#272 
Practices to Prevent Unsafe 
Contamination of Animal Feed from 
Drug Carryover 
Guidance for Industry 
Submit comments on this guidance at any time.  Submit electronic comments to 
https://www.regulations.gov.  Submit written comments to the Dockets Management Staff 
(HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville, MD  
20852.  All comments should be identified with docket number FDA-2022-D-0173. 
For further information regarding this document, contact AskCVM@fda.hhs.gov. 
Additional copies of this guidance document may be requested from the Policy and Regulations 
Staff (HFV-6), Center for Veterinary Medicine, Food and Drug Administration, 7500 Standish 
Place, Rockville MD 20855, and may be viewed on the Internet at https://www.fda.gov/animal-
veterinary, https://www.fda.gov/regulatory-information/search-fda-guidance-documents, or 
https://www.regulations.gov. 
U.S. Department of Health and Human Services 
Food and Drug Administration 
Center for Veterinary Medicine (CVM) 
January 2023  Contains Nonbinding Recommendations 
 
Table of Contents 
 
I.    Introduction .......................................................................................................................... 1 
II.    Background ........................................................................................................................... 1 
A. Drug carryover ................................................................................................................ 1 
B.  Additional regulations covering animal food ............................................................... 3 
III.  Practices to Prevent Unsafe Contamination from Drug Carryover to Protect      
Human and Animal Health .................................................................................................. 3 
A.  Physical Cleanout ........................................................................................................... 4 
B.  Flushing ............................................................................................................................ 5 
C.  Sequencing ....................................................................................................................... 5 
D.  Other Equally Effective Practices ................................................................................. 7 
IV.  References .............................................................................................................................. 7 
i  Contains Nonbinding Recommendations 
 
Practices to Prevent Unsafe Contamination of Animal Feed from 
Drug Carryover 
 
Guidance for Industry 
 
This guidance represents the current thinking of the Food and Drug Administration (FDA, we, or 
Agency) on this topic.  It does not establish any rights for any person and is not binding on FDA 
or the public.  You can use an alternative approach if it satisfies the requirements of the 
applicable statutes and regulations.  To discuss an alternative approach, contact the FDA staff 
responsible for this guidance as listed on the title page. 
 
I.  Introduction 
 
This guidance describes practices available to medicated feed manufacturers to prevent unsafe 
contamination from drug carryover into a non-medicated animal feed or a different medicated 
feed.  This guidance replaces Compliance Policy Guides Sec. 680.500 Unsafe Contamination of 
Animal Feed from Drug Carryover and 680.600 Sequencing as a Means to Prevent Unsafe Drug 
Contamination in the Production, Storage, and Distribution of Feeds, and includes updates and 
additional information.  For purposes of this guidance:   
  you refers to those involved in the manufacturing and distribution of medicated feed.  
  manufacturing and distribution of medicated feed refers to using equipment to 
manufacture, process, pack, hold, and distribute medicated feed, including, for example, 
storing, mixing, and conveying.   
  animal feed or feed refers to animal food produced by medicated feed manufacturers.  
Such animal food may be referred to in this guidance as medicated feed, or non-
medicated feed, depending on whether it is formulated to contain a new animal drug.  
For convenience, we refer to such new animal drugs as simply drugs.   
  drug carryover refers to the presence of a drug in a subsequent batch of animal feed.   
  unsafe contamination of an animal feed refers to a degree of contamination, by a drug 
approved for a medicated feed use, that poses an unacceptable risk to human or animal 
health.   
 
In general, FDAs guidance documents do not establish legally enforceable responsibilities. 
Instead, guidances describe the Agencys current thinking on a topic and should be viewed only 
as recommendations, unless specific regulatory or statutory requirements are cited.  The use of 
the word should in Agency guidance means that something is suggested or recommended, but 
not required. 
 
II.  Background  
 
A. Drug carryover 
 
1  Contains Nonbinding Recommendations 
 
Drug carryover generally occurs when a drug used in the manufacture of a batch of medicated 
feed, for which the drug is approved, gets inadvertently included in a subsequent batch of: (1) a 
non-medicated feed, (2) a different medicated feed for which the drug is not approved (e.g., 
medicated feed for another species), or (3) a medicated feed that contains the same drug that can 
result in a higher drug level than is stated on the labeling.  Drug carryover can occur for various 
reasons, including, for example, the use of the same equipment to manufacture both medicated 
and non-medicated feed; the design, construction, or inadequate maintenance of feed 
manufacturing equipment; poor dust control in a feed mill; inadequate cleanout practices for 
manufacturing and distribution equipment between sequential batches of animal feed; or human 
error (Refs. 1 and 2).   
 
Ideally, carryover of a drug from one batch to another should always be completely avoided.  
However, factors such as the use of shared equipment to manufacture various medicated and 
non-medicated feeds, and the design and performance of such equipment used for animal feed 
manufacturing may not allow for an absolute avoidance of all batch-to-batch drug carryover.   
 
The current good manufacturing practice (CGMP) regulation for medicated feeds, found in 21 
CFR part 225, contains requirements for the manufacturing, processing, packing, and holding of 
medicated feed.  Some facilities, such as feed mills, are required to have a medicated feed mill 
license to manufacture certain medicated feeds (see 21 CFR 510.455(f), 21 CFR 558.4, and 21 
CFR 558.5(g)).  Section 21 CFR 225.1 applies to all medicated feed mills.  Sections 21 CFR 
225.10 through 225.115 apply to facilities that are required to hold an approved medicated feed 
mill license.  Sections 21 CFR 225.120 through 225.202 apply to facilities that are not required 
to hold a license.  
 
The CGMP regulation for medicated feeds requires that adequate procedures be established and 
used for all equipment used in the manufacture and distribution of medicated feed to avoid 
unsafe contamination of medicated and non-medicated feeds with drugs (see 21 CFR 225.65 and 
225.165).  Therefore, you should focus on preventing unsafe contamination of medicated and 
non-medicated feeds by minimizing or, if possible, avoiding drug carryover altogether.   
 
Failure of a facility to comply with the requirements of the CGMP regulation for medicated 
feeds (21 CFR part 225), including failure to establish and follow adequate procedures for 
cleanout of equipment to avoid unsafe contamination of animal feed, causes medicated feed 
manufactured, processed, packed, or held at the facility to be adulterated under section 
501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act).  In addition, if the 
medicated feed you manufacture contains a drug that is not approved for use in that animal feed, 
the animal feed containing the drug may be considered unsafe within the meaning of section 
512(a)(2) of the FD&C Act and adulterated under section 501(a)(6) of the FD&C Act.   
 
When drug carryover from the manufacturing, processing, packing, or holding of medicated feed 
results in drug contamination of non-medicated feed, the contaminated animal feed is considered 
adulterated under section 402(a)(2)(C)(ii) of the FD&C Act. 
 
For animal drugs used in food-producing animals, FDA establishes a tolerance for the drug 
residue in human food as part of the animal drug approval process (see 21 CFR 514.1(b)(7) and 
2  Contains Nonbinding Recommendations 
 
part 556).  Drug residues detected in excess of an established drug tolerance in food derived from 
food-producing animals (e.g., edible animal tissues such as meat, milk, honey, or eggs), or any 
residues detected from a drug not approved for use in a food-producing animal, would result in 
that human food being adulterated under section 402(a)(2)(C)(ii) of the FD&C Act.   
 
B.  Additional regulations covering animal food 
 
Additional regulations that may be applicable to your operations contain requirements intended 
to help ensure the safety of animal food.   
 
The Current Good Manufacturing Practice, Hazard Analysis, and Risk-Based Preventive 
Controls for Food for Animals regulation, found in 21 CFR part 507, establishes requirements 
for baseline safety and sanitation standards (CGMPs) and hazard analysis and risk-based 
preventive controls for the manufacturing, processing, packing, and holding of animal food 
(which includes pet food, animal feed, and raw materials and ingredients).  For guidance on 
CGMP requirements in 21 CFR part 507, see our Guidance for Industry (GFI) #235, Current 
Good Manufacturing Practice Requirements for Food for Animals.1  For our current thinking on 
the hazard analysis and risk-based preventive controls requirements in 21 CFR part 507, see our 
GFI #245, Hazard Analysis and Risk-Based Preventive Controls for Food for Animals.2  If you 
are subject to 21 CFR part 507, subparts A, C, D, E, and F (the animal food preventive controls 
requirements), and you have identified drug carryover as a hazard requiring a preventive control, 
you must follow the preventive control requirements in part 507.  Compliance with the relevant 
requirements of part 507 is used to determine whether your facilitys animal food is adulterated 
within the meaning of sections 402(a)(3) and (4) of the FD&C Act (see 21 CFR 507.1(a)).   
 
The Sanitary Transportation of Human and Animal Food regulation is found in 21 CFR part 1, 
subpart O.  In general, persons involved in the transportation of animal food, including 
medicated feed, must comply with the requirements as applicable.  For information on this 
regulation, see our Small Entity Compliance Guide, Sanitary Transportation of Human and 
Animal Food: What You Need to Know About the FDA Regulation.3  
 
III.  Practices to Prevent Unsafe Contamination from Drug Carryover to Protect Human 
and Animal Health  
 
If you manufacture medicated feed for which an approved medicated feed mill license is 
required, you must ensure that all equipment that comes in contact with the active drug 
component, feeds in process, or finished medicated feed is subject to all reasonable and effective 
procedures to prevent unsafe contamination of manufactured feed (see 21 CFR 225.65(b)).   
 
If you manufacture medicated feed for which an approved medicated feed mill license is not 
required, you must establish and use adequate procedures for all equipment used in the 
 
1 https://www.fda.gov/media/97464/download  
2 https://www.fda.gov/media/110477/download  
3 https://www.fda.gov/media/108944/download  
3  Contains Nonbinding Recommendations 
 
production and distribution of medicated feed to avoid unsafe contamination of medicated and 
non-medicated feeds (see 21 CFR 225.165).   
 
If you manufacture medicated animal feed and you are subject to 21 CFR part 507, then the 
discussion below may suggest practices to use in your implementation of certain requirements of 
part 507.   
 
Some factors you should consider when developing your practices to prevent unsafe 
contamination from drug carryover include:   
  risks to human and/or animal health  
  types of animal feed you manufacture (e.g., medicated, requiring a license) 
  animal species 
  production stages of the animals  
  the drugs being used and their levels  
  equipment used in your facility 
 
As with all practices used to prevent unsafe contamination from drug carryover in animal feed, 
your cleanout practices should be designed to protect the health of the animals consuming the 
animal feed and, in the case of food-producing animals, protect human health.  There are known 
health risks to animals from unsafe contamination of animal feed from drug carryover that you 
also should consider when developing your practices.  Human health may be at risk if humans 
consume a product derived from animals that have consumed animal feed contaminated from 
drug carryover.  To protect human health, it is important to minimize the potential exposure of 
food-producing animals (e.g., animals near slaughter, lactating dairy animals, and laying hens) to 
unsafe contamination from drug carryover.   
 
Since every animal feed manufacturing system is unique, the steps you take to establish adequate 
practices to prevent unsafe contamination from drug carryover for your operations may be 
different from those appropriate for other facilities.  You should ensure that all personnel 
involved in animal feed scheduling and production understand the practices you establish for 
your operations.  You should have a plan for reevaluating your practices periodically to ensure 
that unsafe contamination from drug carryover does not occur.   
 
The most commonly used practices are described below.  Many animal feed manufacturers use a 
combination of these methods to suit the requirements of their manufacturing systems, 
production schedules, and distribution equipment to prevent unsafe contamination from drug 
carryover and thus protect human and animal health. 
 
A.  Physical Cleanout 
 
Physical cleanout of manufacturing and distribution equipment used to mix and handle animal 
feed is a practice that may include dry-type cleaning (e.g., vacuuming, sweeping, or scraping 
equipment used to make dry feed), or wet-type cleaning (e.g., washing equipment used to make 
4  Contains Nonbinding Recommendations 
 
liquid feed).  Physical cleanout often can be effectively used on a single piece of equipment 
when physical cleanout of the entire system is impractical or may not be necessary to ensure 
animal feed safety.  You should evaluate the entire production line when determining the pieces 
of equipment on which to perform physical cleanout.  Physical cleanout is an important practice 
used to prevent unsafe contamination from drug carryover.   
 
B.  Flushing  
 
Flushing is a practice that uses a predetermined volume of a non-medicated feed ingredient to 
help clean out residual drugs from the manufacturing line following a batch or lot of medicated 
feed to prevent unsafe contamination of subsequent batches of animal feed.  The type and 
quantity of flush material and the frequency of flushing will vary depending on the facility, the 
types of medicated feed manufactured, and the capacity of the equipment based on the 
manufacturers specification.  Commonly, the amount of flush material used is 5-10% of the 
manufacturing equipment capacity.  Corn, soybean meal, and peanut hulls often are used for this 
purpose due to their abrasiveness.  If you manufacture medicated feeds for which an approved 
medicated feed mill license is required, the flush material must be properly identified, stored, and 
used in a manner to prevent unsafe contamination of other feeds (21 CFR 225.65(b)(2)).  
However, even if you are not subject to 21 CFR 225.65, we recommend you follow these 
procedures for your flush material to prevent unsafe contamination.  When properly 
implemented, flushing can be an effective cleanout practice for equipment that is difficult to 
clean physically.   
 
C.  Sequencing  
 
Sequencing is a preplanned order of production, storage, and distribution of different animal 
feeds designed to direct drug carryover into subsequent feeds that will not result in unsafe 
contamination.  Sequencing should begin with knowledge of the last batch of feed produced, and 
subsequent production order as appropriate.  When the same equipment is used, the greatest 
potential for drug carryover is in the first batch of animal feed manufactured following the 
manufacture of a batch of medicated feed.  Therefore, sequencing helps ensure that any 
carryover into the next batch of animal feed you make after a medicated feed does not result in 
unsafe contamination.  For sequencing to be effective, sequencing practices should be carefully 
planned and executed.  Whenever sequencing is interrupted or not followed through as planned, 
cleanout practices, such as those described in sections III.A. Physical Cleanout and III.B. 
Flushing, should be considered.   
 
The following list provides factors you should consider when designing your sequencing practice 
to prevent unsafe contamination from drug carryover and to protect human and animal health.  
You should consider your specific manufacturing system when designing a sequencing practice.  
This is not an all-inclusive list.   
 
  Animal feed for animals near slaughter, lactating dairy animals, or laying hens should not 
be manufactured and handled on the same equipment immediately following the 
manufacture of medicated feeds containing drugs requiring a withdrawal period or drugs 
not approved for use in those species and production classes, unless adequate cleanout 
5  Contains Nonbinding Recommendations 
 
practices are implemented.   
 
  Animal feed that cannot contain a drug requiring a withdrawal period (e.g., feed intended 
for animals near slaughter, lactating dairy animals, or laying hens) should be 
manufactured first in the sequence.  Medicated feed with the highest potential to cause 
unsafe contamination from drug carryover should be manufactured last in the sequence, 
followed by adequate cleanout of the system before restarting the 
manufacturing/processing/sequencing cycle.   
 
  Manufacture of medicated feed containing drugs requiring withdrawal, such as Category 
II4 drugs, may be followed by manufacture of animal feed intended for growing animals 
of the same species because such growing animals are far enough from slaughter that 
carryover drugs should be cleared from their tissues by the time of slaughter.   
 
  Medicated feed containing drugs that could cause an unsafe residue in an animals edible 
tissues if consumed by finishing animals should be manufactured after other animal feed.  
For example, non-medicated swine finishing feed should be manufactured before a 
medicated feed.   
 
  When you are manufacturing multiple lots of medicated feed containing the same drug, 
the sequence should be scheduled to produce the feed containing the highest 
concentration of the drug first and feed containing the lowest concentration of the drug 
last.  The feed with the lowest concentration of the drug in the sequence could then be 
followed by a non-medicated feed for the same species or a medicated feed containing 
that same drug for another species.   
 
  Horses are particularly sensitive to ionophore drugs (e.g., monensin or lasalocid); 
ingestion of these drugs may result in severe or fatal effects in horses (Ref. 3).  Horse 
feed should not be manufactured immediately after production of medicated feed 
containing an ionophore drug.   
 
  Swine are sensitive to the interaction of the drug tiamulin with a polyether ionophore 
drug (e.g., narasin); the interaction could result in ionophore toxicity in swine (Ref. 4).  
To avoid this interaction, you should manufacture other animal feeds in between the 
manufacture of a feed containing a polyether ionophore and a swine feed containing 
tiamulin, or conduct a physical cleanout.   
 
  Pre-ruminating calves are sensitive to salinomycin; ingestion of this drug may result in 
severe or fatal effects in pre-ruminating calves (Ref. 5).  Pre-ruminating calf feed (e.g., 
 
4 Drugs approved for use in animal feed are placed into one of two categories: Category I or Category II.  Category I 
drugs require no withdrawal period at the lowest use level in each major species for which they are approved (or are 
approved for use only in minor species).  Category II drugs require a withdrawal period at their lowest approved use 
level for at least one major species, or are regulated on a no-residue basis or with a zero tolerance (21 CFR 
558.3(b)).   
6  Contains Nonbinding Recommendations 
 
milk replacer) should not be manufactured immediately after production of medicated 
feed containing salinomycin.   
 
D.  Other Equally Effective Practices  
 
You may use alternative, equally effective practices to prevent unsafe contamination of animal 
feed from drug carryover other than those discussed in this guidance.  We encourage you to 
contact the Center for Veterinary Medicine (CVM), Division of Food Compliance at 
AskCVM@fda.hhs.gov to discuss alternatives to the practices presented in this guidance that you 
would like to use.   
 
IV.  References  
 
1.  Food and Drug Administration. 2018. Warning Letter, Gilman Cooperative Creamery 
Association, October 10, 2018. Accessed Sept. 30, 2022. https://www.fda.gov/inspections-
compliance-enforcement-and-criminal-investigations/warning-letters/gilman-cooperative-
creamery-association-563944-10052018. 
 
2.  Food and Drug Administration. 2017. Warning Letter, Burkmann Industries Inc., August 29, 
2017. Accessed Sept. 30, 2022. https://www.fda.gov/inspections-compliance-enforcement-
and-criminal-investigations/warning-letters/burkmann-industries-inc-533330-08292017. 
 
3.  Matsuoka, T., et.al. 1996. Review of Monensin in Horses. Journal of Equine Veterinary 
Science. Volume 16, Number 1:  8-15. 
 
4.  Carpenter, Jane A., et. al. 2005. Tiamulin and narasin toxicosis in nursery pigs. Journal of 
Swine Health and Production. Volume 13, Number 6: 333-336. Accessed Sept. 30, 2022. 
https://www.aasv.org/shap/issues/v13n6/v13n6p333.pdf. 
 
5.  Huyben, M.W.C., et.al. 2001. Salinomycin poisoning in veal valves. The Veterinary 
Record. August 11. 2001:  183-184. 
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