Cross-contamination of medicated animal feeds
While testing to validate and then verify the effectiveness of “cross contamination” controls does require some effort, there are benefits to doing so.
By David Eisenberg, MicroTracers
Concern with Cross-Contamination of Medicated feeds has existed since the early 1970’s or earlier when the USDA found residues of DES (Diethylstilbestrol) and furazolidone drugs in beef and pork respectively. USDA in cooperation with the FDA traced this to residues of these drugs in the finisher feeds for the intended species.
In 1976, the FDA requested the American Feed Manufacturers-AFMA) now the American Feed Industry Association (AFIA) to propose “cross contamination” limits in feeds but AFIA never did so and the matter and the matter was quiet in the USA until 1986 when Japan found sulfamethazine in USA pork at limits above the limits set by USDA of 0.1ppm. Japan condemned these shipments and the price of pork in the USA sunk 10%. The National Pork Producers Association (NPPC) advised its 100,000 members not to use sulfamethazine and sales of that drug in ASP-250 plummeted, as did the incidence of violative drug residues in pork..
The problem of “cross contamination” of medicated feeds was supposedly the basis for the FDA’s 2nd Generation medicated feeds regulations enacted in 1986 and still the law of the land.
2nd Generation turned over the regulation of 80% of the commercial feed mills in the USA (10,000 total) to the States with FDA only regulating the larger feed mills. The criteria for deciding if a feedmill needed to be registered with FDA was whether they used Type A concentrated animal drug products added to feeds at 5-lbs or less per 2,000-lbs. Feed mills using Type B medicated articles added to feeds at 25-lb.s or 50-lbs per ton would be regulated by the States and only subject to FDA inspection if the USDA traced a violative drug residue in animal tissue residue to the feedmill. There was no scientific evidence the concentration of drug products had any impact on drug residues in meat, poultry or fish and 2nd Generation was opposed by the National Broiler Council and National Cattlemen’s Beef Association and others.
In 1990, the FDA proposed that feed mills still registered with it test for completeness of feed mixing but the AFIA objected arguing that legally it was the obligation of the FDA to prove a feed mill was making dangerous feeds not the obligation of the feed mill to prove it was making safe feeds. The FDA wrote that it disagreed but then quietly withdrew the requirement.
Thirty-four years have past and in the USA anyway there have seemingly not been any problems.
The FDA issued Guidance Document #252 on “Practices to Control Cross-Contamination of Feed””, January 2023 but this document included no advice on how to test to validate effectiveness of “cross contamination” controls.Control of “cross contamination”
A major reason is that low level “cross contamination” of drugs fed at therapeutic levels may lead to bacterial resistance to the drug and then in time to other animal drugs and then in time to drugs used for treatment of humans. Proof of this is very limited.
Another issue of concern in the EU is that drugs that are permitted at high levels for therapeutic use can due to “cross contamination” appear in feeds at “growth promotant” use levels in violation of EU regulations- providing a competitive advantage to feed mills that purposefully want “cross contamination”.
Probably the most important issue is that if finisher feed for an intended species contains drugs with mandatory withdrawal times based on extensive scientific investigation, such feeds will lead to drug residues in meat, poultry and fish above acceptable/safe levels with the potential to be unsafe to humans consuming meat, poultry and fish.
What levels of “cross contamination” of medicated feeds are considered acceptable?
The USA has set no standards but they will likely come..
In 2009, the EU set standards for coccidiostats and homeostasis at 3% of the formulated level of the drug into any feed where the drug was not intended and at not more than 1% into any finisher feed for the intended species or any milk or egg feed. In 2023, it set a standard for 24 feed antibiotics at a maximum of 1% into any feed where the drug was not intended.
Brazil in May 2023 set a standard of note more than 2.5% of the formulated drug into any feed where the drug was not intended.
Brazil included regulations on “cross contamination” of medicated feeds including requirement XXX11- “validation of the production sequencing plan…” and XXXIV- “validation of the line cleaning procedures…with view to removing residues of the active ingredient and reducing contamination to acceptable levels”. And V- “monitoring can be done by direct analysis of the active ingredient or other indicators, as long as there is a correlation with the results of the concentration of the active ingredient obtained in the validation study”.
In 2023, Japan issued similar regulations on the matter and regulations are developing in other major feed manufacturing markets.
The EU has left the details of testing to each member country. The Netherlands (TNO leading to GMP+), France (Tecaliman feed research institute) and Germany (IFF and Micro-Tracers Services Europe GmbH ) have published detailed methodology for sampling, analyzing and interpreting “cross contamination” testing that are used in other EU countries and around the world..
In developing their testing protocols, each country first focused on analyzing for animal drug active ingredients but all concluded such testing is expensive and/or of limited value.
In many cases assays for drugs added to feeds that are accurate and reliable at formulated levels in a complex formula feed but are not adequate at trace levels of 1% to 3% of the formulated levels. Advanced analytical procedures using HPLCMSMS and other instruments have been able to quantify “cross contamination” in complex formula feeds for nearly all animal drugs at low levels but at substantial cost per analysis and with time delays in obtaining results.
Another problem is that using one drug as an indicator for others may have limited value. Drug products behave differently from one another. The FDA determined in the 1980’s that powdered sulfa drugs “carried over” more than granulated products, and as a result mandated that all sulfa drugs added to feeds be graduated. This has been studied and provided by Tecalimn as well.
As a result of these problems, the U countries now rely largely on using indirect “tracers” to validate and verify feedmill “cross contamination controls”.
In the Netherlands, for many years under GMP+ Test Methods, cobalt and manganese have been used to determine “cross contamination” as have Microtracers ® F, FS and FSS (colored uniformly sized iron and stainless steel particles).
In France, Tecaliman- the French feed research institute at Nantes after extensive studies of many “tracers” settled on using Microtracer RF-Blue-Lake (iron powder and water insoluble FD&C Blue #1 “lake” food color).
In Germany, Micro-Tracers Services Europe GmbH (MTSE) developed the use of Microtracer FSS-Red#40- particle count 500,000/gram) now used in Germany, Benelux, Scandinavia and other markets.
Performing a “cross-contamination” validation study with Microtracers F (colored uniformly sized iron particles, 25,000/gram)..
One must consider:
#1. Addition of the tracer to the feed (typically at 50 grams, 2,000-lbs of feed mixed into diluent and added at the same time and location as “hand add” feed products..
#2. Sampling the feed (typically a minimum of four spaced “grab” samples each weighing .a minimum of 100 grams from the batch the tracer is added to and a minimum of four spaced ‘“grab” samples each weighing a minimum of 1,000 grams from “fushes” and following batches of feed. Generally, the “flushes” and following batches should take the identical route through the feedmill so results will evidence a “worst case” scenario.
#3. Analyzing the feed (using a Rotary Detector laboratory magnetic separator, 10+ analyses possible per hour..75 gram subsamples of the batch of feed where the tracer was added to yield an expected count of 103 particles/colored spots, 750 gram subsamples of the “flushes” and following batches so a count of 103 will evidence approximately 10% cross contamination, a count of 10 about 1% cross-contamination.
If no control procedures such as cleaning, flushing or sequencing are employed- “cross contamination” of mash feeds will average 2-3% of the formulated level of the drug with 5% for pelleted feeds being typical at truck loading of bulk poultry feeds..
If feed follows the identical route through the feedmill, cross contamination” will typically be 0.3% for samples taken from the mixer, 1.5% for samples taken from a surge bin after the mixer, 2.5% for samples taken from a screw conveyer exiting the surge bin, 5% from sample taken at the top of a bucket elevator and 6% for samples of the pellets- after the pellet mill and at truck loading.
These percentages are based on taking four samples from each batch of feed and may overstate the actual levels.
“Cross contamination” will be highest in the first sample of a following batch of feed, then far lower for middle samples, then higher for the last sample.
Tecaliman (France) found plastic bucket elevator systems to be a major source for cross-contamination.
Researchers in Thailand found “flushes” should be a minimum of 10% of the volume of each batch of feed.
While testing to validate and then verify the effectiveness of “cross contamination” controls does require some effort, and then the cost to modify manufacturing procedures of facilities may be significant, even these costs are trivial when compared with alternatives of building a separate feedmill to manufacture poultry breeder feed to keep them separated from other feeds or not using animal drugs.