WARNING LETTER An inspection of your licensed medicated feed mill, Cargill, Inc. 1000% higher than the levels indicated on the product's label. ...

Public Health Service Food and Drug Administration

Seattle District Pacific Region 2201 23rd Drive SE Bothell, WA 98021-4421

Telephone: 425-486-8788 FAX: 425-483-4996

June 25, 2008

CERTIFIED MAIL RETURN RECEIPT REQUESTED

Gregory R. Page, President and CEO Cargill, Inc. 15407 McGinty Road West Wayzata, Minnesota 55391

In reply refer to Warning Letter SEA 08-22

WARNING LETTER

Dear Mr. Page:

An inspection of your licensed medicated feed mill, Cargill, Inc., located at 1406 Industrial Avenue, Billings, Montana, conducted by the U.S. Food and Drug Administration (FDA) on February 25, 26, and 27, 2008, found significant deviations from current Good Manufacturing Practice (cGMP) regulations for Medicated Feeds (Title 21, Code of Federal Regulations, Part 225 (21 C.F.R. 225)). These deviations cause feeds being manufactured at this facility to be adulterated within the meaning of section 501 (a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(a)(2)(B)]. In addition, your llama feed, Llama Mineral, was found to contain the new animal drug [redacted] (chlortetracycline), which is not approved for use in llama feed. The use of the new animal drug, Type A, medicated article [redacted] (chlortetracycline), contrary to its approved labeling causes the drug to be deemed unsafe within the meaning of section 512(a)(1) of the Act [21 U.S.C. § 360b(a)(1)] and adulterated with in the meaning of section 501 (a)(5) of the Act [21 U.S.C. § 351(a)(5)]. In addition, the llama feed containing [redacted] (chlortetracycline) is deemed to be unsafe within the meaning of section 512(a)(2) of the Act [21 U.S.C. § 360b(a)(2)] and adulterated within the meaning of section 501 (a)(6) of the Act [21 U.S.C. § 351(a)(6)].

We reviewed your firm's response, dated March 13, 2008, to the FDA-483. We found that the response lacks sufficient detail, explanation, documentation, or substantive corrective action plans to adequately address the deviations noted during the February 2008 inspection of your licensed medicated feed mill in Billings, Montana.

We acknowledge your firm has made some changes and corrections in response to Agency findings and requests. However, we have found that, while some individual cGMP deficiencies may have been corrected, your firm has failed to institute sufficient corrections for your firm's manufacturing processes to conform to the following cGMP requirements in 21 C.F.R. 225:

1. When results of laboratory assays of drug components indicated that medicated feeds were not within permissible assay limits, your facility did not implement investigations and corrective actions, as required by 21 C.F.R. 225.58(d). For example:

a. An assay of the cattle feed "NB TRANS PL 5LB [redacted]" manufactured on March 29, 2007, and submitted for sulfamethazine analysis on or about April 12, 2007, determined a sulfamethazine level 26% above the claimed potency. No investigation or corrective action was undertaken at that time.

b. An assay of the cattle feed "NB TRANS PL 10LB [redacted] manufactured on May 15, 2007, and submitted for sulfamethazine analysis on or about June 12, 2007, determined a sulfamethazine level 24.4% above the claimed potency. No investigation or corrective action was undertaken at that time.

We acknowledge your firm's response that the importance of performing an immediate investigation into the reason for an out-of-tolerance assay result and implementing corrective action has been reviewed with appropriate personnel to ensure compliance with regard to any future out-of-tolerance assays. We further acknowledge your firm's action of completing investigations into these two assays at the time of the February 2008 inspection. However, the results. of the assays were reported to your Billings, Montana feed mill seven to ten months prior to the February 2008 inspection. FDA does not consider an investigation occurring after a seven to ten month delay to be sufficient. Further, your response states that with respect to the February 2008 investigation, "no manufacturing errors were noted." However, FDA was informed by your firm at the time of inspection that the assay of the feed manufactured on March 29, 2007, failed because [redacted] mixer was not functioning properly. The malfunction of [redacted] mixer constitutes a manufacturing error.

2. When results of laboratory assays indicated that medicated feeds failed to meet the labeled drug potency, your facility did not take corrective actions that included discontinuing distribution of the feeds, as required by 21 C.F.R. 225.58(e). For example:

a. An assay of the cattle feed "NB TRANS PL 5LB [redacted]" manufactured on March 29, 2007, and submitted for sulfamethazine analysis on or about April 12, 2007, determined a sulfamethazine level 26% above the claimed potency. No investigation or corrective action was undertaken at that time, including discontinuing distribution of the affected feed products.

b. An assay of the cattle feed "NB TRANS PL 10LB [redacted]" manufactured on May 15, 2007, and submitted for sulfamethazine analysis on or about June 12, 2007, determined a sulfamethazine level 24.4% above the claimed potency. No corrective action was undertaken at that time, including discontinuing distribution of the affected feed products.

We acknowledge your firm's response that the importance of withholding such feed from distribution has been reviewed with appropriate personnel to ensure compliance with regard to any future out-of-tolerance assays. Your response also notes that there was no product available for recovery. This is understandable as the investigation into the assays that showed the feeds not to be in accord with permissible limits did not occur for seven to ten months after the assay results were reported. However, as discussed above, FDA does not consider corrective action taken seven to ten months after the reported assay results to be sufficient.

3. Laboratory analysis results demonstrate that the cleanout procedures established and used in the production of your facility's medicated feeds are not adequate to prevent unsafe contamination of feed, as required by 21 C.F.R. 225.65(b). For example:

a. Laboratory analysis by the Montana State Department of Agriculture found chlorotetracycline in Nutrena Naturewise Lamb and Sheep Feed, manufactured on February 4, 2008, at 550 grams per ton, which is 10 times higher than the level of 50 grams per ton indicated on the product's label. FDA analysis of a sample collected from a different portion of the same lot of lamb and sheep feed found levels of chlorotetracycline at 160 grams per ton (320 % of formula).

b. FDA analysis of a retain sample collected from a lot of medicated cattle feed manufactured at your facility, identified as "Nutrabeef Cattle Grower Feed," found levels of chlortetracycline at 4.8 parts per million (ppm). This product is formulated to contain no chlortetracycline.

c. FDA analysis of a retain sample collected from a lot of medicated cattle feed manufactured at your facility, identified as "Miller FDLT 45/27," found levels of chlortetracycline at 88.0 ppm. This product is formulated to contain no chlortetracycline.

d. FDA analysis of a retain sample collected from a lot of non-medicated llama feed manufactured at your facility, identified as "Llama Mineral," found levels of chlortetracycline at 96.0 ppm. This product is formulated to contain no chlortetracycline.

We acknowledge your firm's response that the incident described above regarding Nutrena Naturewise Lamb and Sheep Feed represents an isolated incident.

However, this response is inadequate in light of analytical sample results confirming cross contamination in several additional products (i.e., "Nutrabeef Cattle Grower Feed," "Miller FDLT 45/27," and "Llama Mineral"). As these analytical results indicate that this is not an isolated incident, FDA continues to have concerns regarding the adequacy of the cleanout procedures at your Billings, Montana facility.

4. Your facility does hot utilize proper sequential production of medicated feeds on a predetermined basis designed to prevent unsafe contamination of feeds with residual drugs in the manufacture of medicated and non-medicated feeds, as required by 21 C.F.R. 225.65(b)(3). For example:

a. On February 4, 2008, your facility produced a medicated feed, identified as "Nutrena Naturewise Lamb and Sheep Feed," which is formulated to contain relatively low levels (0.55 lbs per ton) of the Type A, medicated article [redacted] (chlortetracycline), following the production of a medicated feed, identified as "Nutrena CTC 10 Gram," which is formulated to contain relatively high levels (222 lbs per ton) of the Type A, medicated article [redacted]. This resulted in levels of chlortetracycline in the lamb and sheep feed up to 1000% higher than the levels indicated on the product's label.

b. On January 8, 2008, your facility produced a lot of non-medicated feed, identified as "Llama Mineral," which is formulated to contain no chlortetracycline, following the production of a medicated feed, identified as "Nutrena CTC 10 Gram," which is formulated to contain relatively high levels (222 lbs per ton) of the Type A, medicated article [redacted] (chlortetracycline). This resulted in cross contamination of the "Llam a Mineral" with levels of chlortetracycline at 96.0 ppm.

c. On November 19, 2007, your facility produced a lot of, medicated feed, identified as "Miller FDLT 45/27," which is formulated to contain no chlortetracycline, following the production of a medicated feed, identified as "Nutrena CTC 10 Gram," which is formulated to contain relatively high levels (222 lbs per ton) of the Type A, medicated article [redacted] (chlortetracycline). This resulted in cross contamination of the "Miller FDLT 45/27" with levels of chlortetracycline at 88.0 ppm.

d. On November 5, 2007, your facility produced a lot of medicated feed, identified as "Nutrabeef Cattle Grower Feed," which is formulated to contain no chlortetracycline, following the production of a medicated feed, identified as "Nutrena CTC 10 Gram," which is formulated to contain relatively high levels (222 lbs per ton) of the Type A, medicated article [redacted] (chlortetracycline). This resulted in cross contamination of the "Nutrabeef Cattle Grower Feed" with levels of chlortetracycline at 4.8 ppm.

We acknowledge your firm's response that: (1) the incident described above regarding Nutrena Naturewise Lamb and Sheep Feed represents an isolated incident; (2) the Billings, Montana facility has reviewed its sequencing and flushing procedures and has determined that the procedures for sequencing feeds are adequate and substantiated with appropriate residue testing analysis; and (3) the importance of proper sequencing and flushing has been reviewed with appropriate personnel. We further acknowledge your firm's decision to no longer manufacture the medicated feed identified as "Nutrena CTC 10 Gram" at the Billings, Montana facility. Though the firm has suspended its production of the Nutrena CTC 10 Gram, this response fails to detail any changes in the firm's sequencing procedures to prevent future cross-contamination of products.

As a manufacturer of medicated feeds you are required to use all Type A, medicated articles and Type B medicated feeds in accordance with their labeled mixing directions. However, you did not use the Type A, medicated article [redacted] in accordance with its labeled mixing directions when you added it directly into feed ration mixes rather than following the product's labeled mixing direction, which indicates to [redacted] and then [redacted] therefore, the use of the new animal drug, Type A, medicated article [redacted] (chlortetracycline), contrary to its approved labeling causes the drug to be deemed unsafe within the meaning of section 512(a)(1) of the Act [21 U.S.C. § 360b(a)(1)] and adulterated within the meaning of section 501(a)(5) of the Act [21 U.S.C. § 351(a)(5)].

We acknowledge your firm's response stating that adding this drug directly from the bag to the mixer "is a long-time standard industry practice" and that "[d]rug reconciliation records, mixer efficiency tests and laboratory assays have all substantiated this practice...." However, this response is inadequate as it fails to indicate what efforts the firm will undertake to bring its manufacturing processes into compliance with the [redacted](chlortetracycline) labeled mixing directions.

The above is not intended to be an all-inclusive list of violations. As a manufacturer of medicated and non-medicated feeds, you are responsible for assuring that your overall operation and the products you manufacture and distribute are in compliance with the law.

You should take prompt action to correct these violations and you should establish procedures whereby such violations do not recur. Failure to promptly correct these violations may result in regulatory and/or administrative sanctions. These sanctions include, but are not limited to, seizure, injunction, and/or notice of opportunity for a hearing on a proposal to withdraw approval of your Medicated Feed Mill License under section 512(m)(4)(B)(ii) of the Act [21 U.S.C. § 360b(m)(4)(B)(ii)] and 21 C.F.R. 515.22(c)(2).

Based on the results of the February 2008 inspection, evaluated together with the evidence before FDA when the Medicated Feed License was approved, the methods used in, or the facilities and controls used for, the manufacture, processing, and packing of medicated feeds are inadequate to assure and preserve the identity, strength, quality, and purity of the new animal drug therein. This letter notifies you of our findings and provides you an opportunity to correct the above deficiencies in your operations.

You should notify this office in writing, within fifteen (15) working days of receipt of this letter, of the specific steps you have taken to correct the noted violations. Your, response should include an explanation of each step being taken to correct the cGMP violations and prevent their recurrence. If corrective action cannot be completed within fifteen (15) working days, state the reason for the delay and the date by which the corrections will be completed. Include copies of any available documentation demonstrating that corrections have been made.

Please send your written response to the Food and Drug Administration, Attention: Michael J. Donovan, Compliance Officer, 22201 23rd Drive SE, Bothell, Washington 98021. If you have questions regarding any issue in this letter, please contact Mr. Donovan at (425) 483-4906.

Sincerely,

/S/

Charles M. Breen District Director

Enclosure:

Form FDA 483

cc: Terry Wright, Plant Manager Cargill, Inc., 1406 Industrial Avenue, Billings, Montana 59101-3127

Sue Carson, Quality Assurance and Regulatory Manager Cargill Animal Nutrition, P.O. Box 5614, Minneapolis, Minnesota 55440-5614

Bob Church, Agricultural Specialist Montana Department of Agriculture, Feed and Fertilizer Division 303 North Roberts, Helena, Montana 59620-0201


http://www.fda.gov/foi/warning_letters/s6856c.htm


> This resulted in levels of chlortetracycline in the lamb and sheep feed up to 1000% higher than the levels indicated on the product's label. ...


holy smokes! no wonder many of us are becoming resistant to antibiotics. ...


http://staphmrsa.blogspot.com/


Chlortetracycline plus lasalocid sodium

http://www.fda.gov/cvm/FOI/141-250033106.pdf


Chlortetracycline review history and regulatory outcomes


snip...

Final review and outcomes

The APVMA completed the Chlortetracycline Review Final Report* in May 1999 but did not publish a final report because only a small number of registrants were involved. The APVMA found that the registration and approvals of the products containing chlortetracycline could be varied to meet the current requirements for continued registration.

In the final review the APVMA recommended:

cancelling approval for the use of chlortetracycline in sheep, lambs and lactating animals
ancelling approval for the use of chlortetracycline in animals producing milk for human consumption. Product labels must carry the statement, ‘Do not use in lactating cows where milk or milk products may be used for human consumption.’
increasing withholding periods for pigs, poultry, and cattle for some use patterns
withdrawing MRLs for milk, sheep, lambs and lactating animals
establishing new MRLs for pig offal (liver and kidney)
establishing MRLs for cattle, eggs and poultry.

Chlortetracycline as a topical application is currently listed in Table 5 of the MRL Standard; Table 5 applies to ‘Uses of substances where maximum residue limits are not necessary‘.

For more information please contact the Chemical Review Program on (02) 6210 4749 or by email to chemrev@apvma.gov.au

* Contact the APVMA for copies of this document

http://www.apvma.gov.au/chemrev/chlortetracyclineHistory.shtml



TSS