Key Challenges

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Challenges in designing and developing dosage forms for animals are similar to those for humans. However, there are also specific issues that necessitate additional exploration and understanding. Issues can range from ensuring product stability to using inexpensive excipients and manufacturing methods to produce cost-effective products. They can encompass product-specific issues relating to a given delivery device to broad issues such as antimicrobial resistance. Some of the challenges a veterinary formulation scientist may encounter are discussed further below.

Interspecies and Intraspecies Differences

One of the most obvious differences and challenges is caused by the wide variety in both anatomy and physiology within and between species. Excellent reviews on differences between various animals and humans have been published (31,32). Others have studied specific differences in gastrointestinal physiology compared with those of humans (33,34), the effect of age and body size in dogs on drug absorption (35-39), or the value of dogs in modeling human drug absorption (40). These interspecies and intraspecies differences present formulation issues to those developing a product that must span different breeds or even species.

The end user can often successfully deal with solutions or suspensions that contain the same amount per volume and which can be administered at different volumes for different-sized animals. However, these liquid products are sometimes not so easy to transfer across species, as palatability becomes an issue. For example, cats are known to lack a gene allowing them to taste sugar/sweets, so a sweet formulation for dogs will not gain the same acceptance in cats. Solid dosage forms can be challenging as a wide range of dosing amounts are often needed between species, and administering a handful of tablets to a large dog may not be a viable option. One feasible alternative is to consider developing single- or double-scoring tablets. For farmed animals, a solution is to develop a flexible product that can be produced in different sizes during the manufacturing process. The TimeCapsule (Fig. 1) achieves this through its simple formulation approach and flexible manufacturing process.

Formulation

A good understanding of physicochemical properties of the active is required. An awareness of the drug and product stability profile (sensitivity to moisture, oxygen, light),

Figure 1 Various sized TimeCapsule intraluminal bolus administered to a range of sheep and cattle of different age and weight.

active forms like polymorphs and crystal form, hygroscopicity, powder characteristics (like density, flow, compression indices) are all important to study. Fundamental pharmacokinetic understanding is also similar with the added requirement in veterinary medicine to consider drug and metabolite residue levels. Ensuring formulations are effective and safe for animals is the same goal as new formulations developed for humans; however, a number of unique scientific and logistical/marketing formulation challenges exist with veterinary medicines.

Logistical/marketing Logistically, the time allotted for formulation scientists to design and develop formulations is considerably less than in the human health care arena. Reasons include the ability to get into the test subject very quickly (less time to recruit study subjects), less complex clinical study designs, which saves time, the need to understand ADME so that residue limits and withdrawal times can be set, and the pressure of less ultimate profit from the new product, resulting in the need to complete things quicker and less expensively to make the new medicine a profitable endeavor. Moving a compound from discovery through to filing takes approximately 7 years in the veterinary arena, while in human health care it takes around 10 years.

Other logistical/marketing-type problems center around cost of goods and the price an owner/producer will pay. All companies developing new animal medicines will from the beginning be examining the cost of goods (contributed by API, formulation excipients, manufacturing processes, packaging) and comparing that price with what the customer will pay. Developing a dosage form that is profitable remains one of the biggest challenges to the veterinary formulation scientist today.

Formulation design and development The challenges for developing a specific dosage form type vary, and, again, are quite similar to those dosage forms developed for humans. Some unique challenges with particular dosage forms are mentioned further in this chapter when discussing specific dosage forms. However, three examples are given in this section to highlight the potential formulation challenges associated with palatability, in-use stability (often called "broached" stability), and large package sizes.

While sweet, sour, bitter, salty, and umami (if one believes in the L-glutamine theory) are the tastes associated with human taste receptors, similar knowledge is not readily available for animals. The area of taste acceptance understanding for animals is ripe for research, with only a few published articles (41). Mainly through trial and error with flavorings (e.g., fish, meat), chewable delivery systems have become popular for dogs and cats. One frequently debated problem is whether laboratory animals can accurately represent the ultimate patient. It is thought that the owner-animal relationship (i.e., the bond) can affect the results and that is hard to simulate with laboratory animals. Additionally, one-time use medication is different from daily administration of drugs, where the animal may eventually tire of that "bad"-tasting solution or tablet. Sometimes it may have nothing to do with the active's taste or the formulation; a side effect like nausea due to the active could result in the animals not liking the dosage form. The important point to remember is that while designing a palatable formulation, the challenges could be quite difficult, lengthy, and resource consuming.

In-use or broached stability is the period of time a product can be used after the initial packaging is opened. It is particularly important in the veterinary field for liquid products. In the treatment of animal health, particularly in the farmed animal arena, numerous animals are often treated all at the same time; thus, the designing of multiple dose vials is more common than for human health care. This then leads to the question of how long after initial use can the contents of that bottle or vial be used. It is therefore important to understand chemical, physical, and microbiological stability of that broached container. Typically this involves withdrawing a representative amount from the container (e.g., 50% or 75%), then placing the reminder on stability. For microbiological testing, the USP Preservative Effectiveness Testing is often used. The aim is to develop a product that achieves the maximum time that a regulatory authority will allow to enable the most flexible for marketing of the product. While 28 days for sterile products is the maximum allowed in Europe, other sterile products may be 30 days or longer in various countries, and with oral solutions, periods of 6 months could be obtained if the data supports it.

Large package sizes are also more common in animal products compared with human medicines. Like the in-use stability issue, this is due to the large number of animals treated at one time. This could mean containers of 100 mL up to 25 L. Upon first glance, this may not appear to be problematic, but, larger packages take up more space and you may not have enough room in your good manufacturing practice (GMP)-controlled registration stability chambers to accommodate your test batches. Or, when making the registration stability batches you have to now manufacture much larger batch sizes to get suitable samples for stability testing, meaning, more API is required. These larger packages may not fit into secondary packages (i.e., cartons), which give protection during shipping. However, you still need to ensure package integrity during shipping. In fact, your drug may be classified in certain countries as being hazardous and your packaging must be safety tested (e.g., drop tested, leak tested). These are unique challenges that a formulation scientist needs to be aware of and address during the R&D process of a veterinary pharmaceutical.

Analytical

Similarity is seen between human and animal health products in analytical testing conducted to assure the quality attributes of the final product. The validation of these assays is identical in that linearity, precision, accuracy, robustness, and reproducibility are all required. Two examples of analytical areas that may differ include stability and in vitro drug testing.

Stability testing The unique stability testing requirements for animal health products include stability protocols that account for package size, extremes in exposed temperatures, in-use or broach packages, blending with other components (e.g., feeds), and compatibility with unique dosing devices.

As mentioned above, veterinary dosage forms can be very large and packaging of multiple doses achieved through the use of large packages. This presents substantial demands upon stability test chambers due to the sheer volume of product that must be stored. Appropriate sampling-size protocols can aid in the solution of this issue.

While regulatory requirements throughout the world for stability testing are very similar between veterinary and human products, sometimes the practical use of the product will dictate product development to withstand lower or higher temperatures. This impacts heavily on the products' stability requirements, which must be addressed and overcome by the formulator during the development stages of the product. How often in drug development for humans do you need to consider the cold winters of Wyoming and that the physical stability of that oil suspension may be different or the drug distribution of the steroid implant from the ear may be slower due to reduced ear temperature?

Broached packages have been discussed previously, but another "in-use" period that demands consideration is when products such as feed additives are mixed with the feeds. Good knowledge of how long your new drug can withstand high mineral, high water content (corn can have >15% water content) is essential. Equally difficult may be the actual potency assay development as you try to extract the active and degradants from these complex feeds.

Some unique delivery devices are used in animal health as discussed later in this chapter. Knowing the compatibility of the formulation with these devices and whether any deleterious components are extracted from the devices is required. One example would be the rubber or silicone seals in oral drenching guns. Numerous manufactures of these guns exist, and each gun should be examined to be sure that as product contacts the seals those components are not removed that will either affect dosing accuracy and ease or be toxic to the animals receiving the product.

In vitro drug release testing The physical size of some veterinary dosage forms particularly encountered for livestock; the very large quantities of incorporated drug (usually in gram rather than milligram quantities); the very long delivery periods (weeks and months for veterinary products compared with hours or days for human products); the diverse physicochemical properties of the incorporated drug; and the unique shapes and geometries and unique release mechanisms can present difficulties in the development and validation of in vitro drug release tests for veterinary dosage forms. The aim is always to use compendial methods (like the USP-specified apparatus and conditions); however, some scientifically justified deviations from these specifications may be justified on a case-by-case basis to successfully develop a regulatory meaningful assessment method. Large vessels are being introduced, but some tolerance to nonaqueous-based media must be forthcoming. Acknowledgment of the final test capabilities is required by developers. If no in vitro-in vivo correlation can be shown when using a modified test or test conditions, then the test must remain a simple monitor of manufacturing consistency, and not be argued to show biological relevance and used as a surrogate for formulation, site, or manufacturing changes.

Residues

Three areas will be covered with respect to this topic in this chapter: residues within food-producing animals, residues within the environment, and antimicrobial resistance.

Two major disciplines work together to establish allowable residues in animal food products. The first discipline involves those who assess safety of drugs and metabolites who determine whether the compounds have effects on humans and at what dose. This is achieved through testing on mice, rats, dogs, monkeys, or other lab animals that can serve as models for humans. The effects on genes, the potential for causing cancer, and the ability of the drug to be teratogenic are all explored. The potential to cause harm to various organs such as the liver, kidneys, lungs, and heart is also conducted. Studies are conducted with various doses and ideally a "no effect level" (NOEL) with respect to safety is determined. The second discipline involves the pharmacokineticist to study the distribution and elimination of the administered compounds and its metabolites. This typically involves a full tissue residue analysis to be performed, first with radiolabeled drug to determine the sites of deposition, then with nonradiolabeled drug to prove it in the final formulation. By understanding where the drug and metabolites will distribute (i.e., where they might accumulate) and the rate of elimination (i.e., how long they will be around and at what concentrations), the second set of key information is determined. This information is then married with the safety findings and additional safety margins applied to determine the drug's allowable daily intakes (ADIs). From all these data a "tissue withdrawal" time is determined to inform the farmer of when the animal is fit for slaughter. Obviously, the shorter the withdrawal time is for the product, the more desirable the overall product profile. This applies to all food, including meats, milk and eggs. Approved withdrawal times for all marketed products are located in the Compendium of Veterinary Products (42). For those wanting more detailed information, several good review articles are available (43-46).

The residue potential for the environment is also studied. Both the active drug and metabolites could be studied. A focus is on livestock and other animals (e.g., chickens, turkeys, fish) that eliminate waste on to the ground or into the water. The rate of degradation of the drug is examined in water at different pHs and when exposed to light. The adsorption of these drugs on to certain soils is also studied. The goal is to determine the degradation rate to nontoxic compounds. Also examined are the effects on certain aquatic life to gauge toxicity. Dependent on the drug, even soil bacteria can be evaluated during this phase. An excellent review article is available along with VICH (International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products) report (47-49).

Antimicrobial resistance has been a hotly debated issue during the last 15 years. One issue that brought it to the forefront was the use of fluroquinolones in poultry in the mid-1990s. The use of the product in such a large number of animals was purported to increase antimicrobial resistance. While data was presented on both sides of the argument, ultimately the fluoroquinolone poultry product was withdrawn from the market, a decision that was upheld in a U.S. court. To get an antimicrobial approved for food-producing animals in the United States, the sponsor must use FDA-CVM Guidance 152 (50) and follow the guidance to show the benefit of the product and to rank its potential for causing antimicrobial resistance. Again, this process represents an additional hurdle that is placed on the development of animal health products that is not encountered with human drug product development.

Regulatory Considerations

Both human and animal health products need to be safe, efficacious, and of defined quality. For major markets in the world, both animal and human products need to be manufactured in GMP facilities. For human products, regulatory requirements are set for the areas of toxicity, safety, dosing intervals, therapeutic effect, stability, manufacturing, etc. Veterinary products not only include all of the above but are also required to address tissue residue, handler safety, and environmental assessment, particularly if the product is for food-producing animals. If producing a new antimicrobial agent for food-producing animals, the issue of antimicrobial resistance also needs to be addressed. Details about these special requirements were covered in section "Residue" of this chapter.

Unique Products

There are some very unique formulations or delivery systems that are used to treat animals, each of which present unique development challenges. For example, the large feed-additive market dictates that drugs must be stable in a wide variety of feeds even if those feeds have grains containing 10% moisture or more. Or, sometimes those same feeds are fortified with minerals that have the capability of catalyzing drug oxidation degradation pathways. Feed additives are often diluted to parts per million levels, and you need to ensure adequate homogeneity when the local feed-mill blends the product with coarse feeds. Appropriate analytical methods need to be developed to extract the active from those feeds.

The pour-on or spot-on tick/flea products can also present unique challenges to the formulator. With these products there is a need to deliver accurate amounts of active topically and, depending on the mechanism of action, one may wish for the active to stay on the skin or in the hair follicles and be effective for one month or longer. The challenge is that these products must also be inherently safe for children when they pet their dog, or, for example, to the other cattle that may lick the hides of their field mates.

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