Mead Johnson Nutrition Company 10/18/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Detroit District 300 River Place Suite 5900 Detroit, MI 48207 Telephone: 313-393-8100 FAX: 313-393-8139

WARNING LETTER
2011 DET-03

October 18, 2010

VIA UPS

Mr. Stephen W. Golsby, President, CEO, and Director
Mead Johnson Nutrition Company
2701 Patriot Boulevard
Glenview, Illinois 60026-8039

Dear Mr. Golsby:

The Food and Drug Administration (FDA) conducted an investigation of your infant formula processing facility, Mead Johnson Nutrition, located at 2400 West Lloyd Expressway, Evansville, Indiana on September 9, 13-17, 20, and 22-23, 2010. Your firm blends and packages powdered infant formula at this location, Based on our investigation, we have concluded that your Enfamil Premium Infant, Enfamil Gentlease, and Enfamil AR, powdered infant formula are in violation of the Federal Food, Drug and Cosmetic Act (the Act) and the applicable regulations at Title 21, Code of Federal Regulations, Part 106 and 107 (21 CFR 106 and 107), You can find copies of the Act and these regulations through links in FDA's home page at www.fda.gov

Our investigation determined that your firm failed to provide the specifications for the plastic tub and lid assembly in which pouches of Enfamil Premium Infant, Enfamil Gentlease, and Enfamil A,R, infant formula pouches are packaged and marketed, Failure to notify the FDA at least ninety (90) days prior to marketing a new infant formula or formula with a major change is in violation of the Federal Food, Drug, and Cosmetic Act (the Act) Section 412(c)(2)(B), [21 U,S,C, § 350a(c)(2)(B)], Failure to comply with Section 412(c)(2)(B), [21 U,S,C, § 350a(c)(2)(B)] of the Act is a prohibited act under Section 301(s) of the Act [21 U,S,C, § 331(s)],

Specifically, your firm advised the FDA in a notification dated February 26, 2010 that it would begin to blend and package infant formula powder in multi-serve pouches at you facility located in Evansville, Indiana, However, the notification did not include the specifications for the polypropylene tub and lid which is used for packaging the infant formula pouches, Labeling on the product suggests that the powder may be transferred from the pouch to the plastic tub for storage purposes, If used in this manner, the tub and lid become a food contact surface, As required by Title 21, Code of Federal Regulations (21 CFR), Section 106.30(c)(2), the manufacturer of infant formula shall evaluate the effect of changes in processing conditions that could affect the level of nutrients in the finished product. Your notification does not identify the tub and lid as a food contact surface, and does not include an evaluation of the plastic used for the tub and lid.

You should notify this office, in writing, describing the corrective actions that you will take to bring your firm into compliance within fifteen (15) working days of receiving this letter. Your response should include each corrective action that you have or will take to correct these violations and prevent their recurrence. Please include copies of any documentation that demonstrates that the corrections have been made.

Your written response should be sent to Tina M. Pawlowski, Ph.D., Compliance Officer, U.S. Food and Drug Administration, 300 River Place, Suite 5900, Detroit, MI 48207. If corrective actions cannot be completed within fifteen (15) working days of receiving this letter, please state the reason for the delay and the time frame in which they will be completed. If you have any questions concerning this letter, please contact Compliance Officer Pawlowski at (313) 393-8217 or by e-mail at tina.pawlowski@fda.hhs.gov.
 

Sincerely,
/S/
Joann M. Givens
Detroit District Director
Detroit District Office

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Close Out Letter

• Mead Johnson Nutrition Co - Close Out Letter 12/3/10

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Yunnan Hande Bio-Tech. Co. Ltd. 10/15/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Silver Spring MD 20993

Warning Letter

VIA UPS MAIL

WL: 320-11-01

October 15, 2010

Ms. Huang Lei
Chairman
Yunnan Hande Bio-Tech Co., Ltd.
No. 3 Platform Jinding Tech-Zone
Kunming, People’s Republic of China, 650033

Dear Ms. Lei:

During our May 17-21, 2010 inspection of your active pharmaceutical ingredient (API) manufacturing facility, Yunnan Hande Bio-Tech Co., Ltd., located at Jinding Tech-Zone, No. 3 Platform, Kunming, China, investigator(s) from the Food and Drug Administration (FDA) identified significant deviations from Current Good Manufacturing Practice (CGMP) for the manufacture of APIs. These deviations cause your API(s) 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 that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to, or are not operated or administered in conformity with CGMP.

We have reviewed your firm’s response of June 2, 2010, and note that it lacks sufficient corrective actions.

Specific deviations observed during the inspection include, but are not limited, to the following:

1. Failure to thoroughly investigate complaints for APIs batches that do not meet the United States Pharmacopeia (USP) compendial requirements that may have been associated with the specific failure or discrepancy. In addition, your investigation was not extended to other batches that may also be affected.

During the review of a customer complaint for lot (b)(4), related to an out-of-specification in the optical rotation test, our inspection team noticed that the optical rotation test was conducted in a room with no temperature control during the sample analysis. Your firm does not monitor the temperature of the sample inside the polarimeter chamber as required by the USP chapter <781>. Your procedure DM No. 21-3, “Optical Rotation of (b)(4),” requires that a temperature correction factor be used when the reading is above or below 20°C; however you failed to apply the correction factor to any of the lots tested. Your quality unit confirmed this discrepancy during our inspection. You indicated that your firm monitors the sample temperature when conducting the optical rotation test by annotating the air condition thermostat reading of the room. However, our investigators found that the temperature of the Quality Control (QC) laboratory, where the optical rotation is conducted, is not controlled because there is no air conditioner in the room. Please clarify this discrepancy in your response to this letter.

Because your optical rotation testing was not conducted under the required environmental conditions, the test results generated may be inaccurate. In your response, you indicate that the temperature in the sampler (and in the room) will be maintained at 20 ± 0.5°C. However, USP <781> requires that the temperature of the sample be maintained at 25°C ± 0.5°C during the analysis. We recommend that you revise your procedures accordingly.

Although the above test is not conducted in accordance to the USP requirements, we are concerned that your Certificate of Analysis (COA) for (b)(4) API indicates that: “we hereby certify that the (b)(4) Drug Substance manufactured by Yunnan Hande Bio-Tech Co Ltd is meeting the quality specification of US Pharmacopeia.” This is a repeat observation from our 2004 inspection where investigators found USP <61> was not followed.

In your response, please provide evidence that all lots of (b)(4) API manufactured and within expiration comply with the USP compendial requirements. Also, indicate whether you intend to issue new COAs to your customer(s) and what actions you intend to implement in those cases where the USP specification is not met. Your firm needs to implement adequate corrective and preventive actions to ensure that the QC personnel are qualified to conduct all analyses in your laboratory, and that those supervising laboratory operations are qualified to ensure scientifically rigorous operations.

2. Failure to have adequate procedures for the reprocessing of API batches and stability data to ensure that the API batches are not adversely affected by the formation of by products and over-reactive materials.

Your SOP 5018-9, “Leftover Products Processing Procedure,” allows for the manufacture of (b)(4) API batches using reserved or retained samples, batch tails ends, and expired (b)(4) API. The reserved samples are (b)(4) under a new lot number. You fail to demonstrate that the quality of the new batch is not affected throughout the shelf life of the API. We are also concerned that you allow the reuse of retain and expired samples maintained for (b)(4) years (or up to (b)(4) years for lot distributed) without determining if the quality of the API has been adversely affected due to the formation of degradants or impurities. You also fail to have an evaluation of the individual batches prior to being (b)(4) into a new batch.

In response to this letter, provide a retrospective evaluation of the lots that have been manufactured using the above practice. Include evidence that your decision to manufacture (b)(4) using expired and retain samples, (b)(4) tails ends batches is preceded by a careful evaluation to ensure that the quality of the API is not adversely affected due to the potential formation of byproduct and over-reacted material. Note your firm should ensure that the manual process used to produce these batches is validated and adequately described in the approved DMF.

3. Failure to have an adequate performance qualification (calibration) program for the QC laboratory instruments.

Your HPLC calibration lacks a carry over test (sample injection residual test), sample energy (intensity of light source), and lamp use hours determination. You fail to challenge the analytical balances for minimum weight, measurement for uncertainty, and drift value. In addition, you do not calibrate the Karl Fisher syringe used during (b)(4) API water content analysis.

Your firm also fails to maintain raw data associated with the re-qualification and calibration of your laboratory instruments. During the inspection the investigators were informed that the annual re-qualification and calibration of your laboratory equipment (e.g., HPLC, GC, polarimeter, and analytical balance) is performed by the (b)(4). However, you were unable to provide raw data or documentation regarding the qualification and calibration of your instruments and data to demonstrate that your quality unit reviewed and approved the work performed by your contractor.

During our inspection, our investigators learned that the calibration program does not include parameters to challenge the precision and accuracy of the laboratory instruments. Your firm acknowledged that your firm lacks a written procedure describing the qualification and calibration of the laboratory equipment.

We are concerned that the inspection of 2004 reported similar deficiencies related to the qualification of your laboratory equipment. In your response, please provide information to show that the above deficiencies have not adversely affected the accuracy of the analytical results used to release your APIs.

4. Failure to have adequate analytical procedures designed to assure that your APIs conform to appropriate specification. For example,

a. The FTIR assay does not include a (b)(4) USP standard during the performance of the identification analysis nor are the critical analytical parameters documented.

Your firm does not concurrently analyze the FTIR samples with a (b)(4) reference standard. Instead, you analyze the sample against a spectrum stored in the memory of the FTIR. During our inspection, you were unable to provide data to show when and how you prepared and qualified the FTIR spectrum standard.

Additionally, the investigators found that the FTIR parameter (e.g. number of samples scanned, resolution, and bean slitter) are not documented in your laboratory record. Moreover, the expiration date of (b)(4) reagent lot (b)(4), used during the sample preparation is unknown. Also SOP DM No. 02-04 does not include instructions to (b)(4) the (b)(4) reagent under a (b)(4), which is an activity conducted by the QC technicians.

b. The suitability of your testing method for your residual solvent determination has not been demonstrated and verified. Additionally, your acceptance criteria are different to the established by the USP.

Your system suitability test requires that (b)(4) injections of standard be performed and that a Relative Standard Deviation (RSD) of (b)(4)% be met in order for the test to be acceptable. This acceptance criterion is contrary to the USP requirement chapter <621>. During our inspection, you were unable to provide validation data to support your current RSD criteria. Your response is inadequate in that you failed to provide scientific rationale to justify the change in your analytical method for system suitability requirements. In response to this letter, please provide a valid % RSD and the analytical data to support it.

The deviations detailed in this letter are not intended to be an all-inclusive statement of deviations that exist at your facility. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations. If you wish to continue to ship APIs to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.

Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as an API manufacturer. In addition, failure to correct these deviations may result in FDA refusing admission of articles manufactured at Yunnan Hande Bio-Tech Co., Ltd., Kunming, People’s Republic of China, 650033 into the United States. The articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)] in that the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practice within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct deviations. Include an explanation of each step being taken to prevent the recurrence of deviations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Additionally, your response should state if you no longer manufacture or distribute (b)(4) API, and provide the date(s) and reason(s) you ceased production. Please identify your response with FEI # 2002808537.

If you have questions or concerns regarding this letter, contact Rafael Arroyo, Compliance Officer, at the below address and telephone number.

U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Branch
White Oak, Building 51
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-4839
Fax: (301) 847-8741
 

Sincerely,
/S/
Richard L. Friedman
Director
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation and Research

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Close Out Letter

• Yunnan Hande Bio-Tech. Co. Ltd. - Close Out Letter 10/25/11

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Quality Egg LLC 10/15/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Kansas City District Southwest Region 11630 West 80 Street Lenexa, Kansas 66214-3340 Telephone: (913) 752-2100

 

October 15, 2010

SENT VIA UPS

WARNING LETTER

Ref. KAN 2011-01

Mr. Austin J. Decoster, Owner

Quality Egg LLC

2674 Highway 69

Galt, IA 50101

Dear Mr. Decoster:

In early July 2010, the U.S. Centers for Disease Control and Prevention (CDC) identified a nationwide increase in the number of Salmonella Enteritidis (SE) cases. Epidemiologic investigations conducted by public health officials in 10 states since April 2010 identified 26 restaurants or SE outbreak clusters where more than one ill person with the outbreak strain had eaten. Data from these investigations suggest that shell eggs were a likely source of infections in many of these restaurants or SE outbreak clusters. As you are aware, your firm has been implicated as one of the sources of SE-contaminated shell eggs.

On August 12 through 30, 2010, investigators from the United States Food and Drug Administration (FDA) inspected your feed mill and egg laying facilities located in Galt, Iowa; Clarion, Iowa; and Dows, Iowa. FDA laboratory analyses of environmental samples collected during this inspection found the presence of Salmonella Enteritidis in egg laying barns at Layer #2 and Layer #4 (Wright County Egg, Clarion, IA). In addition, FDA laboratory analyses of feed samples collected during this inspection found the presence of Salmonella Enteritidis in a feed ingredient, as well as finished feed, stored in your feed mill (Quality Egg LLC, Galt, IA).

In addition, our inspection found that your firm has serious deviations from the Prevention of Salmonella Enteritidis in Shell Eggs During Production, Storage, and Transportation regulation (shell egg regulation), Title 21, Code of Federal Regulations, Part 118 [21 CFR 118]. The failure to adequately implement the requirements in 21 CFR 118 causes your shell eggs to be in violation of the Public Health Service Act, (the "PHS Act"), Title 42 U.S.C. Section 264(a). In addition, your shell eggs are adulterated within the meaning of Section 402(a)(4) of the Federal Food, Drug, and Cosmetic Act (the "Act"), 21 U.S.A. 342(a)(4), in that they have been prepared, packed or held under insanitary conditions whereby they may have become contaminated with filth, or whereby they may have been rendered injurious to health. You can find the Act, the PHS Act, and the shell egg regulation at www.fda.gov. The observations of concern to us are as follows:

• You must implement your SE Prevention Plan, to comply with 21 CFR 118.4. However, you failed to implement your "Quality Egg Bio-security Plan," ("plan") dated 8/11/10 as follows:

â–º Your plan states that you will (b)(4)(page 8, (b)(4). However, you failed to eliminate rodent hiding places and nesting sites as evidenced by the following observations at Layer 3:

• An approximately 2x6 inch wood board was observed on the ground at House 1.
• Unused wooden structures were observed located approximately 5 feet from the exterior of House 15.
• Grass approximately 12 inches high was observed between Houses 11 and 12.

â–º Your plan references (b)(4)(page 13, (b)(4)). However, you failed to properly seal all of your hen houses as evidenced by the following observations:

• Non-chicken feathers were observed inside Layer 3, House 3. One live wild bird was observed flying above chicken cages inside Layer 1, House 9. Wild birds were observed flying inside and outside of Layer 1, Houses 11 and 12. Pigeons were observed roosting in an air vent where the screen was damaged on the south side of Layer 1, House 14.
• The outside access doors to the manure pits had been pushed out by the weight of manure, leaving open access to wildlife and other animals at the following locations: Layer 1, House 1 and Layer 3, Houses 2, 17, 18.
• Exterior structural damage allowing entrance to the interior of the laying houses was observed at Layer 1, Houses 1,3,4, 7, 8, 11, 12; Layer 2, Houses 7 and 11; Layer 3, Houses 1, 2, 11, 13, 14, 15 and 18; Layer 4, House 3. Observations include holes in the exterior siding, missing siding, holes and/or gaps in the concrete foundation and air vent screens either missing or damaged.
• East and west doors located on the second floor egg laying areas of Layer 1, Houses 1 through 14; Layer 2, Houses 7 and 11; Layer 3, Houses 1,3,4,5,6,9,11,15,16,17, and 18; Layer 4, House 3 were observed to have gaps at the bottom and sides ranging from 1/2 inch to 2 inches.

â–º Your plan states that you will (b)(4) (page 7, (b)(4)). However, you failed to properly bait and seal rodent burrows located along the second floor baseboards inside Layer 1, Houses 1 through 9 and 11 through 13; Layer 2, Houses 7 and 11; Layer 3, Houses 1,3,4,5, and 6; and Layer 4, House 3.

â–º Your plan states that (b)(4)(page 12, (b)(4)). However, you failed to properly eliminate all sources of water in the manure pits as evidenced by the following observations:

• Dark liquid which appeared to be manure was observed seeping through the concrete foundation to the outside of the laying houses at Layer 1, Houses 1 through 5, 8, 11, 12, and 14; and Layer 3, Houses 1,8, 13, 17.
• Standing water approximately 3 inches deep was observed in the southeast comer of the manure pit located inside Layer 1, House 13.

• You must take biosecurity measures to ensure that there is no introduction or transfer of SE into or among poultry houses, to comply with 21 CFR 118.4(b). However, your firm failed to ensure that SE is not introduced or transferred into or among poultry houses as evidenced by the following observations:

â–º Not all egg laying houses had an entry door. Entrances for houses on Layer 1 and Layer 2 were located on even numbered houses. Entrances for houses on Layer 3 and Layer 4 were located on odd numbered houses. Therefore, to gain entry to a house without an entry door, employees had to enter from an adjoining house.

â–º Employees working within the houses did not change protective clothing when moving from house to house. For example, an employee at Layer 6, House 3 was observed walking out of House 3 with a metal scraper and into House 2 without changing protective clothing and without cleaning/sanitizing equipment between houses.

â–º Uncaged chickens were observed in the egg laying operation in contact with the egg laying birds at Layer 3, Houses 9 and 16. The uncaged birds were using the manure to access the egg laying areas.

â–º The entrance door to Layer 3, House 11 was blocked with excessive amounts of manure in the manure pits.

• You must use appropriate methods to achieve satisfactory rodent and pest control as required by 21 CFR 118.4(c). However, your failed to achieve satisfactory rodent and pest control as evidenced by the following observations:

â–º There were between 2 to 5 live mice observed inside the following egg laying houses: Layer 1, Houses 1,5, and 10; Layer 2, House 11; Layer 3, Houses 2, 5, 7, 9,11, and 14; and Layer 4, House 3.
â–º Live and dead flies too numerous to count were observed inside the following egg laying houses: Layer 1, Houses 3, 4, 6, 8, 9, 11, and 12; Layer 2, Houses 7 and 11; Layer 3, Houses 3, 4,5,6, 7, 8, 15, 16, 17, and 18. The flies were observed on and around egg belts, feed, shell eggs and walkways in different sections of each egg laying house. In addition, live and dead maggots too numerous to count were observed on the manure pit floor at Layer 2, House 7.

• You must maintain records documenting the implementation of your SE Prevention Plan, to comply with 21 CFR 118.10(a). However, your firm failed to document the monitoring of the following aspects of your SE Prevention Plan:

â–º Your plan states that you will (b)(4)(page 7, (b)(4)). However, you failed to document your inspections of rodent traps and bait stations at the following locations: Layer 1, Houses 1 through 14 had no records after July 15, 2010; Layer 2, House 1 and 2 had no records; and Layer 3, Houses 1 through 11 had no records after July 14, 2010 and Houses 12 through 18 had no records after July 15, 2010.

â–º Your plan states (b)(4)(page 5, (b)(4)). However, you did not document washing and disinfection of your dead hen truck prior to moving from farm to farm.

This letter is not intended to be an all-inclusive list of violations at your facility. You are responsible for ensuring that your firm operates in compliance with the Act, the shell egg regulation, and the PHS Act. You also have a responsibility to use procedures to prevent further violations.

You should take prompt and aggressive actions to eliminate the Salmonella Enteritidis contamination and the observations described in this letter. Failure to take prompt corrective action may result in regulatory action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure and/or injunction.

FDA is in receipt of your response dated October 5,2010, to the FDA-483 and additional information you submitted reflecting ongoing discussions with the agency of your corrective actions. We acknowledge your commitment to correcting the deviations and will verify your corrections via inspection.

Your reply to this Warning Letter should be sent to Danial Hutchison, Compliance Officer, Food & Drug Administration, 11630 West 80th Street, Lenexa, Kansas 66214-3340. If you have any questions about the content of this letter, please contact Mr. Hutchison at 913-752-2774.

Sincerely,

/S/
John W. Thorsky
District Director
Kansas City District
 

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