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  4. CPG Sec. 680.600 Sequencing as a Means to Prevent Unsafe Drug Contamination in the Production, Storage, and Distribution of Feeds
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CPG Sec. 680.600 Sequencing as a Means to Prevent Unsafe Drug Contamination in the Production, Storage, and Distribution of Feeds March 1995

Docket Number:
Issued by:
Guidance Issuing Office
Center for Veterinary Medicine
Office of Regulatory Affairs


Carryover of drugs from one batch or lot to the next batch or lot of feed manufactured and handled in equipment at medicated feed mills and in bulk delivery trucks is recognized as a problem in the feed industry. Complete breakdown and thorough cleaning of manufacturing and distribution equipment following every batch of medicated feed is impractical. Drug carryover may be of little consequence if it does not constitute a hazard to the health of the consuming animals or to humans consuming the edible products of these animals. Factors to be considered in reaching such a determination include the toxicity of the drug involved, the level of the drug carryover, and species and age of animals for which the subsequent feed is intended.

CGMP regulations, 21 CFR 225, recognize these facts and direct that adequate steps be taken in the production of medicated feeds to prevent unsafe contamination of animal feeds. Unsafe contamination by animal drugs in medicated or non-medicated animal feeds is defined as that level of drug contamination in the animal feed which would result in an above tolerance residue in the edible products of the consuming animal or which is injurious to animals when the feed is fed as directed. The level of drugs in animal feeds which will constitute unsafe contamination may vary among species and ages of consuming animals. * * Each situation must be evaluated on a case-by-case basis.

Sequencing of the manufacture and handling of medicated feeds as a method of preventing unsafe contamination is listed in 21 CFR 225.65 and may be used under 21 CFR 225.165. If properly planned and executed, it may be the most practicable manner of dealing with the drug carryover problem under the current state of feed manufacturing technology. Sequencing is defined as the preplanned order of production, storage, and distribution of different animal feeds designed to direct drug carryover into subsequent feeds which will not result in unsafe contamination. The highest level of drug contamination following a medicated feed occurs in the subsequent batch of feed handled or processed in the equipment.

Therefore withdrawal and dairy cattle feeds should never be mixed immediately after production of a medicated feed containing category II drugs unless adequate measures are taken to prevent the carryover. This principle applies in other instances as well, such as the production of medicated feeds which pose special toxicity problems, e.g., monensin's toxicity to horses. Adequate measures to prevent carryover may include complete physical cleaning of the entire system. Since every system is unique, the firm should take steps to establish procedures which will be adequate for their operation to prevent unsafe contamination. The firm should have a plan for reevaluating the sequencing procedures periodically to demonstrate that unsafe contamination with drug residues is not occurring.

The following are examples of acceptable principles to consider in designing a sequencing procedure.

  1. Withdrawal and dairy cattle feeds should not be manufactured and handled in the same equipment following medicated feeds containing category II drugs, unless adequate cleaning procedures are followed. Drugs with special toxicity characteristics, such as monensin's toxicity to horses, require special attention.
  2. Medicated feeds containing category II drugs may be followed by feed intended for growing animals of the same species which are under market age or weight.
  3. Feeds containing category II drugs may be followed by non-medicated supplements or concentrates or medicated top dressing supplemental free choice type C feeds for growing animals of the same species for which the prior feed was prepared. These feeds do not constitute the sole ration, so the level of any drug contamination would be further reduced either in the final feed or through self-feeding of supplemental feed.
  4. Feeds having a high potential for unsafe drug contamination (withdrawal feeds, dairy feeds, etc.) should be manufactured first in the sequence and the feeds with the most toxic drugs manufactured last in a sequencing procedure, followed by complete physical clean-out of the system.
  5. The sequencing procedures and practices should be clearly understood by all personnel responsible for medicated feed scheduling and production. These should be readily available for their use as needed.


An appropriately designed sequencing plan is an acceptable means of preventing unsafe contamination of medicated and non-medicated feeds with drug residues. The intent of this procedure is to prevent illegal residues in the edible products from the animals consuming the contaminated feed and to prevent injury to the consuming animals. *Warning* Letters are not indicated in drug carryover contamination instances where the drug levels are not unsafe and occur as the result of an appropriate predetermined plan. *A warning letter is appropriate if there is analytical or inspectional evidence that a category II drug, in unsafe amounts, has been incorporated into the sequenced feed due to lack of clean-out and sequencing controls.*

*Material between asterisks is new or revised*

Issued: 7/1/81
Revised: 6/1/86, 3/95

Submit Comments

You can submit online or written comments on any guidance at any time (see 21 CFR 10.115(g)(5))

If unable to submit comments online, please mail written comments to:

Dockets Management
Food and Drug Administration
5630 Fishers Lane, Rm 1061
Rockville, MD 20852

All written comments should be identified with this document's docket number: FDA-2021-D-0639.


Contact Point
Center for Veterinary Medicine
Food and Drug Administration
7500 Standish Pl, HFV-1
Rockville, MD 20855
(240) 402-7002
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