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The Conceptual Basis of Guidance About Biowaivers for Type A Medicated Articles
by Marilyn N. Martinez, Ph.D., Senior Biomedical Research Scientist, Office of New Animal Drug Evaluation
FDA Veterinarian Newsletter 2006 Volume XXI, No II
The Center for Veterinary Medicine (CVM) issued an industry guidance in February 2006 that explains the basis under which CVM can grant biowaivers for Type A medicated articles containing drug substances that are classified as water soluble.
“Guidance for Industry on Waivers of In Vivo Demonstration of Bioequivalence of Animal Drugs in Soluble Powder Oral Dosage Form Products and Type A Medicated Articles” (Guidance for Industry #171) is available on CVM’s website.
The Type A medicated article consists of the active pharmaceutical ingredient (API) plus excipients and is not a finished dosage form. Since the Type A medicated article is only a small component of the final product that is ingested by the animal, the composition of the medicated feed can vary with the nutritional content of the foodstuffs with which it is mixed.
Therefore, with few exceptions, if the drug itself is water soluble across a variety of pH values, the composition of the Type A medicated article will not affect the bioavailability of the drug in medicated feed. (See sidebar for definitions of Type A medicated articles and Type B and C medicated feeds.)
CVM’s basis for granting biowaivers for Type A medicated feeds is that drugs soluble in aqueous media across a range of pH values go rapidly into solution upon contact with the fluids of the gastrointestinal (GI) tract. If the drug readily goes into solution upon contact with the gastric fluids, then the rate at which the drug reaches a remote site of action or absorption is dependent upon the rate of gastric emptying and intestinal transit. These factors reflect physiological rather than formulation-dependent variables.
While adsorption of the drug to the nutrients in a meal may affect product bioavailability1, the clinical impact of drug adsorption to the contents of the Type B or C medicated feed will have been addressed in the original application through the evaluation of product safety and efficacy.
Therefore, assuming that the active ingredients of the test and reference formulations are identical, if a drug is water soluble, the bioavailability of that drug when contained in a Type A medicated article will not be influenced by the composition of the Type A medicated article.
The only exceptions of which CVM is aware are when the formulation contains substances that could cause adverse pharmacologic effects (e.g., altered GI transit time, membrane permeability, or drug metabolism), or when there is inactivation of the drug by, for example, an excipient that chelates the API (where chelation is the combining of a metal ion with a chemical compound).
By definition, solubility is the extent to which molecules in a solid are removed from its surface by a solvent. CVM recommends use of the USP definition of drug solubility. In general, ionized drugs tend to exhibit far greater aqueous solubility than their un-ionized counterparts. Consequently, drug solubility can be markedly affected by the pH of that solvent. For this reason, CVM requires that solubility be tested across a wide range of pH values.
There is no need for statistical comparison of the solubility test results obtained with the pioneer and generic products because, as defined in CVM’s biowaivers guidance document, to be eligible for biowaiver, the API must meet the solubility criteria across all pH conditions. A failure to dissolve in any one condition will disqualify products containing this API from being a candidate for a biowaiver.
CVM recognizes that consistent with the Center for Drug Evaluation and Research (CDER) biowaiver guidance1, there may be occasions when this conservative USP definition of solubility excludes compounds that are administered at doses so low that sink conditions exist in the stomach of the target animal species (i.e., where the concentration of dissolved drug does not influence the further dissolution of that solid dosage form). In other words, the dosage is such that there will be far less than 1 gram of drug per 10 mL of gastric fluid. Therefore, CVM’s biowaiver guidance provides for a dosage-adjusted definition of solubility that is based upon gastric fluid volume and targeted dose.
As described in the CDER guidance1, the entire dose must dissolve in the gastric volume of the targeted species to avoid the possibility of dissolution-rate limited bioavailability.
When using the dosage-adjusted approach, the test conditions and criteria being applied within CVM’s Guidance for Industry #171 are consistent with drugs that are classified as “highly soluble” within the framework of CDER’s biowaiver guidance.
CDER’s biowaiver guidance is applicable to compounds that are highly soluble and highly permeable across the intestinal mucosa (defined by the Biopharmaceutics Classification System as Class I compounds). Unlike CDER’s biowaiver guidance, CVM’s guidance also allows for the granting of biowaviers for drugs that are highly soluble but that exhibit poor intestinal permeability (Class III compounds). For these molecules, it is not the rate of drug dissolution that is rate-limiting, but rather the rate and extent of drug permeation across biological membranes2. Therefore, so long as there are no permeability enhancers included in the formulation, CVM has deemed it appropriate to include both Class I and Class III compounds in its biowaivers guidance.
However, as noted in that guidance, CVM reserves the right to deny a waiver request if there is any component of the Type A medicated article that is believed to either compromise drug solubility or alter intestinal permeability. Examples of “inactive” ingredients that may be of concern include substances known to alter drug solubilization (e.g., a chelating agent), intestinal permeability enhancers (e.g., polysorbate 80) or excipients that can alter GI transit time (e.g., osmotically active substances such as sorbitol and mannitol).3
CVM’s biowaivers guidance is applicable if a generic drug sponsor or if the sponsor owning the rights to the approved New Animal Drug Application (NADA) for the Type A medicated article wishes to develop a revised formulation of the approved Type A medicated article.
However, these same criteria cannot be used to bridge between a Type A medicated article and a water soluble powder. Unlike with tablets, oral boluses, oral suspensions, and injectable formulations, animal behavior (drinking and eating) determines the actual dose received when the drug is administered in the drinking water or in food. While blood level bioequivalence studies employing gavage dosing may confirm the absence of a formulation effect (which is the sole question applied to products that meet the criteria for approval as an abbreviated NADA), it cannot confirm the comparability of rate and extent of drug intake. This difference in intake may be greater in diseased as compared to healthy animals, since diseased animals tend to go off food before they cease to drink.
Therefore, CVM’s biowaiver guidance should not be applied in these situations. Similar questions may arise if going from the administration of drug in total feed versus as a top dress.
1 CDER Guidance For Industry: Waiver of In Vivo Bioavailability and Bioequivalence Studies for Immediate-Release Solid Oral Dosage Forms Based on a Biopharmaceutics Classification System. Issued 8/2000, Posted 8/31/2000).
2 Fleisher, D, Li, C, Zhou, Y, Pao, LH, and Karim, A: Drug, meal and formulation interactions influencing drug absorption after oral administration. Clin Pharmacokinetics 1999;36:233-254.
3 Martinez M, Augsburger L, Johnston T and Jones WW. Applying the biopharmaceutics classification system to veterinary pharmaceutical products. Part I: biopharmaceutics and formulation considerations. Adv Drug Deliv Rev 2002 54; 805-824.
Definitions of Medicated Articles, Medicated Feeds
The Type A medicated article and Type B and C medicated feeds are regulated by the Food and Drug Administration’s (FDA), Center for Veterinary Medicine. Definitions of new animal drugs approved for use in animal feed are provided in 21 CFR §558.3.
- A “Type A medicated article” is intended solely for use in the manufacture of another Type A medicated article or a Type B or Type C medicated feed. It consists of a new animal drug or drugs, with or without carrier (e.g., calcium carbonate, rice hull, corn, gluten) with or without inactive ingredients.
- A “Type B medicated feed” is intended solely for the manufacture of other medicated feeds (Type B or Type C). It contains a substantial quantity of nutrients including vitamins and/or minerals and/or other nutritional ingredients in an amount not less than 25 percent of the weight. It is manufactured by diluting a Type A medicated article or another Type B medicated feed.
- A “Type C medicated feed” is intended as the complete feed for the animal or may be fed “top dressed” (added on top of usual ration) on or offered “free-choice” (e.g., supplement) in conjunction with other animal feed. It contains a substantial quantity of nutrients including vitamins, minerals, and/or other nutritional ingredients. It is manufactured by diluting a Type A medicated article or a Type B medicated feed. A Type C medicated feed may be further diluted to produce another Type C medicated feed.
Companies manufacturing Type A medicated articles must comply with the good manufacturing practice regulations in 21 CFR 226. Type B or Type C medicated feeds are produced using Type A medicated articles or other Type B or Type C medicated feeds. To manufacture some medicated feeds, an approved medicated feed mill license is needed. According to provisions of the Animal Drug Availability Act of 1996, a licensed feed mill may manufacture any approved medicated feed as long as the facility is manufacturing the feed in conform-ance with the good manufacturing practice regulations for medicated feeds (21 CFR 225).