Tag: FDA

Why Recalls Happen: A Sunshine Mills, Inc. Case Study, Part 1 (Aflatoxins)

Sunshine Mills, Inc. (Sunshine) is a manufacturer of pet foods and pet treats, with headquarters in Red Bay, Alabama, and production facilities in six states.

What happened?

On April 3, 2020, Sunshine’s Tupelo, Mississippi, facility sampled, tested AND ACCEPTED a bulk load of yellow corn that exceeded the company’s rejection level for aflatoxin.

The aflatoxin-contaminated batch of corn was used in the manufacture of multiple pet foods between April 3rd and April 5th.

On August 17, 2020, the Louisiana Department of Agriculture and Forestry detected aflatoxin in a sample of Family Pet brand dog food manufactured by Sunshine on April 5th. The aflatoxin level that Louisiana found was 82.4 parts per billion (ppb)—more than four times FDA’s action level of 20 ppb.

On September 2, 2020, Sunshine recalled three products due to the presence of aflatoxin “potentially above the acceptable limit.”

On September 8, 2020, the US Food and Drug Administration (FDA) initiated an inspection of Sunshine’s Tupelo facility.

One month later, on October 8, 2020, Sunshine announced an expansion of its previous recall to encompass an additional twenty-one products that were manufactured using the same batch of corn used in the manufacture of the aflatoxin-contaminated Family Pet dog food.

How did this happen?

According to the FDA inspector’s observations and the company’s formal response (both obtained in response to a Freedom of Information Act request), there were multiple failures, including:

  • The lab technician who carried out the aflatoxin test on the incoming corn did not follow Sunshine’s documented testing procedure and also incorrectly recorded the test result.
  • Sunshine never verified the performance and calibration of the mycotoxin-detection equipment used to test for aflatoxins.
  • Printouts from the mycotoxin-detection equipment were not legible, as the printer had cut off the top of the printed digits, resulting in numerous transcription errors when the data were recorded in the test result logs.
  • The company never validated its sampling method, including how large a sample should be drawn from each bulk grain shipment or how the sample should be collected to ensure that it represents the entire shipment.

What are aflatoxins?

Aflatoxins are a group of naturally occurring toxins produced during the growth of the mold, Aspergillus flavus, on certain agricultural commodities, including corn. They are carcinogens and mutagens, and also can cause liver failure in animals.

Aflatoxin contamination of pet foods resulted in pet illnesses and deaths and multiple recalls of pet foods in 1998, 2005, 2011 and 2013, according to FDA’s Compliance Policy Guide.

The FDA has established action levels for the presence of aflatoxins in human food, animal feeds and pet foods, including an action level of 20 ppb in pet foods.

Common symptoms of aflatoxin poisoning in pets are sluggishness, loss of appetite, vomiting, jaundice (yellowish tint to the eyes, gums, or skin due to liver damage), and/or diarrhea. Some pets may suffer liver damage without displaying any symptoms.

Could this have been avoided?

  • IF the lab technician had been properly trained and supervised, the contaminated bulk grain shipment would have been rejected.
  • IF the equipment had been properly calibrated and certified, the aflatoxin result would have been accurate.
  • IF the Quality Assurance Supervisor had paid attention to equipment maintenance, the printouts would have been legible.
  • IF Sunshine’s preventive controls had included aflatoxin testing for the corn-based ingredient, the problem could have been caught before the ingredient was used in production.
  • IF the bulk grain sampling and testing methods had been properly validated, a contaminated shipment would be more likely to be caught and rejected.

Was this an isolated incident?

In 2018, this same Sunshine facility was responsible for the production of a number of dog foods that contained excessive levels of vitamin D.

An inspection of the manufacturing facility revealed that the company did not have adequate procedures in place to ensure that the vitamin D ingredient it purchased from its supplier met all ingredient specifications.

Sunshine used a vitamin D ingredient that was not accompanied by a Certificate of Analysis and did not perform any lab tests of its own to verify that the ingredient was of the correct concentration.

When Sunshine was notified by one of its private-label customers of a consumer complaint reporting an ill dog, the company determined that the complaint was valid, but did not immediately notify FDA as it was required by FDA regulations.

In its formal reply to the FDA inspection observations, Sunshine blamed its vitamin supplier for the incorrect shipment, and claimed that it believed the owner of the private-label brand would make a report to FDA.

Stay tuned for Part 2 of this case study, which will examine the story behind Sunshine’s 2020 recall of Salmonella-contaminated pet food.

Note: This story is based on information retrieved from the FDA website and on documents obtained as a result of Freedom of Information Act requests.

Salmonella Outbreak Linked to Onions—a Post-mortem

Reported cases: 1,642
Hospitalizations: 246
States affected: 48
Provinces affected: 7
Infectious agent: Salmonella Newport
Probable source: Red onions produced and packed by Thomson International, Inc. of Bakersfield, CA

Two months after the US Centers for Disease Control and Prevention (CDC) and the Public Health Agency of Canada (PHAC) declared this outbreak over, its root cause remains a mystery.

The US Food and Drug Administration (FDA) has plowed through more than 2,000 samples, testing finished products, swab and environmental samples from Thomson’s packing facility, and environmental samples from the vicinity of the fields where the onions were grown.

FDA labs recovered eleven different Salmonella serotypes from the various environmental samples, according to information obtained by eFoodAlert in response to a Freedom of Information Act request.

Although Salmonella Newport was found in two samples described as soil/sediment, neither sample yielded the outbreak strain recovered from patients.

Not one of the onions tested in FDA labs were Salmonella-positive.

Not one of the swab samples obtained from inside the Thomson packing facility were Salmonella-positive.

But this is not the whole story. To understand FDA’s findings, it’s important to know more about onions.

The onion

Onions can be grown from seeds, seedlings, or sets (immature onion bulbs). The crop is ready for harvest when at least one-half of the leaves are dead.

In order to ensure an adequate storage life, the onions must be left in the field to “cure” for at least 12–24 hours. This allows the outer skin to dry. Curing is complete when the neck of the onion (the top of the bulb) is dry and tight.

After curing, the onions are “topped” above the neck to remove the leaves, after which they are ready for eating or for extended storage.

Onions are closely related to garlic and, like garlic, onions produce certain essential oils that possess anti-bacterial properties. Although Salmonella can survive on onions, these essential oils complicate the process of detecting the bacteria.

Thomson’s onion operations

Onions are onions, whether grown in a small backyard or in a large commercial field. The same principles apply. The differences are those of scale.

Thomson’s onions are grown from seeds in two different parts of California. The company uses fields both near Bakersfield, where its packing house is located, and just outside Holtville, in California’s Imperial Valley, approximately 330 miles to the south.

When the onion crop is ready for harvest, Thomson’s crews use specialized equipment to dig beneath the bulbs and cut them out of the ground. The onions are left in the field to cure.

Once the onions have cured, a crew of farm laborers works its way through the field, trimming off the tops and bottoms of the onions, culling and discarding damaged onions, and placing the trimmed onions into buckets.

Culled onions and the trimmed-off tops and bottoms are left in the field to be plowed back into the soil when it is prepared for the next crop.

The full buckets are poured into burlap bags, which are left in the field for additional curing.

Once curing is complete, the onions are either shipped in bulk directly to customers or are transported to Thomson’s Bakersfield packing facility, where they are brushed clean and packed for distribution.

What FDA did not find

  • No “egregious” conditions or violations of the Produce Safety Rule
  • No direct evidence of the outbreak strain in bagged onions
  • No direct evidence of the outbreak strain in any environmental samples either at the packing facility or in and around the fields

What FDA found in Bakersfield

  • Cats in and near the onion packing lines
  • Pigeons flying or roosting inside the packing house
  • Apparent bird droppings on and near the onion packing line
  • A thick build-up of dirt and soil on the packing line even after the most recent cleaning/sanitizing activity
  • Rough, dirty weld points on the packing line
  • Inadequate documentation of cleaning/sanitizing activity
  • Swallow nests overhead within a few feet of an onion-packing line
  • Inconsistent cleaning/sanitation Standard Operating Procedures documentation
  • Inconsistent bacteriological testing of agricultural water for coliforms and E. coli.
  • Salmonella in animal scat, drain sediment, and environmental swab sample and on a water filter

What FDA found in Holtville

  • Worn and uneven areas on field packing equipment that could harbor bacteria
  • Indications of bird activity around the fields and equipment
  • Flock of birds (ibis) in field undergoing flood irrigation adjacent to field where onions had been grown
  • Salmonella, including Salmonella Newport, in several soil/sediment samples

And then there’s the water…

Information received under a Freedom of Information Act request is often heavily redacted, as anyone knows who watches The Rachel Maddow Show on MSNBC. This is what FDA’s investigation report had to say about the source of irrigation water used on the onion fields.

It would appear that irrigation water was drawn from a different source than was usual on at least one occasion. The details and date(s) on which this took place were redacted from the report, as was the diagram showing the flow of water from the source to the fields.

Why does this matter?

Irrigation water polluted by runoff from cattle feedlots has been linked to contaminated produce grown in the Salinas and Imperial Valleys in the past. A quick look at a Google map for the areas around Bakersfield and Holtville reveals the presence of feedlots in both vicinities.

The bottom line

As soon as Thomson onions were identified by CDC and FDA as the probable source of the Salmonella Newport outbreak, the company shut down its harvesting and packing operations.

By the time FDA investigators arrived on the scene, there were no field or packing activities for them to observe. The investigators were able to carry out extensive sampling of the equipment surfaces, the environment, and the stored onions, but were unable see either the harvest or packing operations in action.

Although neither FDA nor the Canadian Food Inspection Agency were able to find the outbreak strain in any of the onion samples, all of the epidemiological evidence from both the CDC and the PHAC points to Thomson’s red onions as the source of the outbreak,

The presence of multiple Salmonella-positive environmental samples lends weight to this conclusion, although the actual source of the contamination likely will never be known.

Order your copy today to learn more about produce safety

Get it fast or get it right? Covid-19 testing and the FDA*

Five months after it first issued nonbinding policy guidance on Covid-19 test authorization, the FDA still has not set specific performance parameters (limit of detection) for these tests, according to spokesperson for the agency.

Why does this matter?

When I was developing and validating new, rapid methods for finding Salmonella in a food sample, I always had to keep one question in mind.

The question had nothing to do with the speed of the test. It had nothing to do with the cost of the test.

It had everything to do with the sensitivity of the test and how its performance compared to the FDA’s “gold standard” test.

How does this relate to Covid-19 testing?

In its rush to make Covid-19 diagnostic tests available in large quantities and across the country, the FDA has resorted to an Emergency Use Authorization (EUA) policy. This means that the FDA has relied upon the developers of these tests to validate their own tests.

On May 11, 2020, the FDA issued an updated nonbinding guidance, outlining the agency’s EUA policy for diagnostic tests. In this guidance document, the agency recommended that developers of Covid-19 diagnostic tests evaluate and submit the analytical limit of detection and assess traceability of their product with any FDA-recommended reference material as a condition of the authorization.

The FDA’s Molecular Diagnostic Template for Commercial Manufacturers sets out these requirements and recommendations in greater detail, including maximum acceptable criteria for false positive (5%) and false negative (5%) results.

However, the FDA has not – nor does it plan to – set specific limit of detection criteria for Emergency Use Authorization of a Covid-19 diagnostic test.

The limit of detection is the lowest concentration of Covid-19 virus particles or virus RNA required to produce a positive test result. The lower the limit of detection, the less likely it is that a test will produce a false negative result.

What has FDA done so far?

The FDA has authorized 270 diagnostic tests for Covid-19, including 213 molecular (i.e., nucleic acid tests), 52 antibody tests and 5 antigen tests so far.

As of September 23rd, the FDA contacted developers of 165 of the authorized molecular assays, to request shipping information for the purpose of sending a Covid-19 diagnostic test reference panel. The purpose of the panel was to obtain directly comparable limit of detection data from the various tests developers.

Eighteen of the developers did not provide shipping information to the FDA and were not sent the test panel.

Forty-five of the developers either have not returned any data to the FDA or the data they returned were “not interpretable.”

Eighteen sets of data are currently “under interactive review.”

Among the tests for which data have been returned and reviewed, the limit of detection ranges from 180 units per millileter (units/ml) to 600,000 units/ml. (One milliliter is roughly equivalent to ¼ teaspoon of liquid.)

The lower the number, the more sensitive the test.

The Abbott ID NOW Covid-19 test, which purports to produce a result in 15 minutes, reported a limit of detection of 300,000 units/ml.

What does the FDA consider to be an acceptable limit of detection?

“The FDA has not yet set optimal ranges,” according to an FDA spokesperson.

When asked for additional clarification, the spokesperson replied that the limit of detection data are a relative, rather than an absolute, indication of test performance. While acknowledging that a lower limit of detection value indicates a more sensitive test, FDA has declined to set a baseline acceptable performance.

What is viral load and how does this relate to limit of detection?

Viral load is the number of virus particles in a sample from a patient, and will vary depending on the individual, the severity of symptoms, how carefully the sample was taken, and the stage of progression of the disease.

In a May 2020 issue of The Lancet, a group of researchers published viral load data from 23 Covid-19 patients in two Hong Kong hospitals. The initial viral load in respiratory tract samples for these patients was as low as ~8,100/ml and as low as ~15,000/ml in patients with severe disease.

The highest recorded viral loads were in the tens of millions/ml in both sets of patients.

No data were available for asymptomatic individuals.

Developers of thirteen of the Covid-19 diagnostic tests authorized by FDA reported a limit of detection of 180,000 units/ml, or more than ten times higher than the low end of the viral loads reported in the Hong Kong study. An additional seventeen tests reported a limit of detection of 18,000 units/ml, teetering on the brink of being unable to detect a low viral load.

If all patients and asymptomatic infected individuals carried viral loads in the tens of millions, this wouldn’t matter.

Unfortunately, that is not the case. A test that needs a high number of virus particles present in order to find the infection is more likely to produce false negative results in patients with a low viral load.

Why do false negative results matter?

  • They matter because false negative results produce a false sense of security.
  • They matter because the medical community relies on test results to trigger contact tracing and quarantine actions.
  • They matter because they affect the overall statistics on Covid-19 infections.
  • They matter because a person can test negative, have no symptoms, and still be able to infect others.

We learned of an example of this just today, when White House Press Secretary Kayleigh McEnany revealed that she had tested positive for coronavirus after having tested negative several days in a row and having interacted during that time, without a mask, with multiple individuals.

Where does Canada stand?

As of today, Canada has authorized 37 Covid-19 diagnostic tests for use, including 27 tests based on nucleic acid technology (so-called molecular tests). 

Canada has established minimum requirements for sensitivity and specificity of Covid-19 serological tests (i.e., for finding antibodies to the virus in the blood), but not for nucleic acid tests.

A nucleic acid tests developer applying for authorization in Canada must provide, in addition to other information, “the known information in relation to the quality, safety and effectiveness of the device.” 

A test is not approved unless Health Canada concludes that there is, “sufficient evidence to support the conclusion that the benefits associated with the COVID-19 medical device outweigh the risks, having regard to the uncertainties relating to the benefits and risks and the urgent public health need,” and that “the health or safety of patients, users or other persons will not be unduly affected.”

Although Canada has decided to use the FDA’s EUA as a starting point for authorizing a diagnostic test for use, Health Canada will be assessing the tests authorized in Canada in light of the data published by the FDA “to see whether the published data would indicate a need for any revisions to the labelling information,” according to a Health Canada spokesperson.

Ontario, Canada’s largest province, is using two of the approved tests on a routine basis: one from Roche and the other from Abbott, according to a spokesperson for the Ontario Ministry of Health. 

The Roche test has a lower limit of detection of 1800 units/ml and the detection limit of the Abbott test is 5400 units/ml, according to the data posted by FDA. Both of these tests should be sensitive enough to find Covid-19 carriers with relatively low virus loads, at least in theory.

What are the FDA’s plans going forward?

At the moment, the FDA has no specific plans to delist developers who have not responded to the limit of detection reference panel invitation or who responded but never returned data.

When asked whether the FDA would review its EUA decisions for the worst performing tests in the list, an agency spokesperson responded, “In the published data, a lower LoD represents a test’s ability to detect a smaller amount of viral material in a given sample, signaling a more sensitive test. However, the data does not indicate how sensitive a particular test is, and, therefore, cannot be used by itself to determine whether to authorize a test or other regulatory action. The FDA will continue to update the table as it receives additional results. The data does not indicate the clinical sensitivity of a particular test, and, therefore, cannot be used by itself to determine whether or not to authorize a test or take other regulatory action. Instead, the data gives laboratories, healthcare providers, and patients a new resource on the relative performance of tests they can use to better inform which tests they select to use.”

Is there a place for a rapid point-of-care test with a high limit of detection?

Some scientists think there is.

Writing in the New England Journal of Medicine, Dr. Michael Mina (Harvard T.H. Chan School of Public Health) and Drs. Roy Parker and Daniel Larremore (Univeristy of Colorado) have proposed shifting emphasis away from the slower, more sensitive tests to frequent use of inexpensive, less sensitive, rapid testing.

They believe that, “…the FDA, the CDC, the National Institutes of Health, and others must encourage structured evaluations of tests in the context of planned testing regimens to identify those that will provide the best Covid filters. Frequent use of cheap, simple, rapid tests will accomplish that aim, even if their analytic sensitivities are vastly inferior to those of benchmark tests. Such a regimen can help us stop Covid in its tracks.”

What’s the bottom line?

Decisions about patient care, contact tracing, quarantine and epidemiology must be based on knowledge to be effective. This includes solid information on the performance of the various tools used to make these decisions.

At the moment, the medical profession is feeling its way down a dark passage, trying to interpret the results of diagnostic tests without having in hand basic information as to the reliability of these tests.

The FDA’s survey of limit of detection performance is a first step. The next step will be for the agency, and for Health Canada, to decide which of the surveyed diagnostic tests deserve to be authorized for use.

At the very least, test developers who decline to participate in a limit of detection study, who agree to participate but does not return data, or whose data are unintelligible should not be granted continued Emergency Use Authorization for their tests.

*Content revised and updated to reflect additional information received after the article was posted.