Veterinarians face imperfect choices when providing care for their patients. Cost considerations can make it difficult to provide the medications a patient needs for optimal treatment. Additionally, most of the drugs prescribed are off-label human medications. As such, they were not developed for animals and are often available in limited dosages and formulations not well-suited for animal use.

As a result, many veterinary hospitals and clinics have traditionally relied on neighborhood or national 503A compounding pharmacies to compound needed drugs at an “exact” dosage that are supposed to be specific to the patient’s needs. However, the dosing can be anything but “exact,” and this variation can have a significant impact on patient outcomes.

With the growth of 503B-manufactured veterinary drugs, there has been an increase in the number of compounded medications available in a range of “standard” dosage offerings appropriate for animal use. These drugs are made in larger batches than the those compounded by neighborhood and 503A compounding pharmacies, so they can be ordered in bulk for office use. They also are manufactured using a validated process that meets the Food and Drug Administration’s (FDA) current good manufacturing practice (cGMP) regulations¹—the same regulations followed by pharmaceutical companies—providing veterinary practices with:

• A stock of drugs with dosages and flavorings tailored to animals’ needs and preferences available for immediate dispensing, improving patient compliance and care.
• Medications that offer consistent delivered dosage accuracy, optimizing patient outcomes and reducing the risk of drug toxicity.
• Medications conveniently are on hand when patients need them, increasing client satisfaction.

With the acquisition of new customers estimated to be five to 25 times more costly than retaining current clients, and pharmacy revenues for veterinary facilities declining over the past few years, having in-demand, high-quality 503B-manufactured medications can help veterinary practices effectively meet the needs of their patients, boost client loyalty, and grow profit margins.

‘Exact’ on-demand vs ‘standard’ validated dosages

“Exact” dosage medications produced on an on-demand prescription basis for veterinary patients are manually compounded by a trained technician at a neighborhood or national 503A compounding pharmacy. Those medications are typically available in capsule form. Although it may seem exact, on-demand drugs offer a way to provide top-tier personalized patient care. Drugs compounded in this fashion are often not as “exact” as they seem for several reasons:

• The accuracy of the dosage is highly dependent upon the training and expertise of the pharmacy technician.
• A theoretical, unvalidated process is used to obtain a 10 percent margin of error, which can result in a significant deviation from the requested dosage. So, if 3.125 mg is requested, the actual delivered dosage can range from 2.8125 to 3.4375 mg and still be within the compounding allowance of +/- 10 percent. However, since the process is not validated, the range may be even wider, falling between 2.5-3.75 mg—a variation range of 1.25 mg.
• Potency testing to ensure a medication is within specification for the necessary concentration of active pharmaceutical ingredient is not required of neighborhood and 503A compounding pharmacies. Further, it is not typically done because it is costly and adds weeks to delivery time (See Table 1).

“Standard” dosage drugs, in contrast, are manufactured by a machine according to validated processes, and are usually available in tablet form. For example, 503B outsourcing facilities specialize in producing large batches of these medications for bulk ordering, enabling veterinary practices to:

• Provide timely treatment to their patients. Treatment delays related to supply chain disruptions or clients investing time in locating an appropriate pharmacy and waiting for their order can be eliminated.
• Minimize medication errors. Dispensing medications from an in-house pharmacy allows the veterinarian to confirm the patient is receiving the right medication at the correct dosage using the optimal formulation. Vets can also counsel clients on how to properly administer the drug.
• Maximize patient and client safety and treatment results. Veterinary facilities with on-hand medications can ensure storage conditions comply with the recommended light, temperature, and humidity parameters to maintain drug safety and effectiveness until patient use. Hazardous drugs, such as chemotherapy tablets, can be ordered and dispensed in unit-dose blister packs,² reducing contact with potentially harmful substances.

Why validating processes matter

503B outsourcing facilities’ adherence to the FDA’s cGMP standards means each batch of medication produced is tested for:

• Potency, ensuring the desired amount of active drug is present
• Endotoxins, when applicable, confirming the drug is safe for patient use
• Stability, ensuring the expiration date assigned is accurate
• Sterility, when applicable, verifying microbial contamination is not present

In addition, 503B outsourcing facilities follow the FDA’s cGMP regulations to develop and execute their manufacturing processes for drugs in a range of standard dosages appropriate for animals. The manufacturing processes used have undergone thorough validation testing ensuring:

• Dosage deviation is often seven percent or less than the expected amount, which is much more accurate than exact, on-demand compounded medications. For example, the “exact” dosage 3.125 mg of a drug can vary from 2.5 to 3.75 mg, while the “standard” dosage is available in a 3 mg tablet that only varies from 2.79 to 3.21 mg in delivered dosage—a variation range of just 0.42 mg.
• There is dosage consistency in every tablet within a batch, and consistency between different batches of the same drug.

Standard validated dosages and drugs with a narrow therapeutic window

Delivered dosage accuracy is especially important for medications with a narrow therapeutic range in the blood, such as thyroid, antiseizure, and chemotherapy medications. With these drugs, even relatively small dosage variations can significantly impact patient outcomes with:

• Underdosing, yielding ineffective treatment outcomes and drug resistance
• Overdosing, leading to toxicity

A recent study conducted by VCA Animal Hospitals,³ led by veterinary oncologist and director of clinical studies, Phil Bergman, DVM, MS, PhD, DACVIM, analyzed the precision of the dose delivered compared with the dose requested for two chemotherapy medications, chlorambucil and cyclophosphamide. In the first round of the study, the two medications were ordered from a wide range of 503A compounding pharmacies and were assessed for:

• The variation in potency between pills within each compounder’s shipment to determine if each pill coming from the same batch offered the same delivered dosage
• The difference between the actual dose delivered versus the ordered dosage for each shipment

A second round of the study was then conducted at a later timeframe to ensure the chlorambucil and cyclophosphamide ordered were being supplied from different batches than the medications delivered in the initial round of the analysis. In this second round, the researchers analyzed:

• The difference in potency between pills within each compounding pharmacy’s shipment
• The dosage difference between the pills sent in the first round of the research and those sent during the second phase of the study by each 503A compounder to determine whether dosage variations existed between batches and, if so, the extent of that variation

Additionally, while no 503B outsourcing facilities were compounding cytotoxic chemotherapy medications during the initial phase of the study, by the second phase, shipments of chlorambucil and cyclophosphamide were available and ordered from a 503B outsourcing facility for analysis, allowing the researchers to determine whether compounded drugs produced using validated processes and tested according to the FDA’s cGMP regulations offered additional accuracy in the delivered dosage versus the expected dosage.

The results of the study were eye-opening. The researchers found:

• The actual dosage delivered varied by 30-40 percent among pills delivered in the same shipment, indicating substantial and problematic dosage variations were occurring within the same batch produced by a 503A compounding pharmacy.
• When comparing the actual dosage delivered by the medications across the different 503A compounding pharmacies, significant variation was present, with the ranges varying from only 60 percent of the ordered dosage at the low end to one- and one-half times the ordered dosage at the high end of the range, creating concerns regarding the risks of underdosing and overdosing.
• The medications from the 503B outsourcing facility demonstrated a significant improvement in the accuracy of the delivered dose compared with the samples from the 503A compounding pharmacies and greater consistency in actual dosage delivered between batches.

Additional studies³ demonstrate that deviations between expected and actual dosage delivered in medications produced by 503A compounding pharmacies are not exclusive to oncology drugs and exist across product categories.

For example, in a study that examined the delivered dosage of veterinary medication chews from 503A compounders,³ it was found none of the chews contained the active pharmaceutical ingredient at a level required to provide effective treatment, so any patient receiving those chews was effectively receiving no treatment at all.

While the difference between “exact” and “standard” dosage medications may seem counterintuitive, the advantages offered by standard dosage medications manufactured using validated processes are clear. As the availability of 503B-manufactured standard dosage drugs continues to grow, veterinarians have an increased ability to provide their patients with medications they can rely on, resulting in improved patient outcomes and client satisfaction. Standard dosage medications from 503B outsourcing facilities set the standard for quality and reliability.

Melissa King, PharmD, is a pharmacist and operations leader for Epicur Pharma. King oversees manufacturing and distribution operations in accordance with current good manufacturing practices (cGMPs). cGMPs are integral to 503B drug manufacturing, and she is working to raise the bar in veterinary medicine. King holds a doctor of pharmacy degree from the University of the Sciences in Philadelphia.

References

1. Food and Drug Administration’s (FDA’s) current good manufacturing practice (cGMP) regulations: https://www.fda.gov/drugs/pharmaceutical-quality-resources/current-good-manufacturing-practice-cgmp-regulations
2. Unit-dose blister packs: https://epicurpharma.com/blister-pack-benefits
3. VCA study: https://epicurpharma.com/2021/06/29/503b-outsourcing-facilities-and-usp-800-with-philip-bergman-veterinary-oncologist/