis (COA) is included with the compounding record. The FDA also requires compounders to report any adverse reactions to the FDA within 15 days. Veterinarians must also provide more patient specific detailed clinical information explaining why a pet cannot use an FDA approved manufactured product.

The FDA has composed a check list for pharmacists regarding veterinary compounding.³⁴

1. Confirm whether patient(s) is a nonfood-producing animal or a food-producing animal. Make sure that chicken is just a pet! Food-production animals (cattle, chickens, etc.) have an additional set of rules (not discussed here). Check the FDA guidelines for more information.³³
2. Follow all state laws and regulations that apply to compounding animal drugs. Compounders need to check their state regulations. It appears that most states tend to merely restate FDA animal compounding guidance.
3. Meet USP standards and FD&C Act requirements. Use FDA-approved drugs or FDA-approved BDS, follow USP guidelines and monographs, if they exist, and follow FD&C act requirements.
4. Include all labeling information. See below.
5. Dispense the compounded drug(s) to the patient’s owner or caretaker or the veterinarian who prescribed or ordered it. A valid veterinarian-client relationship must exist, and a veterinarian must provide a valid prescription.
6. Report adverse events and product defects associated with the compounded drug to the FDA on Form FDA 1932a.
7. Consider other FDA-approved options first. Check to see if alternative options are available. Compounding is permitted if the active ingredient is a different salt, ester, or other derivative.
8. Determine if you are compounding a copy of an FDA-approved product. If the exact form of medication is commercially available, it cannot be compounded.
9. Obtain a medical rationale and retain it in your records if a copy is needed. The rationale for the compound must be documented on the prescription.

Other considerations include determining the physical and chemical compatibility of the drugs, the drugs’ solubility and stability, and the active ingredients’ pharmacodynamics.

Labeling

In addition to including the client's name on the label, the American Veterinary Medical Association (AVMA) recommends veterinarians and compounders in veterinary offices convey the following information to animal owners when prescribing all compounded preparations³⁷:

• Name, address, and telephone number of veterinarian
• Identification of animal(s) treated, species, and number of animals treated, when possible
• Date of treatment, prescribing, or dispensing of drug
• Name, active ingredient, and quantity of the drug (or drug preparation) to be prescribed or dispensed
• Drug strength (if more than one strength available)
• Dosage and duration
• Route of administration
• Number of refills
• Cautionary statements, as needed
• Beyond-use date (BUD)
• Slaughter withdrawal and/or milk withholding times, if applicable

Per FDA regulations, pharmacies must include the following on the compounded drug’s labeling: name and strength or concentration of drug; species and name or identifier of patient(s); name, address, and contact information for the compounding pharmacy and name of the prescribing veterinarian; a beyond use date; the withdrawal time as determined by the prescribing veterinarian; and the following statements must be included³³:

• “Report suspected adverse reactions to the pharmacist who compounded the drug and to FDA using online Form FDA 1932a.”
• “This is a compounded drug. Not an FDA approved or indexed drug.”
• “Caution: Federal law restricts this drug to use by or on the order of a licensed veterinarian.”

CONCLUSION

On June 10, 2021, the FDA finalized Guidance for Industry (GFI) # 263, (not to be confused with GFI #256 which was mentioned previously) requesting that participating animal drug companies voluntarily transition certain antimicrobials from over-the-counter availability to veterinary prescription within two years. The aim of this guidance is to decrease antibiotic resistance in animals, and the target date to introduce new prescription labels onto the market was June 11, 2023.³⁸ These include well known antibiotics such as erythromycin, gentamicin, penicillin, sulfamethoxazole, and tetracycline. This FDA requirement is now in effect for food-production animals and pets, and it may be one reason why many pharmacies have seen an increase in pet prescriptions. Another reason may be that more pet owners trust their local pharmacy to prepare the correct formula for their furry family members.

The field of veterinary medicine is expanding seemingly daily, and it is a field where compounding pharmacies can be instrumental. Veterinary compounding has its challenges, but when collaborating with a veterinarian, the compounder can impart professional judgment to ensure that the compound is safe, effective, and therapeutic. That’s a rewarding practice in the end.

 

 

 

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INTRODUCTION

In 1905, a person in excruciating pain in a dentist’s office would have been thrilled to receive an injection of procaine (Novocain) delivered in a reusable glass hypodermic syringe. Besides the dentist’s white coat, it’s likely nothing else used in the procedure was clean or remotely sterile. Today, given what we know about sterile products, an educated patient would have turned and run in the opposite direction.

Yet, according to the U.S. Food and Drug Administration (FDA), the number of trendy med spas and intravenous (IV) hydration clinics, some mobile, that treat patients with medications such as injectable vitamin infusions, have exploded. Many operate under the FDA’s radar. The FDA may not be aware of which compounders are making such drugs, and some states may have insufficient resources to adequately oversee them. The FDA has recently documented varying offenses from personnel  wearing street clothing and not wearing gloves while preparing injections to using toaster ovens for sterilization.²

 

Human drug compounding is a practice in which ingredients are combined, mixed, or altered to create a medication tailored to an individual patient’s medical needs. The Federal Food, Drug and Cosmetic Act (FD&C Act) governs human compounding. Section 503A describes the conditions under which compounded human drug products are exempt from its regulations²:

• Section 505 concerning approval prior to marketing
• Section 501(a)(2)(B) concerning current good manufacturing practice (CGMP) requirements
• Section 502(f)(1) concerning labeling with adequate directions for use

The FDA act exempts one condition—compounds are exempt when a licensed pharmacist or physician prepares the medication in a licensed facility based on a valid patient specific prescription. An explosion of naturopathic clinics, which often use unapproved nutritional, herbal, and homeopathic products and administer them by injection, have become a growing concern for the FDA. A brief Internet search revealed that nurses run many clinics with a physician consulting offsite. The FDA has become increasingly aware of drug products compounded at medical offices and clinics that may be prepared under unsanitary conditions. The FDA has also become aware of business models, such as IV hydration clinics, medical spas, and mobile IV infusion services, that are compounding drugs that may not meet the conditions of the FD&C Act’s section 503A or comply with state regulations.²

Unsanitary conditions are more common than one would think. The FDA cites a recent example (February 2021) wherein a 50-year-old patient was hospitalized and treated for suspected septic shock with multi-organ failure after receiving an IV vitamin infusion in her home.² The patient’s blood cultures grew Pseudomonas fluorescens, which is a gram-negative bacterium of emerging concern.³ A California medical clinic that specialized in services including IV therapies and vitamin injectables, sexual health products, hormone replacement therapy, weight loss/management products, and diagnostic laboratory assays prepared and dispensed the contaminated bag.² When state and federal agents inspected the facility, they observed several deficiencies²:

• Lack of an International Organization for Standardization (ISO) air quality classification of ISO-5; in other words, a clean room which is certified to contain a particle count of less than 3,520 particles per cubic meter in the air, required for sterile compounding
• Contamination in compounding areas including peeling paint, stained work surfaces, visibly dirty equipment, and air vents with dust and grime
• Difficult-to-clean equipment and surfaces (e.g., carpeting in the IV storage and mixing room)
• Standing water in a refrigerated storage area used to store sterile vials
• Use of expired active pharmaceutical ingredients to prepare drug products intended to be sterile

The full extent of this nationwide problem is unknown since many practitioners operating in medical offices or clinics do not register with the FDA. The FDA encourages all patients who experience adverse effects to report them to the FDA MedWatch Adverse Event Reporting program (www.fda.gov/medwatch/report.htm).² 

Defining Immediate Use Medication

According to the proposed USP<797> Pharmaceutical Compounding-Sterile Preparations, sterile compounding is defined as combining, admixing, diluting, pooling, reconstituting, repackaging, or otherwise altering a drug product or bulk drug substance to create a sterile preparation. Compounding personnel must follow aseptic techniques, processes, and procedures for preparing any sterile medication.¹

Within a hospital setting, urgent situations may arise where compounding cannot occur in a USP<797> compliant area. Often, acute care situations require STAT (meaning with no delay; at once) doses for critical patients, or medication for an unanticipated procedure.⁴ Compounders do not necessarily need to comply with all requirements detailed in USP<797> to make these immediate use medications. These frequently asked questions can help clarify when an immediate use medication may be needed and who can compound it.^1,4

• Can nurses mix compounded sterile preparations (CSPs) for immediate use? Any qualified health professional can prepare an immediate use preparation as long as (1) it is within their scope of practice, (2) the facility’s policies allow it, and (3) the designated person (defined and discussed below) has documented the health care professional’s competency.
• Is docking a vial onto a proprietary bag system considered an immediate use medication? Yes and no. Docking a vial onto a proprietary bag for future activation and use is considered compounding and must be performed in an ISO class 5 environment. However, docking a vial onto a proprietary bag according to manufacturer's instructions for immediate administration to a single patient is considered an immediate use medication and is not considered compounding.
• Can a nurse prepare an immunoglobulin (IGG) solution in a home care setting, by reconstituting the powder vial with the sterile water supplied by the manufacturer in a kit? This is an example of preparation that is compliant with FDA-approved labeling. Preparing a sterile product in accordance with the manufacturer's approved labeling is not considered compounding as long as
  • the product is prepared as a single dose for a single patient
  • the approved labeling includes the following information: the diluent, the final strength, the container closure system, and storage time
• If a nurse reconstitutes an antibiotic vial and adds it to a piggyback bag, is this considered immediate use? If the pharmacy is open, this should be done in a sterile clean room. If it is a STAT dose or the pharmacy is closed, then this could be considered immediate use. The nurse mixing the medication needs to have documented competency and the compound should not involve more than three products. One vial of drug, one vial of diluent, and one piggyback bag are three products, which is allowed.

In 2020, the American Society of Health Systems Pharmacists conducted a study among professionals who compounded outside of the pharmacy setting. Of the 444 respondents, 77% were nurses, and the rest were primarily anesthesia providers and decentralized pharmacists. Eighty-one percent performed compounding in a acute care settings; other locations included ambulatory surgery centers, infusion centers, physicians’ practices, and long-term care.⁵

The most frequently prepared items were⁵

• IV pushes drawn directly from vials into syringes. (i.e., antibiotics, antiemetics, opioids, proton pump inhibitors)
• Intermittent infusions, all of which were proprietary vial and bag systems.
• Intramuscular injections including vaccines, antipsychotics, and antibiotics

 

Personnel and Settings Affected by USP<797>

All personnel who prepare CSPs are required to comply with USP<797> guidelines. This includes but is not limited to chiropractors, dentists, naturopaths, nurses, pharmacists, technicians, physicians, and veterinarians.¹

All sites including but not limited to hospitals, infusion facilities, medical and surgical patient treatment sites, pharmacies, physician or veterinarian sites, and other healthcare institutions must meet at least the minimum requirements in USP<797>.¹

The compounding facility must designate one or more individuals to be responsible and accountable for the facility’s performance, operation, and personnel in the preparation of CSPs and for performing other functions described in USP<797>.¹ The facility’s standard operating procedures (SOPs) must identify the person deemed “the designated person.” All designated persons now have immense jobs; failure to meet the USP’s expectations  comes with considerable consequences.

The Designated Person

The USP mentions the designated person more than 50 times in section <797> alone and several other chapters also refer to the designated person. Below is a list of some, but not all tasks required of a designated person, which will become effective on November 1, 2023. Many states, such as Connecticut and Texas, have already embraced the designated person. The designated person or persons must be identified in the facilities SOPs and registered with the state. In Texas and Connecticut, pharmacists must also complete 30 hours of sterile compounding training to become a designated person. Duties include¹

• Overseeing a training program to ensure competency of personnel involved in compounding, handling, and preparing CNSPs
• Selecting components
• Monitoring and observing compounding activities and taking immediate corrective action if deficient practices are observed
• Ensuring that SOPs are fully implemented. The designated person(s) must ensure that follow-up is carried out if problems, deviations, or errors are identified
• Establishing, monitoring, and documenting procedures for the handling and storage of CNSPs and/or components of CNSPs.

The SIDEBAR discusses an issue of emerging importance.

SIDEBAR: Who Inspects Physicians’ Offices? ⁶

In 2016, the Pew Charitable Trust conducted a study and asked boards of pharmacy in all 50 states and the District of Columbia to respond to several compounding questions. Of the 51 states, 43 responded to the questionnaire. Although the survey consisted of pages of questions, three of them were forward thinking.

1. Does your state have a mechanism to track which in-state physicians’ offices or clinics perform sterile compounding? The answer: 2 % yes, 74% no, 24% don’t know.
2. Does the state require physicians’ offices or clinics to be held to the same quality standards as pharmacies? The answer: 17% yes, 38% no, 45% don’t know.
3. How do states provide oversight of physician’s offices or clinics that perform sterile compounding to ensure compliance with applicable standards? The answer: 7 by the state board of medicine, 1 by the board of pharmacy (way to go, IDAHO!), 24 reported no oversight system to ensure compliance and 11 states chose not to respond to this question.

Who knew Idaho would be so revolutionary? Keep in mind that this study took place in 2016, four years after the New England Compounding mishap of 2012. The Pew study reported, “The Drug Quality and Security Act of 2013, among other reforms, added a new category of compounders called outsourcing facilities that can compound supplies of drugs without obtaining prescriptions.”

The new category—outsourcing facilities—was intended to reduce the number of medications made in offices. However, it is obvious that state policies are not uniform. Some states are still working to advance change, and others have yet to act. The Pew report concluded that we are still in a state of transition and that “The variations in sterile compounding policy across states suggest that an opportunity exists to review state oversight systems for potential weaknesses, and consequently to advance regulatory practices to better protect patients.”

 

Gap Analysis

In some states, as in the state of Connecticut, the designated person must be a pharmacist. That means that the designated person or persons are responsible for the oversight of all compounding within an institution including the operating room, emergency room, clinics, and nursing station medication rooms.

PAUSE AND PONDER: In what areas of your facility could people possibly be compounding without your designated person’s knowledge?

A gap analysis compares the current situation with a future state. Creating a gap analysis could help identify areas where compounding is done without the designated person’s knowledge. A gap analysis is performed in three steps⁷:

1. Identify objectives and goals. Most designated persons will create a sheet with three columns: current state, future state, and actions. They will need to identify who, what, where and when immediate use compounding occurs. Using a team approach and including nurses and physicians is a good place to start.
2. Analyze the current state. Gather data. One critical area to examine is medications in short supply or backordered. (Aren’t there always a few of these lately!?!) Checking purchasing records and delivery slips to see where medications are being used can be eye-opening. Facilities that substitute vials because the premixed bag is backordered will find that this is a target area.
3. Determine how to bridge the gap. Collaborating with the team to create policies and procedures for compounding and writing them into standard operating procedures is critical. Facilities should create a designated compounding area in each unit and establish a cleaning routine. They should also create a training document for nurses and other professionals who compound and set date that each person should complete training as a goal.

Immediate Use Gap Analysis

All facilities that compound need to compare the current (2008) USP<797> Pharmaceutical Compounding-Sterile Preparations guidelines with the proposed (2022) USP<797> guidelines. In short, the proposed changes are few in number but may cause significant impact throughout the facility.⁸ Table 1 compares a few minor changes.

Table 1.  Less Strict Changes to USP<797> ^1,8,9

Subject	Current	Proposed
Compounding Process and number of components	Only low risk level NMT 3 sterile packages	NMT 3 sterile products
Situation	Emergency use or immediate administration	No emergency stipulation
Number of manipulations	NMT 2 entries into any container/bag	Not defined
Maximum BUD	1 Hour	4 hours
Aseptic technique	Aseptic technique is followed	Aseptic technique, processes, and procedures followed per written SOPs
Risk Level	Medium and high risk not prepared as immediate use	Category 1, 2, and 3 requirements do not apply
Hazardous Drugs	Only non-hazardous drugs may be used	Must follow USP<800>

^{BUD = beyond use date; NMT = Not More Than}

A quick glance at the table shows that compounders can now assign a beyond use date (BUD) of four hours for immediate use products. Hurray! This prompts the question, “Is that all I need to implement, and can I do it right now?” Not so fast! These are changes to existing subjects within <797> guidelines, but the proposed guidelines also include many new stipulations, so let’s dig deeper. The following requirements have now been added which pertain to immediate use medications^1,8:

• Written SOPs must be in place and compounding personnel must follow aseptic technique, processes, and procedures.
• Personnel must be trained and demonstrate competency according to the facility SOPs.
• SOPs must include methods to minimize contamination and decrease mix-up errors.
• The product must be compounded in accordance with evidence-based information for physical and chemical compatibility, per labeling or stability studies.
• Any unused starting component from a single use container must be discarded.
• Single dose containers must not be used for more than one patient.
• A compounding record is required when preparing immediate use medications for more than one patient.

 

Training and Evaluation

Training is the elephant in the room. Many nurses and other health professionals have mixed or prepared single use medications for ages, so it might be difficult to teach an old dog new tricks. Demonstration of competency can be difficult and perhaps this is where the nursing team can shine. Luckily, immediate use compounders need not perform fingertip and thumb sampling, or media fill tests as is required for sterile clean room staff.

All personnel who compound must now be initially trained and qualified by demonstrating their knowledge and competency of sterile compounding before they can perform their job independently. The designated person(s) is responsible for creating and implementing a training program but may assign training to other qualified personnel. The training procedure for immediate use CSPs must be written into the facilities SOPs.¹ One interesting note, the proposed USP<797> states that personnel who are compounding in a clean room, or who have direct oversight of those personnel, must complete training initially, and at least every 12 months. However, immediate use compounders only need to complete training as required by the facilities SOPs.¹ A best practice would be to evaluate yearly.

Skills may vary from one location to another, but at a minimum, healthcare professionals who will perform immediate use compounding must demonstrate the following core skills⁸:

• Hand hygiene and proper gloving
• Calculations, measuring and mixing
• Aseptic technique and compounding procedures

Required skills will depend on the clinic’s location; for example, an oncology clinic will need to follow USP<800> Standards for Hazardous Drugs, along with USP<797>. Other skills may include cleaning, garbing, documentation, and labeling and should align with the immediate use procedures in the facilities SOPs.

Competency assessment must be based on the aseptic processes that are related to the tasks being performed, which can be difficult to recreate. Demonstration of a simulated manipulation may be acceptable in most cases. A simulated aseptic manipulation using empty vials, syringes, sterile water, or saline could consist of the three maximum products allowed, with no need to incubate the sample.⁷ Using a convenient checklist, like the one in Table 2, helps trainers evaluate staff and document consistently.

The SIDEBAR highlights one practice that needs to end immediately.

Normal Saline Flush Prefilled Syringes^7,10

The Institute for Safe Medical Practices (ISMP) released the results of a 2018 immediate use compounding survey. Of the 977 practitioners who responded to the survey, almost all were nurses. ISMP discovered that 81% of the respondents used premixed 5 mL and 10 mL normal saline flushes to dilute medications. The FDA considers a premixed normal saline flush as a medical device and they are “not approved for dilution and administration of IV push medications.”

Some clever (but forbidden) uses of prefilled syringes include

• Using prefilled syringes as vials: withdrawing and or adding part of a prefilled syringe into another prefilled syringe for administration (Example: adding 5 mL from one syringe to another 5 mL syringe to make a 10 mL syringe).
• Using a prefilled syringe to reconstitute a powder vial, then drawing the dose back into the same syringe. (Example, using a 10 mL flush, adding 5 mL from the flush, reconstituting, and withdrawing the 5 mL back into the syringe to create a 10 mL dose.)

Using prefilled syringes in these ways is dangerous, since most of the time the health care professional conducting these “procedures” fail to relabel these syringes, so the syringes still have a bright yellow or white label and can be easily picked up by another person and administered in error.

Why would prefilled flushes be used for compounding? First, among the many recent drug shortages, normal saline topped the list for a very long time. Second, they are quick and easy to use, and third, healthcare professionals cling to many misconceptions. Some professionals believe that a syringe does not need to be labeled. There is also a myth that a 10 mL syringe must be used to administer IV push medications. Perhaps it is due to “telephone tag” teaching, where one procedure is passed from one to another.

So, how do we fix this? Clear procedures need to be established for compounding each medication. Staff training is a must, and a simple roll of blank labels in the compounding area can go a long way to avoiding errors.

 

Table 2. Sample Immediate Use Compounding Evaluation

	Name of person assessed: Jonathan the Husky Dog	Location:   Husky Clinic
	Evaluation of Handwashing, Garbing, Gloving and Aseptic technique: In left-hand boxes, indicate for each activity  P = acceptable completion of the described activity in the correct order, X = the order is incorrect or the activity is performed incorrectly or N/O = the activity was not observed.	Notes/ Comments on any of the activities.
	Removes all jewelry and outer garments
	Uses nail pick under running water
	Washes hands with soap and water for 30 seconds
	Dries hands with approved wipe
	Dons required garb
	Applies alcohol-based hand sanitizer, allows to air dry
	Selects the correct pair of gloves
	Correctly dons sterile gloves
	Applies sterile alcohol to gloves, allows to air dry
	Disinfects compounding area with facility approved agent
	Selects proper components
	Disinfects critical sites with 70% alcohol wipe
	Punctures vial at a 45-degree angle to avoid coring
	Withdraws the correct amount of fluid from vial
	Disposes waste in proper container
	Visually inspects final product
	Demonstrates proper labeling
	Applies correct 4-hour BUD
	Name of evaluator________________________Date:_____	Pass   /   Fail

 

CONCLUSION

Whether you are the designated pharmacist or just a team member, it is important for you to recognize immediate use medications and locations where they may be compounded. With the implementation of USP<797> commencing on November 1, 2023, now is the time to look at the pharmacy clean room and all areas in your facility where compounding may be occurring. Huge changes in workflow as well and policies and procedures may need to be adopted. Create a well-balanced team of professionals and get to work!

 

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Introduction

The original “little blue pill” was created in the 1860s and was a popular cure for everything from toothache to tuberculosis.¹ Pharmacists compounded “blue mass syrup” and “blue pills” based on their own recipes or on one of several widespread recipes. Its name probably derives from the use of blue dye or blue chalk (used as a buffer) in some formulations. Blue mass’s ingredients varied, as each pharmacist prepared it himself, but they all included elemental mercury. One recipe for blue mass syrup consisted of¹

• 33% mercury (measured by weight)
• 5% licorice
• 25% Althaea (a root extract, possibly from hollyhock or marshmallow)
• 3% glycerol
• 34% rose honey

 

Pharmacist-compounders produced blue pills by substituting milk sugar or chalk for the glycerol and rose oil for the rose honey. Each pill contained one grain (64.8 milligrams) of mercury and was prescribed two to three times a day, which today we know causes heavy metal poisoning, since the dose is more than 100 times more than the limit set by the Environmental Protection Agency.¹ Products were made without fancy definitions or regard to cleanliness. Times have changed.

 

Pharmaceutical compounding is the act of manipulating a drug product to create a new drug formulation.² Pharmacists and pharmacy technicians still compound drug preparations for a specific patient or group of patients when no drug product exists on the market, or as seen more recently, when the drug product is backordered with no therapeutic alternative(s). It is also interesting to note what the United States Pharmacopeia (USP; described below) does NOT consider to be compounding. Preparing a powdered antibiotic bottle with distilled water per manufacturer’s directions is not considered compounding. Splitting tablets and repackaging is also not considered compounding, nor is preparing a single dose for a single patient to be used within four hours. In other words, making one dose of blue mass syrup and giving it directly to a patient is not compounding. (OK, maybe no one makes blue mass syrup anymore, but crushing a tablet and placing it in a liquid for immediate use is still not a compounded preparation.)

 

Pharmaceutical compounding has two categories: sterile compounding and nonsterile compounding.²

• Sterile compounding is creating a new drug preparation that must be sterile (completely free of pathologic microorganisms) and includes preparations that are primarily infusions, injections, eye drops, and many irrigations.
• Nonsterile compounding is creating a new drug product that is not required to be sterile (although these products should be as “clean” as possible) and are mostly used for oral or topical administration. Nonsterile compounding is often employed for pediatric and veterinary preparations where patients need very small or very large doses. Some examples are medicated creams for neuropathic pain, and anesthetic mouthwashes for oral sores and pains.

 

The USP is an independent non-profit organization of knowledgeable volunteers who set the standards for pharmaceutical compounding to ensure patient safety.³ The USP also distinguishes guidelines for hazardous and non-hazardous compounding. Both sterile and nonsterile compounding can involve manipulation of hazardous drugs. This continuing education activity focuses on non-hazardous nonsterile compounding. More information on hazardous compounding can be found in General Chapter <800> Hazardous Drugs – Handling in Healthcare Settings. Access to the USP Compounding Compendium costs $250.00 for a 12-month membership. There are also various plans for multiple users. Many institutions have a contract with USP. (Readers should check with their designated person or supervisor, as they may already have access to this service.)

 

The origin of nonsterile pharmaceutical compounding in the U.S. cannot be pinned down to one exact date, but historically, the 1800s saw immense growth in not only population but also in disease states as people traveled and settled to new areas. Between 1840 and 1850, it is estimated that more than 1.5 million persons immigrated to the United States. Backyard herbalists became highly regarded apothecaries seemingly overnight.⁴

 

Unfortunately, there were no established compounding standards until 1820 when a small group of physicians raised concerns about the high prevalence of poor-quality medicine across America and the USP was formed. By 1863, during the height of the Civil War, the USP had become the most trusted source for information about medicines.^3.

 

The USP continuously strives to improve the quality of drugs, including compounded preparations. Today we know that the quality of a compounded preparation depends as much on handwashing, gloving and cleaning, as checking the pH of the product itself. These steps are necessary to safeguard the preparation that a pharmacist or pharmacy technician compounds, and ultimately, safeguard the patient.

 

The USP sets standards for pharmaceutical compounding but has no regulatory authority, so it does not enforce the standards it sets. Each state is responsible for regulating pharmaceutical compounding, but the Food and Drug Administration (FDA) is also authorized to regulate all aspects of drugs, including compounding. Both state regulating bodies and the FDA can inspect compounding in pharmacies and take legal action and can amass fines if compounders do not uphold USP standards. However, this action only applies to states that write USP standards into their laws. Depending on the situation’s severity, legal action could result in a loss of license for the pharmacy or pharmacist.

 

The USP sets standards for sterile and nonsterile compounding through General Chapter <797> and General Chapter <795>, respectively. (Here’s a PRO TIP: chapters numbered from 1 to 1000 are enforceable by state and federal agencies). More recently, the FDA has been inspecting compounding pharmacies to ensure they meet General Chapter <797> standards, but it is only a matter of time before these agencies turn their attention to General Chapter <795>.

 

In November 2022, the USP published a revised General Chapter <795> Pharmaceutical Compounding – Nonsterile Preparations. Going forward, we will call these standards the newly revised standards. This revision now includes a designated person (the individual assigned to be accountable and responsible for the compounding facility’s operation, performance, and personnel) requirement to mimic General Chapter <797>. With the implementation of a designated person for nonsterile compounding under proposed General Chapter <795>, when the facility is not up to code, State boards of Pharmacy and the FDA hold the designated person responsible, creating a risk of loss of license. The revised standards will be official in November 2023. Major changes include

• garbing
• cleaning
• training
• beyond-use dating and
• a designated person requirement

 

The focus here is on how to implement the major changes made to the currently enforceable General Chapter <795>, which was revised and reissued in 2020. Going forward, we will call these standards the current standards. Once readers are familiar with this summary of the major changes in the newly revised standards, they are encouraged to review the full text of the proposed chapter <795> to address additional minor changes.

 

So, to repeat, the standards that were revised and reissued in 2020 and are currently enforceable will be called the current standards. The revision that will be adopted in November 2023 will be called the newly revised standards.

 

Garbing

The newly revised standards put greater emphasis on garbing procedures for nonsterile compounding than the current standards do. Pharmacy personnel who compound sterile preparations are well acquainted with garbing, however, garbing is a foreign concept to many who prepare nonsterile preparations. Think back to the past. How often did you go to the back of the store, push some items on the counter aside, and start mixing a magic mouthwash? You probably made it wearing a shirt and tie or more formal dress, while possibly wearing a lab coat, unless it was a really hot day. You might even have washed your hands if you just came back from lunch. Conversely, many hospital pharmacies mix magic mouthwash in so much garb, that you might think that it is a toxic preparation. The SIDEBAR explores this topic in greater detail.

 

 

TECH TALK SIDE BAR⁵

Have you noticed that many pharmacists and pharmacy technicians no longer wear white lab coats? Physicians began to wear white coats in the late 1800s as doctors started to recognize the color white’s effectiveness. It is easier to see dirt and soil that prompts the wearer to launder it, and frequent laundering helps reduce pathogens. Soon all medical professionals adopted the practice. White coats were worn not only to protect one’s clothing, but they were seen as a sign of prestige and respect.

 

Today, white coats are rarely used, because according to Dennis Miller, “White coats cause white coat syndrome” (hypertension) and they “increase the distance between the pharmacist and the customer.” Few states regulate pharmacy technician attire. Many institutions and most large retail chains require pharmacy technicians to wear uniform “scrubs.” Restricting white coats to professional staff may reduce some customer confusion, but in certain situations, scrubs might imply the wearer is a nurse or other hospital professional, which is also confusing. One of this CE’s authors says, “I can’t even tell you how many patients and families would ask if I was a nurse.”

 

Recently, some hospitals have banned pharmacy technicians from wearing scrubs, forcing them to wear civilian clothing. Unfortunately, that makes technicians look like pharmacists again. Of course, some pharmacists like to wear scrubs to work; are they secretly wishing they were technicians? Doubtful. Business attire has certainly gone downhill lately. So, if we can’t wear a white coat and we can’t wear scrubs, what are we to wear?

 

THE ANSWER (which is required by law in many states): A name tag that indicates your position!

 

 

The current standards state that personnel involved in compounding should garb “as needed for personal protection and to prevent contamination” of the compounded nonsterile product (CNSP) prior to preparation.⁶ For example, compounding staff don two pairs of gloves for personal protection when preparing cytotoxic CNSPs for their own safety. More information on hazardous compounding can be found in General Chapter <800> Hazardous Drugs – Handling in Healthcare Settings. The current standards also state compounding personnel are responsible for maintaining good hand hygiene and wearing appropriate clothing to prevent contamination of the CNSP.⁶ These statements give compounding personnel some latitude when they make decisions. For example, currently, some compounders don gloves to make magic mouthwash, while many others prepare it with ungloved hands in their practice. Nonsterile gloves will become mandatory on November first.

 

The newly revised standards now specify hand washing and garbing procedures and provide guidance on personnel who should NOT prepare a CNSP. Compounding personnel are to remove all “garments that cannot be easily cleaned” before entering the designated compounding area. So compounding personnel must now remove personal outer garments (such as jackets, sweaters, hats, and scarves), hand and wrist jewelry, anything that might hinder the use of gloves, and headphones must be removed before compounding something as simple as magic mouthwash. Compounding personnel must wash their hands for at least 30 seconds and dry with one-time use paper towels before compounding as well. After handwashing, personnel must don nonsterile gloves and inspect the gloves for holes, rips, or tears. Compounding personnel should wipe or replace gloves in between different preparations and must remove these gloves before leaving the designated compounding area.⁶ These proposed standards are analogous to the procedures required for sterile compounding. In fact, the format of and definitions within the revised <795> aligns with the revised <797> for sterile products much more closely than in the past.

 

The current standards still require personnel to be in good health and fit for compounding, but the revisions are considerably more specific. Personnel who have new tattoos, oozing sores, open wounds, conjunctivitis, rashes, or active respiratory infections are not considered fit to compound due to risk of contamination of the CNSP. The newly revised standards hold the designated person responsible for deciding if personnel are fit for compounding or not.⁶

 

Cleaning the Designated Compounding Area

Do I need to create an area for compounding? Yes. The newly revised standards describe a designated compounding area in detail. Some readers are thinking, “My pharmacy is small. Can I use the area for tasks other than compounding?” The designated compounding area is a space with a marked perimeter that is required to be clean, orderly, sanitary, well-lit, and have low foot traffic, and no other activities can occur in this space simultaneously. You may perform other duties there if there is no compounding going on as long as someone cleans the area before compounding again. The newly revised standards suggest the designated compounding area be uncarpeted for easier cleaning, which in one of this CE’s author’s opinion should be changed to a must, since carpets tend to harbor dust and dander, and can be very difficult to clean. (Have you ever dropped and broken a bottle on the carpet in your pharmacy? It’s not pretty.)

 

The compounding area must be used in a manner that prevents cross contamination of CNSPs from other areas of the pharmacy. For compounding to be completed in the most efficient manner possible, all equipment in the designated compounding area must be arranged in a way that prevents errors. Last, the facility’s standard operating procedures (SOPs) must always include this information and be available to staff.

 

The current standards simply state that compounding equipment “shall be clean, properly maintained and used appropriately.”⁶ This statement allowed compounding personnel to decide on their own standard of clean when preparing a CNSP and their own definition of when or if they should clean. The newly revised guidelines strengthen the minimum requirements for cleaning the designated CNSP compounding area. The USP dedicates an entire section to cleaning procedures, representing a major change in the standards. The new standards indicate that personnel must clean the perimeters—walls and ceilings—when visibly soiled, after spills, and when surface contamination occurs.⁶ Readers will see that visible soil, spills, and surface contamination form a frequent theme in the newly revised standards!

 

The new standards also establish a routine cleaning schedule. The section, “Cleaning and Sanitizing” states pharmacy personnel must clean work surfaces at the beginning and end of each shift at a minimum, between each CNSP, and again if spills or surface contamination occurs. The standards add that personnel must clean floors daily on days when compounding occurs, and again if spills or surface contamination occurs.^6. Personnel must clean storage shelves every three months, after spills, and when surface contamination occurs. Personnel qualified to clean can be defined as any staff member who has been properly trained and observed in a facilities cleaning procedures. That means that pharmacy staff can train housekeeping staff to complete the cleaning.

 

Personnel need to clean and sanitize, and if two separate products are used—one to clean and one to sanitize—cleaning is done first, followed by sanitizing second. Selecting appropriate cleaning products requires careful attention. They should be (1) compatible, (2) effective, and (3) leave minimal residue. Finally, daily documentation is essential on days when compounding occurs.⁶ An old adage applies here: cleaning is not truly done unless it is documented. High tech organizations commonly complete this documentation using an online platform integrated with other daily documentation requirements such as daily temperature monitoring, but a simple sign off sheet is also acceptable. A best practice is to include any cleaning and its documentation into the compounder’s daily workflow, so it is not forgotten. Daily and or weekly task charts can be created to include all activities that need to be performed.

 

PAUSE AND PONDER: How were you originally trained to compound? Were you told to watch how it was done and then you were on your own?

 

Training

Another major area of change is the training of compounding personnel. The current standards state that compounders must be “proficient in compounding” and suggest that compounders should pursue knowledge by attending seminars or studying literature related to compounding. It also states that compounders must be conversant on General Chapter <795> and familiar with General Chapter <797>. With standards this vague, and no required number of CE credits on this subject, how often do you think compounding personnel previously searched for compounding topics? Also, the current standards simply require at a minimum compounding personnel to be trained and capable of the compounding duties assigned to them, and for someone to document the training. Compounding duties include verifying critical processes like weighing and mixing that occur frequently during compounding.

 

The newly revised standards will require a more structured training program for compounding personnel. All compounding personnel must complete this training program initially before being allowed to compound and every 12 months thereafter. The newly revised standards require compounding personnel to repeat compounding procedures “independently while under the supervision of the designated person or assigned trainer for completion of the training program.”⁶ The organization’s designated person will be responsible for designing the training program, which must include

• the required training, meaning a detailed description of the training
• the frequency of training, and
• the process used to evaluate competency.

 

Table 1 lists the training program’s required topics. It is interesting to note that pharmacists who do not compound but complete in-process checks, verification, or dispensing also must complete the CNSP training program before completing checks, verification, or dispensing. A training program may include an online portion of reading or videos teaching concepts with quizzes to evaluate understanding, and a physical portion to evaluate measuring, mixing, and overall compounding. The designated person or assigned trainers can train personnel, and of course, they must document the completion of the training program.⁶

 

Table 1. Proposed General Chapter <795> Required Topics for Training⁶

Training programs must teach compounding personnel the following:

·       cleaning and sanitizing

·       documentation such as Master Formulation Records and Compounding Records

·       hand hygiene and garbing

·       handling and transporting CNSPs and their components

·       measuring and mixing

·       proper use of compounding equipment and devices

·       understanding General Chapter <795>

·       understanding safety data sheets

·       understanding procedures to complete compounding duties

 

It is important to note this table only lists the minimum requirements, additional requirements may be necessary according to each facility’s needs.

 

The Designated Person

The necessity to designate a person who has oversight and full responsibility for compounding practices now in General Chapter <800> is included in proposed General Chapter <795> and <797>. The current standards again broadly describe the requirements. The chapter states that compounding personnel are responsible for adhering to the general principles of compounding outlined in the current standards. It specifies several responsibilities, which include training, selecting ingredients for compounding, labeling, and cleaning. However, since the compounding process may include many people, the ultimate accountability is unclear.

 

To clarify accountability, the proposed General Chapter <795> requires each organization to designate one or more persons to be responsible and accountable for nonsterile compounding. The designated person’s responsibilities include ensuring the organization develops written formal quality control and quality assurance procedures and reviews them annually. The designated person must monitor and observe compounding, identify areas of error, and take corrective action if needed. The designated person has several other responsibilities. These include⁶

 

• establishing, documenting, and monitoring SOPs within the CNSP compounding area to include component handling and storage
• ensuring that all staff members follow all SOPs
• reviewing complaints
• determining if potential issues are likely with CNSPs
• selecting components to be used in compounding

 

Beyond Use Dates

The final major difference is the establishment of beyond-use dates (BUD) for CNSPs. The current standards hold compounders responsible for establishing BUDs based on their observation of the drug during compounding. Compounders (not a designated person) are held responsible for noticing signs of instability and using their education and experience to assign a BUD to the final preparation.⁶ The current standards also recommend assigning BUDs based on three categories: non-aqueous, water-containing oral, or water-containing topical. The new guidelines are based on the activity of water (a_w) in each product.

 

Table 2 compares the current and proposed BUD recommendations.⁶

 

 

Table 2. A Comparison of BUD Requirements^6,7       

Description	Minimum BUD requirement
	Current USP <795>	Proposed USP <795>
Aqueous non-preserved	14 days in refrigerator	14 days in refrigerator
Aqueous preserved	14 days in refrigerator	35 days controlled room temp or refrigerator
Aqueous topical (Cream, lotion, shampoo, nasal spray, gel, rinse, foam, etc.)	30 days	35 days if preserved 14 days if non-preserved See activity of water chart
Nonaqueous oral (Oil or powder filled capsule, glycol or oil based oral solution, compressed tablet, powder for inhalation, troche, lollipop, etc.)	6 months	90 days
Nonaqueous (Medicated stick, ointment, suppository, etc.)	6 months	180 days (6 months)

 

Proposed General Chapter <795> determines BUDs based on a preparation’s water activity (a_w, see SIDEBAR), which is more clearly defined as aqueous and non-aqueous by the following distinction:

 

• CNSPs with an a_w ≥0.6, considered aqueous dosage forms
• CNSPs with an a_w <0.6, considered non-aqueous dosage forms

 

 

SIDEBAR: Activity of Water^7-10

The water in a preparation can “participate in chemical, biochemical, or physicochemical reactions.” However, it is not the water content (such as % water in the CNSP), but rather the activity of water that determines the water’s availability to participate in degradation reactions and allow microbial growth. Therefore, compounders must determine a BUD by considering the preparation’s water activity and not the preparation’s water content.

 

Water activity is roughly equivalent to relative humidity, except that relative humidity is expressed in terms of percent and water activity is expressed as a fraction. So, a water activity of 0.6 is roughly equivalent to 60% relative humidity. If the dosage form with a water activity of 0.6 were to be sealed in a package, any surrounding space would eventually have a relative humidity of 60%. Compounders can measure water activity for a specific preparation by the procedures outlined in General Chapter <922> Water Activity. However, the proposed General Chapter <795> provides an easy classification system (see Table 3).

 

The a_w cut-off of 0.6 established in USP comes from various studies showing no microbial growth of any kind in foods below this value. Although the water activity determination was constructed using food, it is also the basis of USP <1112> Water Activity Determination and is the foundation for the BUD rationale in the proposed <795>. A product with an a_w greater than or equal to 0.6 has been shown to have increased bacterial, fungal, and other microbial growth. However, in products with an a_w below the threshold of 0.6, no microbial growth was found.

 

 

The newly revised standards recommend adding antimicrobial agents to any CNSP with an a_w at or exceeding 0.6 when assigning a BUD of 35 days. Even components as simple as ascorbic acid can help extend the BUD. As always, careful research must be done to determine suitable preservatives for each product and if an extended BUD date is assigned, the preparation must be tested for antimicrobial effectiveness. Consider one formula for magic mouthwash, which might have an a_w of 0.73 and contains no preservatives. With no USP monograph, one would refer to Table 3 to determine that the BUD should be limited to 14 days when stored in the refrigerator. We are sure that pharmacists compounding blue mass syrup could have cared less about the activity of water in their concoctions. We wonder if they would have viewed mercury as a preservative.

 

Compounders can assign non-aqueous dosage forms with an a_w less than 0.6 a maximum BUD of 90 days for an oral liquid and 180 days for alternative routes.

 

While the newly revised standards provide strong guidance on determining a CNSP’s BUD, compounders should only use its tables if no other stability information is available. The designated person is responsible for searching for stability information for each CNSP and determining if a CNSP can have a BUD beyond that specified in Table 2. If the designated person finds an extended BUD appropriate, compounding staff must test it for antimicrobial effectiveness. However, if compounding staff is following a United States Pharmacopeia- National Formulary (USP-NF) monograph for CNSP preparations, the BUD must not exceed that which is indicated in the monograph. Last, the CNSP’s components should drive the overall expiration date, which is not a change from the current standards.

 

Table 3. Proposed General Chapter <795> classification of commonly compounded dosage forms as non-aqueous or aqueous partial list.

Nonaqueous Dosage Forms aw <0.6

Aqueous Dosage Forms aw ≥0.6

-       ­Animal treat, oil based -       Capsule: oil filled or powder filled -       Oral solution: glycol based or oil based. -       Glycol based gel -       Stick or lip balm -       Tablet compressed or triturate -       Sorbitol based lollipop -       Ointment: hydrophilic petrolatum polyethylene and mineral oil based -       Oral suspension: fixed oil -       Powder for inhalation -       Suppository: polyethylene glycol base or fatty acid base -       Troche or lozenge: gelatin based or glycol based

-       Animal treat -       Foam -       Shampoo -       Cream: oil in water emulsion, emollient cream, petrolatum, and mineral oil gel: alcohol free aqueous or hydroxypropyl methylcellulose gel -       Lotion -       Nasal spray -       Rinse -       Oral solution: water based, low sucrose syrup vehicle -       Oral suspension

 

 

CONCLUSION

Compounders face many of the same challenges today as they did in the 1800s. They were faced with a limited drug list, similar to a closed formulary in today’s world. They searched for alternative therapies, and they did, as we still do, face many drug shortages. The main difference is that we have advanced knowledge to make better products to keep patients safer.

 

The time has come to designate your area, designate your person, and train your staff, including pharmacists who may not actually be compounding! Keep the designated area clear for compounding use only, if possible, and remove any unnecessary items before entering. Set up a cleaning routine for the entire space, including floors, walls, and shelving, and incorporate the routine into the daily workflow so it is never forgotten. Train your staff well to the new standards and reevaluate every 12 months. Look into the literature to determine the best BUD for each CNSP and when information is not available, use USP guidance for assigning a BUD date. Choose a designated person wisely, as they need to be responsible and organized with taking responsibility and accountability for all nonsterile compounding occurring in the facility.

 

Remember, improvements in non-sterile compounding standards will make for higher quality and safer compounded non-sterile products for our patients and are enforceable come November 1, 2023.

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