FROM THE 2015 FEED ADDITIVE COMPENDIUM
by Richard Sellers
Richard Sellers is senior vice president of legislative and regulatory affairs for the American Feed Industry Assn., a national trade association representing the interests of nearly 600 feed manufacturers, distributors, ingredient suppliers, equipment manufacturers, nutrition consultants and animal health distributors. He holds a B.S. from the University of Memphis and an M.S. in poultry science from the University of Arkansas.
With the growing popularity of liquid supplements going back 35 or more years, it became common practice to include a number of the same drugs used in dry feeds — particularly antimicrobials. Subsequent experience revealed some problems with chemical, physical and/or positional stability with the products that did not go into solution. The result was a tightening of controls and a more restrictive use of drugs in liquid feeds.
The limited number of approved products for liquid feed has remained rather static for some time. In addition, approved use includes only a few new products. This situation has placed an economic hardship on liquid manufacturers and users, particularly with respect to high demand new products. New rules published in 2004 have assisted somewhat in alleviating this problem.
All animal drugs to be used in feeds — whether dry or liquid — must be cleared with FDA by securing an approved new animal drug application (NADA). An NADA is also known as a Form FD-356V. Usually the drug manufacturer or sponsor will secure the approved NADA from FDA. This is a long and expensive process, which may require up to 7-10 years and considerable expenditures of resources. Studies done to secure approval must demonstrate that the drug is safe and effective for its intended purpose. Safety includes safety to the animal and to humans consuming products derived from the animal.
Once the drug manufacturer or sponsor has secured an approved NADA, a regulation is published by FDA describing the conditions under which the product may be used. If the drug is categorized as Category I — i.e., there is no withdrawal requirement at its lowest continuous use level — the drug is available to all who wish to use it under the conditions specified in the governing regulation. It should be noted that there may be a withdrawal time for higher use levels, but this does not affect a drug’s status as Category I. If the drug is classified as Category II — i.e., there is a withdrawal requirement associated with its lowest continuous use level or there are special concerns about its nature — users of the higher potency premixes (Type A articles) had to secure an approved medicated feed application (MFA) prior to being able to purchase and use the Type A articles to produce medicated feeds. Today, the multiple MFA/FD-1900 has been replaced by a single, federal medicated feed mill license. Lower potency sources of these Category II drugs, known as Type B medicated feeds, can be purchased and used without the necessity of securing a license.
Two points must be noted. An initial approval of a drug for use in feed is normally predicated on use in dry feed and this does not permit use in liquid products. Drug use in liquid supplements or free-choice type feeds is not automatic. These feeds are “special” conditions of use which must be specifically pursued and approved.
The use of an animal drug in liquid feed (Type B or Type C medicated feed) requires a license unless a specific approval has been obtained and manufacturing criteria have been codified in the Code of Federal Regulations. Master files may contain proprietary data, including feed formulas for an individual company. However, the approval is required to come through the NADA for the drug or drug combination. The regulation provides the specific requirements for manufacturing the medicated liquid feed. There are nine Category I drugs that are approved for use alone in liquid feed, many of which do not require a medicated feed mill license. They are bambermycins, decoquinate, laidlomycin, lasalocid, melengestrol acetate, monensin, poloxalene, ractopamine and tylosin. The Category I drugs requiring a license (an exception from dry feed animal drugs) are determined by 21 CFR §558, i.e., if the information is not made public (in the regulations), then it is proprietary, which means a license is required for use of that drug in liquid feed. Furthermore, the same Category I drug may or may not require a license depending on the individual regulation governing physical stability of the drug and its proprietary nature. Category I drugs in combination may or may not require a license depending on the individual drug regulation.
Use of S-methoprene and ronnel in liquid feed are governed by the pesticide/feed ingredient agreement between FDA and EPA. If these products are used alone, i.e., without other approved animal drugs, then FDA considers them food additives and governed by EPA. However, if they are added to a liquid feed with other approved animal drugs, then approval for use in liquid feeds would be required.
The use of an animal drug in a liquid feed, whether for mixing or free-choice feeding, carries with it some special considerations and requirements. These are described below.
Medicated Liquid Feeds for Mixing
Assuming the drug manufacturer or sponsor has secured an approved NADA, and an appropriate regulation has been published by FDA for use in dry feeds, the use of the drug in liquid supplements for mixing purposes will require the following actions:
Chemical stability. The drug must be proven chemically stable in the intended liquid supplement matrix. This can be done with a specific formula or with formulas representing the parameters of expected formulation. The drug sponsor or a liquid supplement manufacturer can perform these studies.
If the drug sponsor performs the studies, it is likely only one formula will be involved, and the existing regulation will be supplemented by the NADA holder to provide access to use of the drug with that fixed liquid formula. All interested liquid supplement manufacturers have equal access. If stability in a range of liquid formulas is proven, this fact will be reflected in the supplemented regulation. Again, all liquid supplement manufacturers will have equal access.
If the drug is a Category I product, and there is a published regulation permitting its use in liquid feeds for mixing purposes under stipulated conditions — such as a fixed formula or formula parameters, no medicated feed mill license is required. Otherwise, a license will be required, as will be the case with a Type A, Category II drug source.
If the liquid supplement manufacturer performs the chemical stability studies, it will normally do so with formulas representing an expected range of feed formulation. The information proving chemical stability will be placed in a master file with FDA by the feed firm. Information in such a master file is protected and is accessible only to the agency and to the feed manufacturer submitting the stability information or to those whom the manufacturer designates. If the information is acceptable to FDA, the feed manufacturer subsequently requests the drug sponsor to supplement the basic NADA with a provision providing for the feed manufacturer’s use of the drug in line with the master file information. A license will be needed only if the drug is categorized as Category II and the liquid supplement manufacturer wishes to use a Type A source of the drug.
Physical stability. The drug must be proven physically stable — i.e., positionally stable, in a particular liquid supplement or in supplements falling within established parameters — or the labeling of the supplement must carry directions to agitate prior to use to insure uniform dispersion of the drug. An example of agitation directions can be found in the monensin regulation (21CFR § 558.355).
If a fixed formula is involved, the drug sponsor may elect to demonstrate physical stability but can simply rely on agitation directions. The choice will be reflected in the published regulation. The same alternatives are available to liquid supplement manufacturers using either fixed or flexible formulations. Proof of physical stability by the liquid supplement manufacturer — like proof of chemical stability — is placed in a master file, and the drug sponsor requested to supplement the basic NADA. The supplemented NADA will provide for use of the drug under the conditions specified by the feed manufacturer who created the master file. Again, access to the master file is limited.
Most manufacturers of liquid supplements for mixing purposes have chosen to rely on agitation directions. The cost of performing physical stability studies may simply outweigh the benefits of not having agitation directions on the feed label. Agitation is also good insurance of drug dispersion throughout the liquid supplement at time of use.
Guideline protocols to be used for chemical and physical stability studies are available from FDA. It is suggested anyone interested in obtaining a copy visit www.fda.gov/downloads/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/UCM051556.pdf. Additional guidance documents on controls can be found at www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm123635.htm.
It must be emphasized that FDA concurrence in study protocols is essential to insure acceptance of the study results. Only if FDA is satisfied with the information placed in the master file, can the drug sponsor secure the modification of the regulation requested by the feed manufacturer.
Again, assuming the drug manufacturer or sponsor has secured an approved NADA, and an appropriate regulation has been published by FDA for use in dry feeds, the following actions must be taken for use in free-choice liquid supplements:
Chemical stability. Chemical stability in free-choice liquid matrix must be established as previously described for liquid mixing supplements.
Physical stability. Inherent physical or positional stability of the drug — i.e., continuing uniform dispersion — must be demonstrated for liquid supplements intended for free-choice feeding. Agitation is not, for obvious reasons, a viable alternative. As described under mixing supplements, either the drug sponsor or the liquid supplement manufacturer can demonstrate inherent physical stability.
Range of effectiveness. The inherent variable consumption associated with free-choice feeding requires a drug that is effective over a relatively broad range of intake. If a range of effectiveness has not been proven, it will be necessary that this is done. The proof of a range of effectiveness normally falls to the drug sponsor.
Free-choice feasibility. The feasibility of administration via the free-choice route must be demonstrated before a drug can be used in any free-choice feed whether dry or liquid. This is necessary because there may be intermittent consumption by animals. Free-choice feasibility can be demonstrated using any physical form of feed — meal, pellets, blocks or liquids. Once the concept of free-choice administration has been proven, it is accepted by FDA for all physical forms of free-choice feed.
Either the drug sponsor or the feed manufacturer can perform the studies to demonstrate free-choice feasibility. If the drug sponsor performs the work, the governing regulation will be modified to provide for free-choice feeds. The regulation will provide for use only with a proven formula or formulas. Only minor modifications are permitted to such formulas. If the feed manufacturer performs the feasibility studies, this information will be placed in a master file, and the drug sponsor requested to modify the NADA to provide for the feed firm’s use in free-choice products. There is an additional condition attached to the use of a drug in free-choice feeds. That condition is consumption — i.e., proof of expected consumption.
Consumption. Approval of a drug in free-choice feeds is dependent upon a demonstration of consumption within predetermined target limits. If the drug sponsor has secured acceptance of consumption on a fixed formula, then the feed manufacturer willing to use that fixed formula can produce free-choice feeds. If, however, the feed manufacturer wishes to utilize his own individual formulations, he will have to perform consumption studies on his products. The results of those studies will be placed in a master file, and the drug sponsor requested to supplement the NADA to provide for the feed firm’s use in free-choice feeds in line with the studies filed in the master file.
License requirement. The use of any drug, Category I or Category II, in free-choice feeds including free choice liquid feeds, requires a medicated feed mill license. It is hoped the foregoing will serve to aid in understanding the regulatory scheme for medicated liquid feeds. A list of drugs currently cleared for use in liquid feeds and a listing of other sources of information appears below.
Future changes. FDA has published draft documents indicating that all growth promotion and feed efficiency approved drugs should be moved to therapeutic claims with veterinarian oversight with data submitted by the drug sponsor. It is expected that therapeutic drug uses will be by veterinarian oversight provided by the Veterinary Feed Directive (see pages 43-50). At press time, a draft of the VFD process changes had been issued by FDA. However, this is a three-year process with the changes likely being phased in.
Sources of Information
The following references are suggested for further, more detailed information:
Center for Veterinary Medicine, www.fda.gov/cvm.
Code of Federal Regulations — Title 21, Part 558 — New Animal Drugs for Use in Animal Feeds.
Code of Federal Regulations — Title 21, Part 510 — Section 510.455 — New Animal Drug Requirements Regarding Free-Choice Administration in Feeds.
Code of Federal Regulations — Title 21, Part 558 — Section 558.355 (p)(3)(b) Limitations — Agitation requirement example.
Drugs currently cleared for use in liquid feeds
Bambermycins 21 CFR 558.95 Cattle
Decoquinate 21 CFR 558.195 Cattle, sheep, goats
Fenbendazole 21 CFR 558.258 Dairy and beef cattle
Laidlomycin 21 CFR 558.305 Cattle
Lasalocid 21 CFR 558.311 Cattle, sheep
Melengestrol acetate 21 CFR 558.342 Cattle
Monensin 21 CFR 558.355 Cattle, goat
Poloxalene 21 CFR 558.465 Cattle
Ractopamine 21 CFR 558.500 Cattle
Tylosin 21 CFR 558.625 Cattle
Zilpaterol hydrochloride 21 CFR 558.665 Cattle