FDA Warning Letters This Week 2/22/17

warning-letters

The week goes by and new letters come out. Looks like we’ve only got one food letter this week so let’s get into it.

Don’t know what warning letters are? Check out this post for a brief overview of what they are and why FDA sends them out.

WL# 17-PHI-04

CDC Public Health Image library #2287 Credit Elizabeth White (2002)
CDC Public Health Image library #2287 Credit Elizabeth White (2002)

Subject: CGMP/Food/Prepared, Packed or Held Under Insanitary Conditions/Adulterated/L. monocytogenes

Ohhhhh it’s an L. mono letter, always interesting. Already we have to pause for some background.

At the end of 2013, CDC and FDA partnered up to stop foodborne outbreaks of Listeria monocytogenes through the utilization of whole genome sequencing (WGS). This technology used to be effectively impossible 30 years ago, and prohibitively expensive and time consuming even 10 years ago.

What this means is that when L. mono is found in foods or a sick person in the hospital, they can sequence it’s entire genome to determine how closely it might be related to other L. mono cultures found in the network. The network consists of genome databases Pulsenet, GenomeTrakr, and The Listeria Initiative, which are jointly managed by CDC, FDA, and local health departments.

Once L. mono has been found and sequenced, in tandem with a traditional epidemiological investigation (interviews, additional sampling of products and environments, illness reporting), the sequence is compared to those in the database to determine if the strain that was found is “closely related” to others and see if there is a link. This is how the listeria found in the Blue Bell products/plant was traced to 10 illnesses that occurred as early in 2010, even when the listeria in the ice cream wasn’t found until 2015. Across several states and 5 years no firm link was established until WGS sequencing revealed the relationship.

There’s some debate about how transparent CDC is about determining when related isolates are causal, or to what level this data should be considered definitive in the absence of confirmed positives in products. However, FDA is going full steam ahead with using WGS as a new enforcement and Epi tool, and CDC has some good data to support the effect on outbreaks it may have had. Whether that’s because manufacturers are more careful in light of the enforcement activities or because the enforcement activities have prevented outbreaks is unclear. But no matter the end result, it’s a win for public health.

The last bit of debate is as to the extent that L. mono can be considered an adulterant. Here in the U.S. we’ve made the determination that if there is any present in the food, it’s adulterated. This is different from several other countries, including Australia/New Zealand and the UK, which allow a non-zero legal limit if L. mono is not expected to be able to grow in the product over it’s shelf life. There’s debate over that as well.

So back to the warning letter:

FDA’s laboratory analysis of fifty environmental swabs collected on September 12, 2016, confirmed that eighteen of the fifty environmental swabs were positive for L. monocytogenes. Of most importance:

Three positive environmental swabs were collected from the following direct food contact surfaces in your cheese processing room during the production of your RTE cheeses:
  • The top of the cheese slicer
  • The cheese slicer string
  • The inside of a plastic crate used to store finished cheese before packaging
–    The remaining fifteen positive environmental swabs were collected from locations adjacent to food contact surfaces and from non-direct food contact surfaces.
–    One positive sample was collected from your RTE feta cheese

They also found a positive in unpasteurized cheese during the facility visit.

This is a pretty solid connection given they found Listeria in the product itself, especially a post-pasteurization product, and that they found it on product contact surfaces where it could continuously inoculate that pasteurized product.  There are other warning letters that claim the products are adulterated when “we found it in the threshold of your entryway to the plant” that don’t always feel solid, but this one is not one of them.

On September 12, 2016, the lift arm and bowl support brackets of the mixer contained areas which appeared to be rusted and contained rough surfaces. In addition, the beater shaft housing area of the mixer, directly above the bowl support brackets, was observed to contain areas which appeared to be rusted and contain food particulates and/or foreign matter.
Food processing tools like my hand mixer have hard to clean areas that can collect food particles like cookie dough, you’ve got to check those areas every time!

Rust happens, and plants have to do regular walkthroughs and replace what needs to be replaced as it ages. But even with the best of intentions, not everything always gets replaced by the time FDA walks through. This makes it a common violation (do you have any rusty or damaged bowls or pots in your cupboard that you plan to replace soon?). But the food particulates are a good find and an indicator of a less-than-robust sanitation standard. Small, hard-to-clean areas around bolts and inside moving parts like the underside of a kitchen-aid (see picture to left) don’t get properly inspected and cleaned unless you have a dedicated program to seek these areas out.

The floors in the processing room and walk-in cooler were observed to be in disrepair, containing areas where the concrete is cracked, rough, and peeling

This one is also common, as mentioned on this site before, cracked/pitted/porous floors are a potential point where environmental pathogens like listeria and salmonella can hide from getting properly cleaned, waiting to jump back out. It’s also a common finding because refinishing or extensive repair of floors is expensive, normally planned on a long-term basis (maybe the slow season so the plant can close or when the contractor has availability), and because in other manufacturing industries it isn’t always a problem (e.g. machine shops).

We have reviewed your written responses to the Form FDA-483, received October 24, 2016, and December 7, 2016…We will ascertain the adequacy of your corrective actions during our next inspection.

Also as discussed here in the past, this is a good sign that FDA knows this company is taking the findings seriously and making real change. Otherwise they would respond with “this is inadequate” and request additional action or proof of change before closing the letter.

Greater than twenty flies landing on the floor, food processing equipment, food processing utensils, and other food contact surfaces and non-food contact surfaces…Three fly catcher tapes containing multiple flies hanging in different areas of the processing room… Dead flies on the window sills near the batch pasteurizer and three bay sink areas.

Well, they had fly catchers, so they know that flies aren’t supposed to just keep flying around, so there’s that. The manufacturer responded that they would purchase a fly zapper and new tapes, but FDA wasn’t satisfied. With pest control, you’re supposed to keep them out of the building and away from your products. So your interventions need to prevent access (find access points, block holes and unscreened windows, create breezeways and air curtains, etc.), and keep them from getting to products with interventions like ILTs.

Your maintenance of the grounds is inadequate to protect against contamination of food, as required by 21 CFR 110.20(a)… Live chickens and pigs coming within approximately one foot of the main door to the production facility and what appeared to be remnants of dead chickens and goats in close proximity to the production facility…Multiple items within approximately twenty feet of the outside perimeter to your production facility which may constitute an attractant, breeding place, and  harborage areas for pests, including, but not limited to, a chicken coop, an abandoned truck, a small four-wheeled loader, wood paneling, vegetation over six feet tall, and other small items which appear to be refuse.

Yep, sounds like a small farm/dairy. I can just picture it, can’t you? Some animals wandering, tall grass, chicken coop, and a couple old trucks and tractors getting overtaken by weeds

Outside of the animal carcasses (obvious pest and disease attractant), this is FDA throwing a little muscle at this farm to clarify that they need to treat it as a food processing facility and not as just a farm. The letter indicates that the company took action to clean up all of these items, however FDA was unsatisfied because they apparently didn’t send them pictures of the cleaned up areas nor discuss how they would keep livestock from hovering around the entrances of the food plant. FDA again noted that they would confirm the changes made were effective at the next inspection, continuing to show that that the inspection itself and initial 483 response must have gone well and the company is doing the right things post-inspection.

Sounds like this company has some work left to do, and that in this case FDA found some tangible and realistic findings of sanitation and facility problems. It helps that the findings were also supported by the L. mono data to really drive home to the company why they should be doing these things. Always nice when cause and effect tie together with GMP’s to drive positive food safety changes home.

Staphylococcus aureus diversity and subclinical mastitis

This is the first study I’ve found that was interested in cataloging bacterial diversity among subclinical (or asymptomatic) infections. While they may be less threatening to the animal’s overall health, these infections have great significance in the world of animal agriculture, where they restrict growth (or in this case, milk production), and encourage the use of medicated feeds which in turn motivate people to purchase organic products. Identifying the risk factors and causes of these infections could therefore impact both the management of food animals, and any legislation defining how and when medications can be used. With that in mind, let’s jump back into mastitis, and everyone’s favorite gram-positive, S. aureus.

It’s because of my plasmids, people can’t help but stare.
Image from http://cellimagelibrary.org/

S. aureus is one of many bacteria that cause mastitis, however it is of additional importance as it often causes chronic or recurring cases of mastitis that result in unusable milk and discomfort of the animal. In this study, the authors investigated 11 dairy farms where they expected to find S. aureus, based on previous culture findings at each farm. They defined cows that they took milk samples from as having new or chronic infections based on somatic cell counts (SCC) in the milk. If values were >200,000 cells/mL for the month of collection the infections were considered new, whereas if cell counts were  >200,000 cells/mL for more than 2 months, those infections were considered chronic. They took a single milk sample from each teat of the infected cows, for a total of 1,354 mammary glands from 350 cows.

Pulse field electrophoresis was used to identify the different subspecies/serotypes/pulsotypes (pick your word), and to identify the genes coding for enterotoxin production that had been amplified by PCR. An ELISA test was used last to detect the presence of several enterotoxins.

As the majority of exposure to enterotoxins produced my S. aureus is through milk and dairy products, subclinical infections of S. aureus are very important as a food safety control point. Unlike cows with clinical cases that are removed from production, cows with subclinical infections continue to contribute milk that makes it to the consumer, provided that the SSC is <750,000 cells/mL. The authors were unable to detect a large amount of enterotoxin in their samples, but many of the pulsotypes contained the genes coding for their production. Other studies cited by the author report the common presence of these genes in S. aureus  samples, but expression rates are inconclusive or unexplored. This means that theoretically, subclinical cows could be introducing these bacterial toxins into consumer milk in small amounts.

It’s difficult to tell how significant these amounts might be. Toxic doses of one of the enterotoxins, “Toxic Shock Syndrome Toxin 1”, has been found to be as low as 100 micrograms/Kg in miniature pigs. The concentrations that may be introduced through contaminated milk, and the bioavailability when ingested, should be explored. Takeuchi et al. (1998) were able to detect the presence of TSST- 1 in bulk milk tanks, but no one has yet to quantify the amounts of TSST- 1 potentially present in pasteurized milk.

All that being said, what good is this new information? It can be argued that because these infections are chronic and/or subclinical that these strains of S. aureus aren’t very pathogenic, but they’re still causing inflammation. By identifying common serotypes and factors leading to the subclinical infection of a herd, perhaps there are simple management changes that can prevent infection. Milking is an almost sterile procedure, with sanitation of the teats both prior and following milking, wearing gloves, and forestripping; but there could be other tricks that would target risk factors related to the spread of subclinical pathogens, especially those that are specific to a location.

 

ResearchBlogging.org

Bulanda M, Zaleska M, Mandel L, Talafantova M, Travnicek J, Kunstmann G, Mauff G, Pulverer G, & Heczko PB (1989). Toxicity of staphylococcal toxic shock syndrome toxin 1 for germ-free and conventional piglets. Reviews of infectious diseases, 11 Suppl 1 PMID: 2928643

Oliveira L, Rodrigues AC, Hulland C, & Ruegg PL (2011). Enterotoxin production, enterotoxin gene distribution, and genetic diversity of Staphylococcus aureus recovered from milk of cows with subclinical mastitis. American journal of veterinary research, 72 (10), 1361-8 PMID: 21962279

Takeuchi, S., Ishiguro, K., Ikegami, M., Kaidoh, T., & Hayakawa, Y. (1998). Production of toxic shock syndrome toxin by Staphylococcus aureus isolated from mastitic cow’s milk and farm bulk milk Veterinary Microbiology, 59 (4), 251-258 DOI: 10.1016/S0378-1135(96)01253-9

Article Review: A review of the causes of poor fertility in high milk producing dairy cows

The more I read, the more I’m extremely grateful for the rigor that my reproduction class required. None of this would have made sense to me last year, and it’s amazing how many of the details I’ve been able to keep in my conscious memory. I’m sad that I’m missing the advanced repro course offered in the fall, but hopefully the experience I’m gaining here will be just as valuable, and I can continue applying what I’ve learned so that I don’t lose the knowledge.

I was extremely impressed with this article. It felt like a lecture rather than a textbook, and as a reader it was easy to finish, but still full of great content. The focus is on how while our dairy cows have been engineered to crank out milk, we’ve seen a dramatic drop in their reproductive success which hurts the efficiency of dairy operations.

Pretty amazing what selective breeding can do. But we knew that, we managed to make dachsunds from wolves.

The article explains that rather than a minimalist approach that looks at only one factor (such as inadvertent selection for poor reproductive fitness) to correct the problem, a more inclusive or holistic approach is needed. I learned a lot more about common problems such as lameness, mastitis, metritis, and poor BCS and how they relate specifically to resumption of estrus after parturition and zygote viability. I’m always amazed how farmers can actually succeed at maintaining herd numbers when conception and birth rates are so low.

There was a lot written about heat stress, and that always seems obvious when it gets over any comfortable temperature. But heat and other environmental stressors are actually a lot more dangerous to reproductive health than I was aware. According to the article, “exposure of ovarian oocytes to unfavorable physiological events during follicle development from primadorial to pre-ovulatory stage may result in the ovulation of defective oocytes up to three months after the insult (Britt, 1992; Fair, 2010).” When you have 60-90 days to breed your cattle to stay on schedule, this is extremely influential to your breeding program. This also makes the situation down in Texas more dangerous in that, with the dry weather during their normal wet season, any excess stress surrounding parturition could delay or destroy what’s left of their breeding program. Once they can’t even breed replacement heifers, its all over.

So, after looking at multiple conditions that hurt reproductive efficiency and discussing their prevention. The article sums itself up with a nice poster identifying the key areas they covered.

(Walsh, 2011)

For the causes and preventative measures covering these you can check out the article. It finishes up by making the point that we can’t just develop a new antibiotic for metritis or mastitis, but we need to reevaluate our genetic selection and more importantly, our management strategies to ensure as many of these factors are met as possible.

Walsh SW, Williams EJ, & Evans AC (2011). A review of the causes of poor fertility in high milk producing dairy cows. Animal reproduction science, 123 (3-4), 127-38 PMID: 21255947

Reference: University of Illinois lactation biology website

In searching for information on mastitis, I came across this treasure trove of information. It was too good for me not to post here. It’s got great summaries, information, and a large collection of case studies. I almost wish the site itself was a book I could keep on the shelf, but for now I’ll just add it to my favorites. I want to recommend the page covering mastitis treatment and control for some light reading. It gives a really quick dirty rundown on industry methods and research. I was especially interested in the attempts to make vaccines, specifically ones for Staphylococcus Aureus, which can cause chronic infections that force dairy farmers to cull cows.

If you want to learn more about lactation biology, or are a student studying milk production, you need to visit this site and use it as a resource. Thank you to Dr. Walton Hurley for making your teaching materials available to everyone.

 

Research: Effects of Bovine Somatotropin Treatment on Performance, Reproductive, and Physiological Responses of Replacement Beef Heifers

Oh yes, rBST (or BST, rBGH, “hormone injections”, “chemicals”, or any lay term the media can come up with), clearly the reason we are all getting cancer with every steak we eat and glass of milk we drink (second only to cell phone radiation and airport scanners). Animal science faces many of the same problems as food science. If the media can report on it and with scary images, all the while promoting ignorance of the processes of food production, then they will gladly jump on any and all practices in food production. This is super effective because everyone eats, and so we are sensitive to news that what we eat may harm us. I’ll discuss a little more about rBST use in Oregon, but fist I want to examine this proposal we’ll be examining at the EOARC.

The premise of the proposal is that in cow-calf operations, replacement heifers become less and less financially viable if they take longer to reach puberty, or miss their first breeding season. Previous research done at the EOARC has shown that higher IGF-1 (insulin like growth factor 1) concentrations are found in heifers that reach puberty by 12 months compared to non-pubertal heifers of the same age (Cooke et al., 2007). These levels are usually encouraged by using a high plane of nutrition; however, in eastern Oregon we generally run our cow-calf operations on poor forage because it’s economical, it’s what we have, and what we can take advantage of. The idea of the study then, is to see if rBST administration will result in higher IGF-1 levels which will hasten puberty compared to untreated cattle. Additionally, because the normal high plane of nutrition would also raise levels of insulin, blood glucose, and leptin which could also affect onset of puberty, this study will single out IGF-1 levels and determine if the absence of those other factors plays a role in puberty onset.

The procedures are pretty standard, so I won’t rewrite them all here, I’ll post the proposal below so you can read them yourself if you want to examine the methods. One thing I’m impressed by is the rotation of bulls between the treatment and control groups to account for bull effects. I’ve learned about estrus synchronization and other pheromone effects in repro, but the effects a specific bull might have are even more interesting. I wrote about one of these effects when looking at stallions kept on home pasture with pregnant mares a while ago, and was fascinated by the idea of spontaneous (or conscious!) abortion in the presence of specific stallions.

One thing I was a little concerned about is the sample size of the proposal. I’m told anything over 20 is considered viable, but you can’t really lock in any trends you may find with a sample size that small. This particular study will use 40 cattle, which makes the control and treatment groups composed of 20 animals. I think that we’ll still get good data, but that more research with more animals will be necessary to fortify the conclusions that come out of this study.

So that’s pretty much all I have for this one, it’s pretty straightforward. The only problem I have is that, while I support the use of rBST, the current trend is to abandon its use, which may end up making this research obsolete.

This needs to be said in any discussion about the hormone, and it isn’t said enough: the FDA has not found any significant effects resulting from the ingestion of milk from rBST treated cattle. It’s clever advertizing! And we as consumers have to start making the harder choices. We either have to start paying more for our food, or allow our farmers to use safe treatments to increase yields. We can’t have it both ways. I admire people who buy organic items because by purchasing them at a higher price they acknowledge that our agriculture industry needs to make money, and that the margins for small farms are incredibly slim. It’s the ones who want to limit the industry by preventing the use of tools that increase production, but still want to pay 2 dollars for a gallon of milk that make it harder and harder to strengthen the industry.

Coincidentally, this is why student fees and current national budget are so hard to set. No one ever wants to pay more, but we certainly can’t take away any of our provided services either. Something has to give there.

 

You can read the full research proposal here.

You can read a statement from the FDA on “rBST free” labeling here.

You can read a short statement (followed by a list of stores that sell rBST free milk) from the Oregon Physicians for Social Responsibility here. This group has worked hard to discourage use of rBST in small dairy’s across Oregon.