FROM THE 2015 FEED ADDITIVE COMPENDIUM

by David A. Fairfield

David A. Fairfield is vice president of feed services for the National Grain & Feed Assn., a national trade association representing the interests of more than 1,050 companies involved in feed and feed ingredient manufacturing, and grain handling, processing and milling. He joined NGFA in 2001 after spending 20 years in operations management positions within the feed industry. Fairfield holds a B.S. in feed science and management from Kansas State University.

Facilities should be aware of the Food & Drug Administration’s approval requirements before purchasing animal drugs, or manufacturing or repackaging a medicated animal feed. Requirements associated with FDA’s animal drug approvals and uses are very specific. Animal and human health protection requires the use of animal drugs in feeds be in accordance with FDA approval.

Medicated Feed Requirements

(How medicated animal feeds are classified and regulated.)

FDA’s medicated feed requirements encompass all medicated feed manufacturers. The requirements that a medicated feed manufacturer is to comply with depends upon the category of animal drugs used and types of medicated feeds produced.

New Animal Drug Categories. New animal drugs for use in medicated animal feeds are classified as either Category I or II. Category I new animal drugs are drugs that require no withdrawal period at the lowest use level in each species for which they are approved. Category II new animal drugs are drugs that: (1) require a withdrawal period at the lowest use level for at least one species for which they are approved; or (2) are regulated on a “no-residue” basis or with a zero tolerance because of a carcinogenic concern regardless of whether a withdrawal period is required, or (3) are veterinary feed directive drugs. 21 Code of Federal Regulations (CFR) 558.4(d) identifies each drug by Category I or II and lists the maximum drug level permitted in Type B medicated feeds.

Types of Medicated Feeds. FDA has established the following types of medicated feeds.

• Type A medicated articles are intended solely for use in the manufacture of other Type A medicated articles and/or a Type B or Type C medicated feeds and consist of an approved new animal drug(s), with or without carrier (e.g., calcium carbonate, rice hulls, corn gluten) and with or without inactive ingredients. Type A medicated articles contain a drug(s) at an approved potency higher than what is permitted in Type B feed levels (see 21 CFR 558.4(d) or Category I and II maximum Type B drug tables at the beginning of Section 3 of this Compendium). With some technical exceptions, manufacture of a Type A medicated article requires Form FDA-356v approval under 21 CFR 514.105, as well as compliance with current good manufacturing practices (cGMPs) for Type A medicated articles (21 CFR 226).

• Type B medicated feeds are intended solely for the manufacture of other Type B and/or Type C medicated feeds and contain a substantial quantity of nutrients including vitamins and/or minerals and/or other nutritional ingredients in an amount not less than 25% of the weight. Type B medicated feeds are manufactured by diluting a Type A medicated article or another Type B medicated feed. Maximum concentration of a Category I drug in a Type B medicated feed is 200 times the continuous use level, while the maximum concentration of a Category II drug in a Type B medicated feed is 100 times the continuous use level for the particular drug. If the drug is not approved for continuous use, the highest level used for disease prevention or control is used in place of continuous use level. These levels are shown in 21 CFR 558.4(d), as well as the Category I and II maximum Type B drug tables at the beginning of Section 3 of this Compendium. Type B medicated feeds manufactured from a non-standardized drug component (bulk or drum-run dried crude fermentation product) require an application approved under 21 CFR 514.105 or an index listing granted under 21 CFR 516.

• Type C medicated feeds are intended for feeding as a complete feed or manufacture of other Type C feeds and may be fed free-choice or as a top dress if approved for such use. Type C medicated feeds are manufactured by diluting a Type A medicated article, or a Type B or Type C medicated feed. Type C medicated feeds manufactured from a non-standardized drug component (bulk or drum-run dried crude fermentation product) require an application approved under 21 CFR 514.105 or an index listing granted under 21 CFR 516.

Regulatory Framework

                                                Category I Drugs                                        Category II Drugs

Manufacture of                           Premixes containing drugs                           Premixes containing drugs

Type A Medicated                       at levels greater than                                   at levels greater than

Article                                       permitted in Type B feed                              permitted in Type B feed

                                                • FDA-356 approval required                         • FDA-356 approval required

Use of Type A                            License and registration • License required

Medicated Article                        required, and full cGMPs apply                     • Establishment registration

                                                if manufacturing medicated                          • Subject to routine FDA inspection

                                                liquid feeds or medicated                             based upon designated risk factors

                                                free-choice feeds with                                 • Full cGMPs apply

                                                proprietary formula and/or                            • For feeds requiring a license, assay

                                                specifications; otherwise:                             three samples containing each drug

                                                • No license                                               or drug combination used each year

                                                • No establishment registration

                                                • No mandatory FDA inspections

                                                • Relaxed cGMPs apply

                                                • No required drug assays

Use of Type B                            License and registration                               License and registration requirements,

or Type C                                  requirements, and full cGMPs                       and full cGMPs apply if manufacturing

Medicated Feed                          apply if manufacturing                                 medicated liquid feeds or medicated

                                                medicated liquid feeds                                 free-choice feeds; otherwise:

                                                or medicated free-choice                              • No license

                                                feeds with a proprietary                               • No establishment registration

                                                formula and/or specifications;                       • No mandatory FDA inspections

                                                otherwise:                                                  for compliance with cGMPs

                                                • No license                                               • Relaxed cGMPs apply

                                                • No establishment registration                     • No required drug assays

                                                • No mandatory FDA inspections

                                                • Relaxed cGMPs apply

                                                • No required drug assays

Type B and Type C medicated feeds also are classified as either Category I or II, based upon the category of the drug source used to manufacture the respective medicated product.

Based upon the established categories of animal drugs and types of medicated feeds, a medicated feed manufacturing facility is to be registered with FDA as a drug establishment and hold an FDA-approved Medicated Feed Mill License (MFML) to produce:

• Type B or Type C medicated feeds from a Category II, Type A medicated article;

• Liquid or free-choice feeds using a Category II drug, and

• Liquid or free-choice feeds using a Category I drug and a proprietary formula and/or specifications.

The manufacture and distribution of medicated feeds subject to an approved MFML is to conform to the cGMP requirements established within 21 CFR 225.10 through 225.115. Included among the cGMP requirements are detailed drug control procedures and mandatory drug assays. Historically, facilities holding a MFML also have been subject to biennial FDA inspections. However, the FDA Safety & Innovation Act signed into law on July 9, 2012, now instructs FDA to inspect such facilities at a frequency based upon designated risk factors, such as the facility’s compliance and recall history, inherent risk of the drug processed, length of time since last inspection and other factors.

Except for liquid and free-choice medicated feeds as indicated above, the manufacture of Type B or Type C medicated feeds using only a Category I, Type A medicated article or Type B or Type C medicated feed, or a Category II, Type B or C medicated feed is exempt from the requirement for a MFML and drug establishment registration, but must comply with “relaxed” cGMPs specified in 21 CFR 225.120 through 225.202. The “relaxed” cGMPs have less stringent drug control requirements and do not require drug assays. Also, FDA regulations that apply to facilities exempt from holding an approved MFML do not mandate routine inspection for compliance with cGMPs, although such inspections commonly occur.

A table illustrating the regulatory framework for medicated feed products is indicated elsewhere in this article.

Facilities that hold a MFML but wish to use only Category I medicated articles and/or Type B medicated feed sources and do not intend to use Category II, Type B or C medicated feeds to manufacture liquid or free-choice medicated feeds, or use Category I, medicated articles or Type B or Type C medicated feeds to manufacture liquid or free-choice medicated feeds with a proprietary formula and/or specifications, may request that its MFML be withdrawn. In response, FDA will withdraw the approval and remove the facility from its mandatory inspection list.

To request that a MFML be withdrawn, send a letter to: Food & Drug Administration, Center for Veterinary Medicine, Division of Animal Feeds (HFV-220), 7519 Standish Place, HFV-220, Rockville, Md. 20855, or contact your local FDA office. The written request should include the facility’s feed mill registration number and medicated feed mill license number.

Registration of Drug Establishments

If a medicated feed manufacturer is required to obtain a MFML, the manufacturer is required to first register as a “Drug Establishment.”

Who Must Register? Any feed manufacturer using a: (1) Category II, Type A medicated article to manufacture Type B and/or Type C medicated feeds; or (2) Category II, Type A medicated article and/or Type B or Type C medicated feed to manufacture liquid and/or free-choice medicated feeds; or (3) Category I, Type A medicated article and/or Type B or Type C medicated feed to manufacture liquid and/or free-choice medicated feeds with a proprietary formula and/or specifications is to register with FDA as a “drug establishment.” Mobile mixers are required to be registered in the same manner as stationary manufacturing locations. This registration is to be completed regardless of whether the manufactured medicated feeds are shipped interstate, and is required before FDA will approve a MFML. Manufacturers that are exempt from having to obtain a MFML are not required to register as a “drug establishment.”

Individuals mixing medicated feed for feeding only to their own animals are subject to the same regulations and requirements as commercial medicated feed manufacturers.

Also falling under the requirements are toll and franchise manufacturers that produce medicated feeds. However, the manufacture of medicated feeds solely for use in research or teaching is exempt from drug establishment registration (see 21 CFR 207 for complete exemption details).

When and How to Register as a Drug Establishment

With the Food & Drug Administration Amendments Act of 2007 (FDAAA), as of June 1, 2009, drug establishment registration with historic Form FDA-2656 was discontinued. Electronic submission is now required unless a waiver is granted.

Drug establishment registration is based upon the calendar year. Re-registration is required annually, and is to take place during the last calendar quarter of the year. For further information, see 21 CFR 207.20 and 207.21, and section 510(b) and (i) of the Federal Food, Drug, and Cosmetic Act.

Procedures for drug establishment registration are listed on FDA’s website at www.fda.gov/Drugs/GuidanceComplianceRegulatoryInformation/DrugRegistrationandListing/ucm078801.htm.

For questions on the electronic registration and requirements, send an inquiry to [email protected]. For questions about the status of a submission, contact the SPL Coordinator at [email protected].

Medicated Feed Mill License Approval Requirements

In accordance with the FDA approval process, a medicated feed manufacturer that holds a MFML certifies that:

• Animal feeds bearing or containing new animal drugs are manufactured and labeled in accordance with the applicable regulations published pursuant to section 512(i) of the Federal Food, Drug, and Cosmetic Act, or in accordance with the index listing published under section 572(e)(2) of the Act.

• The methods used in, and the facilities and controls used for, manufacturing, processing, packaging and holding animal feeds are in conformity with good manufacturing practice described in section 501(a)(2)(B) of the Act and 21 CFR 225.

• The facility will establish and maintain all records required by regulation or order issued under section 512(m)(5)(A) and 504(a)(3)(A) of the Act, and will permit access to or copying or verification of such records by FDA.

In addition, a medicated feed manufacturer holding an approved MFML commits to:

• Possessing current approved or index listed Type B and/or Type C medicated feed labeling for each Type B and/or Type C medicated feed to be manufactured prior to receiving the Type A Medicated Article containing such drug.

• Renewing registration each year with FDA as required by 21 CFR 207.

• Using only non-drug feed components recognized in the Official Publication of the Association of American Feed Control Officials (AAFCO) or sanctioned by FDA under 21 CFR 573, 582 and 584 as suitable for use in animal feeds.

• Supplementing its license application promptly when changes in ownership or address occur.

• Complying with all other applicable provisions of the Act.

Information Resources

Listed below are several information resources available to assist medicated feed manufacturers determine whether a particular animal drug has been approved by FDA for use in animal feeds, as well as approved indications for use, use levels and limitations in animal feed.

• The Feed Additive Compendium arguably is the most widely used summary of information available on animal drug approval requirements, permitted animal drug uses, animal drug use levels in feed, permitted animal drug combinations in feed and labeling information. Within the FDA status section for each drug and drug combination, the Feed Additive Compendium also indicates whether the use requires a MFML. Although not an official regulatory publication, every attempt is made to ensure that the Feed Additive Compendium is complete and accurate. Regular supplements containing new and changed information are provided to subscribers.

• Animal Drug Suppliers provide information on the animal drugs they market. Many animal drug suppliers provide packets containing information necessary for approvals, including forms and instructions.

• The Federal Register lists proposed changes in regulations under the Federal Food, Drug, and Cosmetic Act, proposed new clearances for the use of animal drugs, proposed tolerances for tissue residues and the final regulations permitting drug use. The Federal Register is published Monday through Friday (except on official federal holidays). It is available online at www.federalregister.gov.

• The Code of Federal Regulations (CFR) is the official reference for animal drug approval requirements, permitted uses, use levels, as well as labeling information, and is a compilation of all final rules published in the Federal Register. Title 21 CFR Part 558 contains the regulation for each animal drug approved for use in animal feeds. The CFR is published yearly, and an electronic version is available online at http://www.ecfr.gov/cgi-bin/ECFR?page=browse.

• Blue Bird Labels. For feeds produced under an approved MFML, manufacturers are to have currently approved or index listed Type B and/or Type C medicated feed labeling (Blue Bird Labels) for each Type B or Type C medicated feed to be manufactured prior to receiving the Type A medicated article containing such drug (within a multi-location company, the Blue Bird Labels may be maintained at the corporate office). The required labels may be obtained from the distributor or drug manufacturer. In addition, FDA has made available a listing of some labels (the listing is not comprehensive) on line at www.fda.gov/AnimalVeterinary/Products/AnimalFoodFeeds/MedicatedFeed/BlueBirdLabels/default.htm

Requirements for Manufacturers Not Holding a MFML

Feed manufacturers not required to obtain a MFML are responsible to ensure that medicated feed is produced and distributed in accordance with the provisions of FDA’s approval for the animal drug in that particular medicated feed. Facilities manufacturing medicated feed not requiring a MFML are required to follow cGMPs specified within 21 CFR 225.120 through 225.202. As such, manufacturers are to ensure that the medicated feed is properly labeled and meets its label declaration (see labeling article in this Feed Additive Compendium for more details on labeling). The medicated feed also is to comply with the appropriate state feed laws where distributed.

While facilities exempt from MFMLs are not subject to routine FDA inspections, state feed control officials and/or FDA inspectors may inspect these facilities to ensure compliance with relevant cGMPs and to investigate reported residue violations.

MFML Requirements

(How to obtain approval of a MFML)

Facilities are to apply for and receive an approved MFML prior to the purchase and use of a Category II Type A medicated article. In addition, as previously noted, facilities are to have an approved MFML when producing liquid and/or free choice medicated feeds with: (1) Category II, Type B drugs; or (2) Category I drugs and a proprietary formula and/or specifications. FDA requires only one MFML for each facility, regardless of the number of Category II, Type A medicated articles used or medicated liquid and/or free choice feeds manufactured.

Prior to shipment of a Category II, Type A medicated article, the seller must have a written statement from the buyer that the buyer has an approved medicated feed mill license and possesses current approved Type B and/or Type C feed labeling for the drug (Blue Bird Labels), unless FDA has exempted by regulation manufacturers of animal feed bearing or containing such drug from the requirements to hold a license. FDA’s Center for Veterinary Medicine (CVM) has a listing of the approved MFML firms and facilities on its website at www.fda.gov/downloads/AnimalVeterinary/Products/AnimalFoodFeeds/MedicatedFeed/UCM089532.pdf. Listing on CVM’s website is sufficient to meet these requirements.

To receive an approved MFML, facilities must first pass a medicated feed mill inspection that determines compliance with requirements established in 21 CFR 225.10 through 225.115. (See article on feed mill inspections in this Feed Additive Compendium.) In addition, the facility must have applied for and obtained a Drug Establishment Registration (see Drug Establishment Registration requirements section of this article).

Following approval of the facility’s MFML, Category II, Type A medicated articles may be purchased and mixed into animal feed only in accordance with the terms of the MFML application.

Completion of a MFML Application (Form FDA-3448)

The following guidelines apply to completing Form FDA-3448:

1. Provide the name and address of the manufacturing location, as well as the telephone and fax numbers for the facility.

2. If you are a multi-facility firm, provide the firm’s home office address and contact phone and fax numbers within the “Mailing Address/Phone Numbers” section.

3. Check the type of application. This generally will be an original submission.

4. Provide the drug establishment registration number that has been assigned to the manufacturing facility or indicate that application for this number has been submitted.

5. Provide the name and title of the person responsible for the firm. This may be one person for multi-facility manufacturers.

6. Provide the signature of the person responsible for the firm (signature is to be provided by the same person as identified in 5 above).

7. Provide the date of signature.

Form FDA-3448 may be obtained from FDA’s website at www.fda.gov/downloads/AboutFDA/ReportsManualsForms/Forms/UCM052278.pdf.

Facilities are to mail completed MFML applications to:

Division of Animal Feeds (HFV-220)

Center for Veterinary Medicine

Food & Drug Administration

7519 Standish Place

Rockville, Md. 20855

FDA Review of MFML Application

By regulation, FDA is to within 90 days from receipt of a MFML application review and reply to the application. If the facility’s application is incomplete or inaccurate, its application may be rejected. The 90-day review period will start over again upon resubmission of an application that was previously rejected. Given these timeframes, a facility’s application should be made well in advance of the date the facility desires to manufacture medicated feed requiring a MFML.

Once an application has been approved, FDA will send the facility a copy of the signed approval. The facility may then register its medicated feeds with appropriate state control officials and manufacture and market medicated feeds.

Free-Choice and Liquid Medicated Feed Approvals

For FDA regulatory purposes, free-choice medicated feed is medicated feed that is placed in feeding or grazing areas and is not intended to be consumed fully at a single feeding or to constitute the entire diet of the animal. Medicated blocks, free-choice minerals and lick tank supplements are examples of free-choice feeds. Such feeds are unique in comparison to dry feeds that typically are consumed by animals under more controlled and stable conditions. Given this, FDA’s approval for the use of animal drugs in such products is stringent and has specified conditions.

Once a drug sponsor has obtained FDA approval for the safety and efficacy of its animal drug in free-choice feeds, a feed manufacturer may obtain approval for use of the animal drug in free-choice feed by demonstrating consumption and/or stability of its free-choice feed formulation within the parameters of the drug sponsor’s efficacy data.

There are several options available to animal drug and animal feed sponsors for free-choice feed approvals as specified in 21 CFR 510.455, “Requirements for free-choice medicated feeds.” In addition, facilities may wish to obtain copies of FDA’s guidance:

• CVM GFI#13 Evaluation of Effectiveness of New Animal Drugs for Use in Free-Choice Feeds-Medicated Block (www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm052197.htm)

• CVM GFI#23 Medicated Free Choice Feeds — Manufacturing Control (www.fda.gov/AnimalVeterinary/GuidanceComplianceEnforcement/GuidanceforIndustry/ucm052665.htm)

FDA’s regulations in 21 CFR 558.5, “Requirements for liquid medicated feed,” detail requirements pertaining to the manufacture of medicated liquid feeds. The regulations clarify what data are required to demonstrate chemical and physical stability of a drug in liquid feed, how such data may be submitted for use in the new animal drug approval process, and which liquid medicated feeds will require an approved medicated feed mill license.

Regarding stability, certain liquid feeds are physically stable and are not required by FDA to have an agitation statement. However, in such cases, manufacturers are to provide data to FDA to demonstrate physical stability of such feeds. In addition, a manufacturer may choose to provide stability data for a drug in its liquid feeds that has not been indicated by the drug sponsor.

For more information on liquid feeds see the article “Proper Use of Additives in Liquid Feeds” within the Feed Additive Compendium. In addition, for more regulatory guidance concerning medicated free-choice feed approvals or unique liquid feed approvals, contact the Division of Production Drugs (HFV-120), Center for Veterinary Medicine, 7520 Standish Place, Rockville, Md. 20855; telephone (240) 276-8300

Call: (240) 276-8300

.

Form FDA-356v Approvals

Facilities that wish to use an animal drug in feed at a level greater than the maximum drug potency permitted in Type B feed are to obtain approval for a Type A medicated article from FDA on Form FDA-356v. To do so, facilities should contact the supplier of the drug that is intended to be used for assistance in completing the form and for the kind of information (i.e., stability, manufacturing and controls) that will be necessary to submit for FDA approval. In addition, facilities likely will need the drug sponsor’s permission to refer to the sponsor’s basic data to support the Form FDA-356v approval. Form FDA-356v approvals typically take a minimum of 180 days to complete.

CVM accepts electronic submissions for Form FDA-356v. Information on such submissions can be found at FDA’s website at www.fda.gov/AnimalVeterinary/DevelopmentApprovalProcess/ElectronicSubmissions/default.htm.

Veterinary Feed Directive

The Animal Drug Availability Act signed into law Oct. 9, 1996, created a new category of drugs called Veterinary Feed Directive (VFD) drugs. Use of a VFD drug is to be under the professional supervision of a licensed veterinarian. The VFD is a written statement issued by a licensed veterinarian in the course of the veterinarian’s professional practice that orders the use of a VFD drug in or on animal feed. This written statement authorizes the client to obtain and use the VFD drug in or on an animal feed to treat the client’s animal(s) only in accordance with the directions for use approved or indexed by FDA. A veterinarian may issue a VFD only if a valid veterinarian-client-patient relationship exists, as defined in 21 CFR 530.3(i). The VFD differs from a prescription in that the VFD only authorizes the use of the drug in accordance with its FDA approval. Two drugs have been approved by FDA for use only on the order of a licensed veterinarian. However, FDA currently has proposed revisions to the VFD process to facilitate its expanded use in the future for additional animal drugs that are medically important in human medicine as means to potentially minimize the occurrence of antimicrobial resistance.

For more information, see the article “Use of Veterinary Feed Directive Drugs in Feeds” in this Feed Additive Compendium.

Drug Listing

Drug listing requirements are applicable to animal drug products including Type A drug sources, but are not applicable to medicated feeds (Type B or Type C feeds). See 21 CFR 207 for more information.

Animal Drug User Fee Act (ADUFA)

The Animal Drug User Fee Act of 2003 (ADUFA) amended the Federal Food, Drug, and Cosmetic Act and authorized FDA to collect fees for certain animal drug applications, and for the establishments, products and sponsors associated with these and previously approved animal drug applications, in support of the review of animal drugs. These additional resources support FDA’s responsibilities under the Act to ensure that new animal drug products are safe and effective for animals as well as for the public with respect to animals intended for food consumption.

In response, FDA has published the rates for product, establishment and sponsor fees and payment procedures for those fees online at www.fda.gov/forindustry/userfees/animaldruguserfeeactadufa/default.htm. ADUFA directs FDA to waive or reduce fees in certain situations, including when the animal drug application or the supplemental animal drug application is intended solely to provide for use of the animal drug in a free-choice medicated feed.