Haldiman, Keith And Patricia 6/30/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Minneapolis District Office Central Region 250 Marquette Avenue, Suite 600 Minneapolis, MN 55401 Telephone: (612) 758-7133 FAX: (612) 334-4142

June 30, 2010
 

WARNING LETTER
 

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Refer to MIN 10 - 17

 

Keith and Patricia Haldiman
N9035 Harvestore Road
Hilbert, Wisconsin 54129
 

Dear Mr. and Mrs. Haldiman:

On February 1 and March 11, 2010, the U.S. Food and Drug Administration (FDA) conducted an investigation of your dairy operation located at N9035 Harvestore Road, Hilbert, Wisconsin. This letter notifies you of violations of the Federal Food, Drug, and Cosmetic Act (the Act) that we found during our investigation of your operation. You can find the Act and its associated regulations on the Internet through links on FDA's web page at www.fda.gov.
 

We found that you offered for sale an animal for slaughter as food that was adulterated. Under section 402(a)(2)(C)(ii) of the Act [21 U.S.C. § 342(a)(2)(C)(ii)], a food is deemed to be adulterated if it bears or contains a new animal drug that is unsafe under section 512 of the Act [21 U.S.C. § 360b). Further, under section 402(a)(4) of the Act [21 U.S.C. § 342(a)(4)], a food is deemed to be adulterated if it has been held under insanitary conditions whereby it may have been rendered injurious to health.
 

Specifically,our investigation revealed that on or about June 22, 2009, you consigned (b)(4) to haul your dairy cow #(b)(4) identified with back tag #(b)(4), for slaughter as food. On or about June 22, 2009, (b)(4) slaughtered this animal. United States Department of Agriculture, Food Safety and Inspection Service (USDA/FSIS) analysis of tissue samples collected from this animal identified the presence of sulfamethazine at 37.280 parts per million (ppm) in liver tissue and 65.57 ppm in muscle tissue. The USDA/FSIS analysis also identified the presence of phenylbutazone in kidney tissue. The FDA has established a tolerance of 0.1 ppm for sulfamethazine in the uncooked edible tissues of cattle as codified in Title 21, Code of Federal Regulations, section 556.670 [21 CFR 556.670]. However, this tolerance does not apply to sulfamethazine in lactating dairy cattle. There is no acceptable level of sulfamethazine residue in lactating dairy cattle. There is also no acceptable level of phenylbutazone residue in lactating dairy cattle. The presence of these drugs in edible tissues from this animal causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act [21 U.S.C. § 342(a)(2)(C)(ii)].
 

Our investigation also found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. For example, you failed to maintain complete treatment records that include the dosage amount, route of administration, and withholding period to ensure that treated cattle are not culled before labeled meat and milk withhold times are met. You also failed to maintain an inventory system for determining the quantities of drugs used to medicate your animals. Food from animals held under such conditions is adulterated within the meaning of section 402(a)(4) of the Act [21 U.S.C. § 342(a)(4)].
 

The above is not intended to be an all-inclusive list of violations. As a producer of animals offered for use as food, you are responsible for ensuring that your overall operation and the food you distribute are in compliance with the law.
 

You should take prompt action to correct the violations described in this letter and to establish procedures to ensure that these violations do not recur. Failure to do so may result in regulatory action without further notice such as seizure and/or injunction.
 

We are aware that your veterinarian, (b)(4) DVM, has discussed these matters with you. Specifically, he discussed the appropriate use of prescription medications and the use of medications that are prohibited for certain uses. We refer you to 21 CFR 530.41(a)(9) which prohibits the extralabel use of sulfonamide drugs (such as sulfamethazine) in lactating dairy cattle. Similarly, 21 CFR 530.41(a)(12) prohibits the extralabel use of phenylbutazone in female dairy cattle 20 months of age or older. (b)(4) also reviewed appropriate drug use record keeping and supplied you with appropriate forms.
 

You should notify this office in writing of the steps you have taken to bring your firm into compliance with the law within 15 working days of receiving this letter. Your response should include each step that has been taken or will be taken to correct the violations and prevent their recurrence. If corrective action cannot be completed within 15 working days of receiving this letter, state the reason for the delay and the time frame within which the corrections will be completed. Please include copies of any available documentation demonstrating that corrections have been made.
 

Your written response should be sent to Timothy G. Philips, Compliance Officer, U.S. Food and Drug Administration, at the address located on the letterhead. If you have any questions about this letter, please contact Mr. Philips at (612) 758-7133.
 

Sincerely,
/S/

Howard E. Manresa
Acting Director
Minneapolis District

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Closed Out Letter

• Haldiman, Keith And Patricia - Closed Out Letter 11/15/10

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Hi-Tech Pharmacal Co., Inc. 6/28/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	New York District 158-15 Liberty Ave Jamaica, NY 11433

  
June 28, 2010

WARNING LETTER NYK-2010-21

VIA UPS

David Seltzer, President/CEO
Hi-Tech Pharmacal Co., Inc.
369 Bayview Avenue
Amityville, NY 11701

Dear Mr. Seltzer:

During our October 21, 2009 through December 3, 2009 inspection of your pharmaceutical manufacturing facility located at 369 Bayview Avenue, Amityville, NY 11701, Investigators from the Food and Drug Administration (FDA) identified significant violations of Current Good Manufacturing Practice (CGMP) regulations for Finished Pharmaceuticals, Title 21, Code of Federal Regulations, Parts 210 and 211. These violations cause your drug products 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.

In addition, your firm manufactures a prescription drug without an approved application. As described below, this drug is an unapproved new drug without an approved application, and by introducing it into interstate commerce, you are in violation of sections 301(d) and 505(a) of the Act  [21 U.S.C. §§ 331(d) and 355(a)]. This unapproved new drug is misbranded pursuant to section 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)], and by introducing it into interstate commerce you are in violation of section 301(a) of the Act [21 U.S.C. § 331(a)].

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

CGMP Violations

1. Your firm failed to establish laboratory control mechanisms to include the detennination of conformance to applicable written specifications for the acceptance of each lot within each shipment of components used in the manufacture, processing, packing, or holding of drug products [21 C.F.R.§ 211.160(b)(1)].

For example, lot 26910 of Prednisolone API failed to meet the acceptance specifications for two unknown impurities and was released. This lot was used to manufacture (b)(4) distributed lots of Prednisolone Oral Solution drug product. Your firm's out of specification (OOS) investigation (b)(4) states the initial samples of this lot yielded OOS results for two unknown impurities. Although the lot was re-sampled and retested as a part of the OOS investigation, results from the retest failed and your firm failed to reject the lot as required by your SOP P-14-04. Your firm continued to resample and retest until test results met the acceptance specifications. Your firm's investigation report attributed the OOS results to probable glassware contamination or instability of the sample solution, even though there was no scientific evidence to support these conclusions. Furthermore, your firm's own laboratory management stated that glassware contamination and instability of solutions did not cause the OOS result in an email dated February 18, 2009.

2. Your firm has not established scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure drug products conform to appropriate standards of identity, strength, quality, and purity [21 C.F.R. § 211.160(b)].

For example,

a. Your firm failed to perform residual solvent testing for (b)(4) drug products (including Paregoric Liquid USP and Prednisolone Oral Solution USP) which used API's that were manufactured using solvents that are required to be limited in drug products.

b. Your firm failed to dry in-house reference standards or determine the water content of those standards before use in analyzing your drug products. Your firm uses in-house reference standards on an "as-is" basis without drying or determining water content before use. Your firm then assigns the in-house reference standards an "as-is" purity factor with a one year expiration date as required by your SOP QC-057-05. However, there is no data to demonstrate that these "as-is" purity factors will remain accurate over the one-year expiry period of the standard. Your use of these "as-is" purity factors have resulted in erroneous assay calculations for your drug products.

For example, your firm failed to determine the anhydrous purity factor of Riboflavin 5' Phosphate Sodium (Vitamin B2), Lot 26630 standard as required by your SOP. Your firm used the anhydrous purity factor from the supplier's certificate of analysis (COA), which became the "as-is" reference standard. Because you used this "as-is" purity factor instead of drying the standard or using a loss-on-drying factor, your calculations for the assay of Poly-Vitamin Drops, Lot 602774 resulted in a (b)(4) % error.

c. Your firm failed to confirm the normality factors provided by suppliers for commercially prepared volumetric solutions. Your firm purchases commercially prepared volumetric solutions and uses the normality factors supplied on the certificates of analysis without verification testing to confirm the accuracy of the supplier's results.

3. Your firm has not recorded and justified any deviation from the written specifications, standards, sampling plans, test procedures or other laboratory control mechanisms [21 C.F.R. § 211.160(a)).

For example, your firm failed to follow your SOP QC-057-05 for expiration dating of "in-house" reference standards. Your firm uses Riboflavin 5' Phosphate Sodium (Vitamin B2) raw material as a standard for the analysis of Poly-Vitamin Drop products. It is classified as a non-compendial reference standard and assigned a two-year expiration date, even though this substance is a compendial (USP) product and should be assigned as a "in-house" standard with a one-year expiration date, according to your SOP.

4. Your firm failed to establish and document the accuracy, sensitivity, specificity, and reproducibility of test methods [21 C.F.R. § 211.165(e)].

For example,

a. Your firm failed to validate methods used for the assay analysis of six Poly-Vitamin Drop products, four Tri-Vitamin Drop products, and Sodium Fluoride Drops.

b. Your firm failed to include the following characteristics: accuracy, robustness, ruggedness and specificity in your validation of the UPLC assay method (b)(4) used for the analysis of Pyridoxine Hydrochloride (Vitamin B6), Riboflavin 5' Phosphate Sodium (Vitamin B2) and Thiamine Hydrochloride (Vitamin B1) in Poly-Vitamin Drop products.

c. Your firm failed to generate and document chromatographic data to support the validation of the analytical method (b)(4) used for determination of Urea in Urea Cream 40%. In addition, your firm failed to generate and document chromatographic data to support stress studies for Paregoric Liquid USP to demonstrate that the method is suitable for determining stability.

5. Your firm does not have adequate written procedures for production and process controls designed to assure that the drug products you manufacture have the identity, strength, quality, and/or purity they purport or are represented to possess [21 C.F.R. § 211.100].

Your firm failed to complete the process validation studies for the following four prescription drug products:

1. Tri-Vitamin Drops with Iron and Fluoride 0.25mg
2. Poly-Vitamin Drops with Fluoride 0.25mg
3. Tri-Vitamin Drops with Fluoride 0.50mg
4. Tri-Vitamin Drops with Fluoride 0.25mg

For example, there are no batch records with the original data and test results for the validation study of Poly-Vitamin Drops with Fluoride 0.25mg and Tri-Vitamin Drops with Fluoride 0.25mg. In addition, you implemented revisions to your master formula without adequate change control. Evaluation of the data and records associated with the manufacture of Poly-Vitamin Drops with Fluoride 0.25mg and Tri-Vitamin Drops with Fluoride 0.50mg was not available to assure that the changes made to the batch records (revisions to the master formula) do not impact the product quality.

6. Your firm does not have, for each batch of drug product, an appropriate laboratory determination of satisfactory conformance to final specifications for the drug product, including the identity and strength of each active ingredient, prior to release [21 C.F.R. § 211.165(a)].

For example, your firm failed to perform analytical testing for the following active ingredients to determine conformance to their assay specifications:

1. Vitamin D in Poly-Vitamin Drops with Iron and Poly-Vitamin Drops with Iron and Fluoride 0.25mg
2. Vitamin D and B12 in Poly-Vitamin Drops with Fluoride 0.50mg and Poly-Vitamin Drops with Fluoride 0.25mg

7. Your firm has not conducted at least one specific identity test and has not established the reliability of the supplier's analyses through appropriate validation of the supplier's test results at appropriate intervals [21 C.F.R. § 211.84(d)(2)].

For example, your firm failed to establish the reliability of your suppliers' test results. Specifically, verification of a supplier's residual solvent test results for excipients is limited to testing of only one lot of material to confirm the accuracy of the supplier's test results.

Unapproved and Misbranded Prescription Drug

In addition to the CGMP violations, discussed above, you manufacture and market an unapproved new drug in violation of the Act at your facility. Based on the information your firm submitted to FDA's Drug Registration and Listing System and the information collected during the inspection, you manufacture the following prescription drug:

• Paregoric Liquid, USP (Anhydrous Morphine 2 mg, Alcohol 47.7%)

The above product is a drug within the meaning of Section 201 (g) ofthe Act, [21 U.S.C. 321(g)] because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of diseases. Further, it is a "new drug" within the meaning of Section 201(P) of the Act [21 U.S.C. § 321(P)] because it is not generally recognized as safe and effective for its labeled uses. Under Sections 301(d) and 505(a) of the Act [21 U.S.C. 331(d) and 355(a)] a new drug may not be introduced into or delivered for introduction into interstate commerce unless an application approved by FDA under either section 505(b) or (j) of the Act [21 U.S.C. § 355(b) or [j] is in effect for the drug. Based on our information, you do not have any FDA-approved applications on file for this drug product.

Additionally, under Section 301(a) of the Act [21 U.S.C. § 331(a)], it is prohibited to introduce into or deliver for introduction into interstate commerce a misbranded drug. The above product is misbranded because, as a prescription drug, adequate directions cannot be written for it so that a layman can use this product safely for its intended uses. Consequently, its labeling fails to bear adequate directions for use as required under Sections 502(f)(1) of the Act [21 U.S.C. § 352(f)(1)] and because it lacks a required approved application, it is not exempt from this requirement under 21 C.F.R. § 201.115.

The introduction or delivery for introduction into interstate commerce of adulterated and misbranded drugs or products without approved new drug applications violates Sections 301(a) and (d) of the Act [21 U.S.C. §§ 331(a) and (d)]. Therefore, you should discontinue manufacturing and distributing all of your unapproved drugs at all facilities immediately. We acknowledge the letter from your consultant, (b)(4) dated November 5, 2009, who provided your firm an opinion on the regulatory analysis of your products. Based on our information, you do not have any FDA-approved applications on file for those drug products.

The violations cited in this letter are not intended to be an all-inclusive statement of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations.

You should take prompt action to correct the violations cited in this letter. Failure to promptly correct these violations may result in legal action without further notice including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates, or approval of pending drug applications listing your facility, until the above violations are corrected. FDA may re-inspect to verify corrective actions have been completed.

As stated above, you must cease manufacturing and distributing all your unapproved new drug products. Within fifteen working days of receipt of this letter, you should notify this office to arrange for a meeting to discuss the specific steps you have taken to correct the noted violations. Include an explanation of each step being taken to prevent the recurrence of violations 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. We also request that you outline the action you are taking to discontinue the marketing of the unapproved drug product at your facility, or any other applicable drugs which you may market. Additionally, your response should state if you no longer manufacture or distribute products, and provide the date(s) and reason(s) you ceased production. Please note that if you are no longer marketing this (these) product(s), you must update the Drug Listing files in accordance with 21 C.F.R. § 207.30(a)(2).

Your reply should be sent to the following address: Compliance Branch, Food and Drug Administration, 158-15 Liberty Avenue, Jamaica, NY 11433. Attention: Lillian C. Aveta, Compliance Officer.

Sincerely,

/s/

Ronald M. Pace
District Director
New York District

Enclosure: Fonn FDA 483 dated December 3,2009

 

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Arasys Perfector Inc 6/28/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	10903 New Hampshire Avenue Silver Spring, MD 20993

 

 

 

June 28 2010

VIA UPS EXPRESS

Dr. Xanya Sofra-Weiss
CEO, Director of R&D
Arasys Perfector, LLC
7773 Waikapu Loop
Honolulu, HI 96825

Dear Dr. Weiss:

 

The Food and Drug Administration (FDA) has learned that your firm is marketing the Arasys, Perfector, Ion Magnum, and iPico Perfector in the United States (U.S.) without marketing clearance or approval, in violation of the Federal Food, Drug, and Cosmetic Act (the Act).

The Office of Compliance (OC) in the Center for Devices and Radiological Health (CDRH) reviewed your websites; http://www.arasysperfector.com for the Arasys, Perfector, Ion Magnum, and iPico Perfector; and http://www.arasysperfectorusa.com. for the Arasys and Perfector. These products are devices within the meaning of Section 201(h) of the Federal Food, Drug, and Cosmetic Act. Specifically, your websites contain statements which represent or suggest that the Arasys is safe and effective in producing the following, but not limited to, effects: muscle building acceleration, stamina increase, strength and performance boost, power detoxification, abs tightening, buttocks contouring, healthy lymphatic drainage promotion, tightening of loose skin, breast enhancement, body revitalization, and cellulite appearance reduction.Additionally, your websites contain statements which represent or suggest that the Perfector, Ion Magnum, and iPico Perfector are adequate and effective in producing the following, but not limited to, effects: erasure of wrinkles, discolorations, acne, and scars.

The Arasys, Perfector, Ion Magnum, and iPico Perfector are adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. 351(f)(1)(B), because you do not have approved applications for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. 360e(a), or approved applications for investigational device exemptions (IDE) under section 520(g) of the Act, 21 U.S.C. 360j(g). The devices are also misbranded under section 502(o) of the Act, 21 U.S.C. 352(o), because you did not notify the agency of your intent to introduce the devices into commercial distribution, as required by sections 510(k) of the Act, 21 U.S.C. 360(k). For a device requiring premarket approval, the notification required by section 510(k) of the Act, 21 U.S.C. § 360(k), is deemed satisfied when a PMA is pending before the agency. The kind of information you need to submit in order to obtain approval or clearance for your device is described on the Internet at http://www.fda.gov/cdrh/devadvice/3122.html. The FDA will evaluate the information you submit and decide whether your product may be legally marketed.

Your firm should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations 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, injunction, and/or civil money penalties. Also, federal agencies are advised of the issuance of all Waming Letters about devices so that they may take this information into account when considering the award of contracts.

Please notify this office in writing within fifteen (15) working days from the date you receive this letter of the specific steps you have taken to correct the noted violations, including an explanation of how you plan to prevent these violations, or similar violations, from occurring again. Include documentation of the corrective action you have taken. If your planned corrections will occur over time, please include a timetable for implementation of those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.

Your response should be sent to: Jennifer Medicus at the Food and Drug Administration, 10903 New Hampshire Avenue, W066-2626, Silver Spring, MD 20993-0002. If you have any questions about the content of this letter please contact Jennifer Medicus via telephone at (301)796-5615 or via facsimile at (301)847-8128.

Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter may be symptomatic of serious problems in your firm's manufacturing and quality assurance systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.

Sincerely,

/s/

Timothy  A. Ulatowski
Director
Office of Compliance
Center for Devices and Radiological Health
 

 

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Arasys Perfector Inc - Close out letter

• Arasys Perfector Inc - Close out letter

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Pozner, Jason M.D. 6/25/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	10903 New Hampshire Avenue Silver Spring, MD 20993

WARNING LETTER

VIA UPS EXPRESS

June 25, 2010

Jason Pozner, M.D.
4800 N. Federal Hwy, Suite 100
Boca Raton, FL 33431

Dear Dr. Pozner:

This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection conducted at your clinical site from February 12, 2010, to March 24, 2010, by investigators from the FDA’s Florida District Office. The purpose of this inspection was to determine whether activities and procedures related to your participation in the clinical study entitled, “A Multicenter, Randomized, Controlled Study with Independent, Masked Assessment, to Evaluate the Safety and Efficacy of the UltraShape® Contour Plus™ System, for Non-Invasive Abdominal Fat Reduction for the Purpose of Body Contouring,” UltraShape® Contour Plus™ System, Investigational Device Exemption (IDE) #(b)(4) complied with applicable federal regulations. The UltraShape® Contour Plus™ System is a device as that term is defined in section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act), 21 U.S.C. 321(h). This letter also requests prompt corrective action to address the violations cited and discusses your written response, dated April 8, 2010, to the noted violations.

The inspection was conducted under a program designed to ensure that data and information contained in requests for IDE, Premarket Approval (PMA) applications, and Premarket Notification submissions (510(k)) are scientifically valid and accurate. Another objective of the program is to ensure that human subjects are protected from undue hazard or risk during the course of scientific investigations.

Our review of the inspection report prepared by the district office revealed several violations of Title 21, Code of Federal Regulations (21 CFR) Part 50 - Protection of Human Subjects, and Part 812 - Investigational Device Exemptions. At the close of the inspection, the FDA investigator presented the inspectional observations Form FDA 483 for your review and discussed the observations listed on the form with you. The deviations noted on the Form FDA 483, your written response, and our subsequent review of the inspection report are discussed below:

1. Failure to adhere with the regulation that prohibits representations that an investigational device is safe or effective for the purposes for which it is being investigated. [21 CFR 812.7(d)].

A sponsor, investigator, or any person acting for or on behalf of a sponsor or investigator shall not represent that an investigational device is safe or effective for the purposes for which it is being investigated. You have failed to adhere to the above-stated regulation. Examples of your failure include, but are not limited to, the following:

• On your website, http://www.smacboca.com/ultra shape.html, the investigational device is being represented as safe and effective. The website states “A unique feature of Ultrashape technology is its highly sophisticated optical tracking and guidance system engineered to ensure safe, effective and uniform treatment.” Although the website includes information regarding the device’s status as unapproved and under clinical trials, the representation on your website nonetheless indicates that the UltraShape® is safe or effective for the purposes for which it is being investigated.

In your response, you stated that the website was an oversight on your part and that you used an outside public relations firm that was not aware of FDA regulations. You have since added your own marketing department in which you will have complete control of all your marketing efforts. You state that you will seek IRB approval for marketing material in future studies, although IRB approval by itself will not ensure that your labeling and marketing material are in compliance with 21 CFR part 812. Your response appears adequate and may be verified during a future inspection.

2. Failure to conduct the investigation according to the signed agreement, the investigational plan, applicable FDA regulations, and any conditions of approval imposed by an Institutional Review Board (IRB) or FDA. Also failure to adhere to the regulation that governs an investigational device to be used only with subjects under the investigator’s supervision. [21 CFR 812.110(b) and (c)].

A clinical investigator is responsible for ensuring that an investigation is conducted according to the signed agreement with the sponsor, the investigational plan, and applicable FDA regulations and any conditions of approval imposed by an IRB or FDA. Also, a clinical investigator shall permit an investigational device to be used only with subjects under the investigator’s supervision. You have failed to adhere to the above stated regulations. Examples of your failures include, but are not limited to, the following:

• Section 6.2 of the Study Protocol versions July 29, 2008, and December 1, 2008, states that the Screening Exam must occur up to 30 days prior to Day 0, and must include the collection and review of subjects’ laboratory values to determine eligibility. Prior to subjects receiving their first treatment, laboratory reports were to be reviewed for out-of-range values and assessed for clinical significance. However, the following subjects’ reports were reviewed by you approximately 2 to 7 weeks after subjects received their first treatment.

o The (b)(4) for Subject (b)(4) was collected on September 12, 2008 and reported on September 13, 2008. The first treatment occurred on September 19, 2008; however, you signed the lab report stating you reviewed the report on November 7, 2008. The lab report contained numerous out-of-range values that were determined to be clinically significant. An email exchange between the Safety Monitor, Dr. (b)(4) from (b)(4), and (b)(4) confirms these out-of-range values and that the subject should have been marked as a screen failure. As a consequence of late reviews, this subject was withdrawn after having received the first treatment.

o The (b)(4) for Subject (b)(4) was collected on August 25, 2008 and reported on August 26, 2008. The first treatment occurred on September 3, 2008; however the lab report was not reviewed by you until September 19, 2008, in which you indicated that there were numerous out-of-range values which were clinically significant.

• Sections 6.12.11 and 7.2 of the Study Protocol, version July 29, 2008, and Sections 6.13.11 and 7.2 of the Study Protocol, version December 1, 2008, the clinical investigator is instructed to “refer to the Contour Plus User’s Manual.” However, the correct user manual for the investigational device, the Contour Plus™ System, was not available at your site. Rather the manual on site was for a different device, the Contour 1 System.

• Section 6.12.3 of the Study Protocol version, July 29, 2008 and Section 6.13.3 of the Study Protocol version, December 1, 2008, state that, “The Principal Investigator (or designed physician) will mark the treatment area prior to each treatment, with a dark non-permanent marker while the subject stands upright.” However, you did not perform this procedure for any subjects. You also did not supervise (b)(4), the medical assistant/study coordinator, who performed these tasks.

• Section 6.16 of the Study Protocol version, July 29, 2008 and Section 6.17 of the Study Protocol version, December 1, 2008, state that, (b)(4)“.” However, you did not perform this global assessment examination for any subjects. You also did not supervise (b)(4), who did perform these examinations.

• Section 15.1.3 of the Study Protocol versions, July 29, 2008, and December 1, 2008, state that “The Investigator will be responsible for the timeliness, completeness, and accuracy of the information on the CRF.” In addition, 21 CFR 812.140(a)(3) requires investigators to maintain accurate, complete, and current records of each subject’s case history, which includes all relevant observations, such as the information and data on the condition of each subject upon entering the investigation. However, there is no source documentation (e.g., medical record entries) in your study records to show that “(b)(4)” examinations were performed on any subjects, or any results of such examinations, during the physical examination of the treatment area as part of the screening process. The boxes on the case report forms (CRFs) were marked “Yes” to indicate that the “(b)(4)” examinations were completed.

Please note that as a result of your non-performance of various study duties listed above and lack of oversight of the clinical trial, FDA has concerns about the Global Assessments examination data validity and accuracy because they are one of the secondary efficacy variables stated in Section 8.0 “Efficacy and Safety” of both study protocol versions.

In your response you stated that the sponsor did not mean that the PI needs to be present at each procedure, but to be responsible for the proper conduct of each procedure. You also stated that delay in the reporting of the blood tests will not happen in future studies. Your response is inadequate in that it does not describe your corrective and preventive actions for performing all physical examinations and global assessments of research subjects and reviewing lab results prior to subjects receiving treatments, as required by the protocol and the investigator agreement. Your response also does not describe your corrective and preventive actions for ensuring the adequate supervision of delegated responsibilities, as stated in the study protocol. Please explain how you plan
to correct these failures and provide mechanisms for preventing any recurrence.

3. Failure to maintain accurate, complete, and current records of receipt, use, or disposition of a device that relate to the type and quantity of the device and the dates of receipt. [21 CFR 812.140(a)(2)].

A clinical investigator is responsible for maintaining accurate, complete, and current records of receipt, use, or disposition of an investigational device that relate to the type and quantity of the device, the dates of receipt, and the names of all persons who received, used, or disposed of each device. You failed to adhere to the above-stated regulation. Examples of your failure include, but are not limited to, the following:

• The “Product Accountability Log” only listed the UltraShape system once and seven (b)(4). There are no records of receipt, use, or disposal of any (b)(4) or the UltraShape system. A total of (b)(4) subjects were enrolled at your site; however, the log does not provide information related to which subjects were treated with which (b)(4).

• The product accountability log shows the receipt date for one investigational device and five (b)(4) on June 30, 2008, and lists receipt of two additional (b)(4) but no receipt date.

• There are no records of the disposition of the , including any shipping receipts.

In your response you acknowledge these errors and you indicate that in future studies you will make sure that the “Product Accountability Log” is complete, accurate and contains all study-related inventory. Your response is inadequate in that it does not describe your corrective and preventive actions for maintaining complete and accurate device records, including receipt and return of the UltraShape system, (b)(4), and other supplies (e.g., treatment packets, etc.). Please explain how you plan to correct these failures and provide mechanisms for preventing any recurrence.

4. Failure to maintain accurate, complete, and current records of each subject’s case history. [21 CFR 812.140(a)(3)].

A clinical investigator is responsible for maintaining accurate, complete, and current records of each subject’s case history and exposure to the device, which encompasses the case report forms (CRFs) and supporting data. You have failed to adhere to the above-stated regulation. Examples of your failure include, but are not limited to, the following:

• A note-to-file dated, September 9, 2008, states that subjects through were brought back to the site for reassessment; however, there is no documentation in the subjects’ files or on-site to show that the subjects returned for the reassessment.

• The “Signature Authorization Log” that delegated study-related responsibilities is incomplete and inaccurate in that you did not initial and date the log or change the study coordinator listing. The Signature Authorization Log shows (b)(4), as the study coordinator for the study; however, (b)(4) was only involved in part of the study. (b)(4) became the study coordinator, though she is listed as a “treater” in the Signature Authorization Log

In your response you acknowledge these errors and indicate that in future studies you will make sure that the “Signature Authorization Log” is complete, accurate and closely supervised by the investigator. Your response is inadequate in that it does not describe your corrective and preventive actions for maintaining complete and accurate CRFs, maintaining and updating the subjects’ visits log, recording results from physical examinations performed during the visits, maintaining a current and accurate Signature Authorization Log, and maintaining on-site an accurate investigational device user manual. Please explain how you plan to correct these failures and provide mechanisms for preventing any recurrence.

The violations described above are not intended to be an all inclusive list of problems that may exist with your clinical study. It is your responsibility as a clinical investigator to ensure compliance with the Act and applicable regulations.

Please note that when the IRB approves subsequent substantial changes to the informed consent it is a best practice to notify subjects that signed previous versions of the informed consent of these changes. Four subjects ((b)(4)) were enrolled in the study with no documentation on file to show that they signed the revised informed consent version, dated December 1, 2008. The December 2008 version of the informed consent document contained the following additional information: (b)(4)“

Within fifteen (15) working days of receiving this letter, please provide written documentation of the additional actions you have taken or will take to correct these violations and prevent the recurrence of similar violations in current or future studies for which you are the clinical investigator. In addition, please provide a complete list of all clinical trials in which you have participated for the last five years, including the name of the study and test article, the name of the sponsor, the number of subjects enrolled, and the current status of the study. Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action without further notice to you. In addition, FDA could initiate disqualification proceedings against you in accordance with 21 CFR 812.119.

You will find information to assist you in understanding your responsibilities and planning your corrective actions in the FDA Information Sheets Guidance for Institutional Review Boards and Clinical Investigators, which can be found at http://www.fda.gov/oc/ohrt/irbs/.

Any submitted corrective action plan must include projected completion dates for each action to be accomplished.

Your response should reference “CTS #:(b)(4) ” and be sent to: Attention: Linda Godfrey, Food and Drug Administration, Center for Devices and Radiological Health, Office of Compliance, Division of Bioresearch Monitoring, 10903 New Hampshire Avenue, WO66-3462, Silver Spring, Maryland, 20993-0002.

A copy of this letter has been sent to the FDA’s Florida District Office, 555 Winderley Place, Suite 200, Maitland, FL 32751. Please send a copy of your response to that office.

For further information concerning the Bioresearch Monitoring program, please visit our Internet homepage at http://www.fda.gov/cdrh/comp/bimo.html. Valuable links to related information are included at this site. The Division of Bioresearch Monitoring also developed introductory training modules in FDA-regulated medical device clinical research practices, which are available on the FDA website. The modules are for anyone involved in the clinical research enterprise and, can be found at http://www.fda.gov/Training/CDRHLearn/ucm162015.htm.

If you have any questions, please contact Ms. Linda Godfrey by telephone at (301) 796-5490 or via email at Linda.Godfrey@fda.hhs.gov.

Sincerely yours,

/S/

Michael E. Marcarelli, Pharm.D., M.S.

Director

Division of Bioresearch Monitoring

Office of Compliance

Center for Devices and Radiological Health

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AMPAC Fine Chemicals, LLC 6/25/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	San Francisco District Pacific Region 1431 Harbor Bay Parkway Alameda, CA 94502-7070 Telephone: 510-337-6700 FAX: 510-337-6701

Warning Letter

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

June 25, 2010

Mr. Aslam Malik, Ph.D., President
AMPAC Fine Chemicals, LLC
Highway 50 and Hazel Avenue
Rancho Cordova, CA 95670

Dear Dr. Malik:

During our February 9-19, 2010 inspection of your active pharmaceutical ingredient (API) manufacturing facility, AMPAC Fine Chemicals, LLC, located at Highway 50 and Hazel Avenue, Rancho Cordova, CA, 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 APls 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 dated March 12, 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 properly maintain buildings used in the manufacture of API production in a manner that prevents contamination.

For example, dirt, blistering paint, rust, and oil droplets were found to be in close proximity to manufacturing equipment in several building locations.

In addition, on January 9,2009, operators observed paint chips in the material while manufacturing Temozolomide API, which was later rejected. Your variance report, (b)(4) indicates that paint chips could have fallen into the reactor during solid charging (e.g., during preparation of the crude or during the purification of the material). Your variance report, (b)(4) listed (b)(4) locations that could have been the source of the contamination. In addition, in the report you stated that the implemented corrective actions following the investigation were not effective and you provided no information concerning subsequent corrective actions implemented to reduce the risk of contamination.

In your response, you state that your cleaning procedures will eliminate the dirt, corrosion, blistering paint, and oil droplets before initiating manufacturing operations. You also state that you currently have adequate "controls and methods of detection" to prevent contamination and/or inadvertent release of product containing foreign matter. However, your response is inadequate because you do not describe such controls and methods of detection.

2. Failure to ensure documentation of cleaning of major equipment after each batch is processed; and failure to clean non-dedicated equipment between the production of different APIs to prevent cross-contamination.

For example, your cleaning log for a processing room (building (b)(4)) indicates that cleaning was performed on December 22, 2009. This room was used to manufacture the chlorambucil API from January 4 to 18,2010. On January 22, 2010, the room was released by your Quality Engineer and Production Manager for the manufacture of another material, temozolomide API, without performing any cleaning. According to your (b)(4)," the Quality Engineer and Production Manager are required to perform and document a room readiness audit (using the (b)(4) Form) verifying that the subject area is clean and suitable for use (including an audit of the cleaning logs) prior to the start of a manufacturing process. Although the cleaning log for the processing room lacked documentation of cleaning, the (b)(4) Form contains affirmations that the cleaning log was "complete and up-to-date."

In your response, you state that this occurrence was an "isolated incident, and not indicative of the effectiveness of [your] overall facility audit process." Your response is inadequate because
you do not describe how you will ensure that cleaning was performed or will be performed prior to starting manufacturing operations between different batches of APIs.

3. Failure to identify and quarantine returned APls.

For example, you stored a drum of returned temozolomide API (batch 07-185-385) in the warehouse storage area with other drums of temozolomide API that were labeled as accepted and ready for release. The returned drum was not properly identified (e.g., tag or attached status label).

In your response, you state that you have developed new procedures regarding rejected batches. Your response is inadequate because you have not addressed how you will manage returned APIs. It is your responsibility to ensure that returned APIs are properly identified and quarantined separately from material approved for distribution.

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. It is your responsibility to assure compliance with all requirements of federal law and FDA regulations.

You should take prompt action to correct the deviations detailed in this letter. Failure to promptly correct these deviations may result in legal action without further notice including, without limitation, seizure and injunction. Other federal agencies may take this Warning Letter into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export certificates or approval of pending drug applications listing your facility, until the above deviations are corrected. FDA may re-inspect to verify corrective actions have been completed.

Within fifteen (15) 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
taken to prevent the recurrence of deviations and copies of supporting documentation. If you cannot complete corrective action within fifteen (15) working days, state the reason for the delay and the date by which you will have completed the correction.

Your reply should be sent to the following address: Mr. Carl Lee, Compliance Officer, Food and Drug Administration, San Francisco District, Pacific Region, 1431 Harbor Bay Parkway, Alameda, CA 94502. If you have any questions about the content of this letter please contact Mr. Lee at (510) 337-6737 or by fax at (510) 337-6703.

Sincerely,
/S/

Gerald Berg

Acting District Director

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Close out Letter

• AMPAC Fine Chemicals, Inc. Close out Letter 4/25/11

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American Pecan Co. LLC 6/25/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Dallas District 4040 North Central Expressway Dallas, Texas 75204-3128

June 25, 2010

2010-DAL-WL-11

WARNING LETTER

Certified Mail
Return Receipt Requested

Rogelio A. Gonzales, President
American Pecan Co. LLC
P.O. Box 151
Yancey, Texas 78886

Dear Mr. Gonzales:

From January 11 to February 10, 2010, investigators from the U.S. Food and Drug Administration (FDA) conducted an inspection of your pecan repackaging facility located at 330 County Road 743, Yancey, Texas 78886. The inspection confirmed that you process ready-to-eat, raw pecans in 1 pound consumer size containers that were adulterated within the meaning of sections 402(a)(1) [21 U.S.C. 342(a)(1)] and 402(a)(4) [21 U.S.C. 342(a)(4)] of the Federal Food, Drug, and Cosmetic Act (the Act). You can find the Act and its associated regulations on the Internet through links on the FDA web page at www.fda.gov.

On February 9,2010, FDA collected a sample (Sample 597164) of Pecan Pieces (Medium) in 1 pound packages, which are sold directly to consumers at your onsite retail store and through mail orders. Analysis of the sample revealed the product to be contaminated with Salmonella oranienburg (S. oranienburg). Salmonella, including S. oranienburg, is a micro-organism that is known to be pathogenic to humans. Ready-to-eat pecans containing Salmonella pose a danger to humans and are adulterated within the meaning of Section 402(a)(1). We acknowledge that your firm initiated a recall of the affected product on February 26, 2010.

The inspection also included the collection of environmental samples from various locations within your processing facility, including plywood flooring in the area where pecans are processed and packaged. FDA laboratory analyses of the environmental samples (FDA samples 570472 and 570473), found Salmonella spp. in seven subsamples taken from seven different locations within your facility. Each of these positive subsamples was further serotyped and six were determined to be Salmonella newport (S. newport), and one was determined to be Salmonella oranienburg (S. oranienburg).

Pulsed Field Gel Electrophoresis (PFGE) testing determined that the six isolates of S. newport were indistinguishable from one another. The recovery of an indistinguishable S. newport serotype pattern is significant because this indicates that Salmonella may have established a niche in your manufacturing facility, and further emphasizes the need for strict sanitation measures to ensure effective cleaning and sanitizing of food contact and non-food contact surfaces. Accordingly, FDA's analytical results for environmental samples cause your firm's ready-to-eat pecan products to be adulterated within the meaning of section 402(a)(4) of the Act, in that they were prepared, packed, or held under insanitary conditions whereby they may have been rendered injurious to health.

Misbranding
A review of your product labels reveals violations of the Act and FDA's labeling regulations contained within Title 21, Code of Federal Regulations, Part 101 (21 CFR 101). As a result of these violations, several of your products are misbranded within the meaning of section 403 of the Act [21 U.S.C § 343].

Your bulk pecan products, are misbranded within the meaning of section 403(i)(1) of the Act [21 U.S.C. § 343(i)(1)] in that they fail to declare a statement of identity in accordance with 21 CFR 101.3(a).

We note that several of your pecan products fail to bear a Nutrition Facts panel as required by 21 CFR 101.9. Your firm may be eligible to file for a small business nutrition labeling exemption for products which do not declare nutrient information, nutrient content or health claims on the labels, labeling or advertising. In accordance with 21 CFR 101.9(j)(18), a firm may qualify for this exemption if the firm has fewer than 100 full time employees and fewer than 100,000 units of a product are being sold in the United States, provided that the product labels, labeling, and advertising do not provide nutrition information or make a nutrient content or health claim. A firm is required to file an exemption notice each year with FDA unless the firm has fewer than 10 full time equivalent employees. We have no record of your firm having filed a Small Business Nutrition Labeling Exemption Notice.

This letter does not list all the violations at your facility. The inspection revealed serious violations of the Current Good Manufacturing Practice (CGMP) regulation for foods, Title 21, Code of Federal Regulations, Part 110 (21 CFR 110), including the observation of painted plywood floors in areas where pecans are sorted, cut, packaged, and stored. FDA laboratory analysis of an environmental sample collected from your plywood floor confirmed the presence of S. newport. Because plywood floors are not easily cleanable, organisms such as Salmonella, may not be adequately controlled, or eliminated during normal cleaning operations, and thus, may remain as a resident organism.

FDA acknowledges the written response from your firm's Manager, Reynaldo Elizondo, dated February 2, 2010, which addresses observations listed on the FDA 483 issued to your firm. Further, we acknowledge a teleconference on February 4, 2010 between Mr. Elizondo, and members of the Dallas District Compliance Branch. During this teleconference, we informed Mr. Elizondo of FDA's continued concerns with your manufacturing operation.

Upon further contact, Mr. Elizondo indicated your firm was considering sterilizing pecans using a third party vendor. Mr. Elizondo was advised to provide information regarding this change and changes made to your firm's plywood floors, in a written correspondence to the agency. We have not received correspondence from you regarding these two concerns.

You are responsible for ensuring that your processing plant operates in compliance with the Act and the Current Good Manufacturing Practice regulation (21 CFR Part 110). You should take prompt action to correct the violations noted in this letter. Failure to promptly correct these violations may result in regulatory action without further notice, such as seizure and/or injunction.

You should respond in writing within 15 working days from your receipt of this letter. Your response should outline the specific steps you are taking to correct these violations. You should include in your response documentation and other useful information that would assist us in evaluating your corrections. If you cannot complete all corrections before you respond, you should explain the reason for your delay and state when you will correct any remaining violations.

Your reply should be directed to Sherrie L. Krolczyk, Compliance Officer, at the address indicated on the letterhead.

Sincerely,

/S/

Reynaldo R. Rodriguez, Jr.

Dallas District Director

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Thumb Oilseed Producers' Cooperative 6/24/10

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
2010-DT-15

June 24, 2010

VIA UPS

Joann F. Rutkowski
Chief Operating Officer
Thumb Oilseed Producers' Cooperative
2145 Leppek Road
Ubly, MI 48475-9790

Dear Ms. Rutkowski:

The Food and Drug Administration (FDA) conducted an inspection of your soy grit and soy flour manufacturing facility located at 2145 Leppek Road, Ubly, MI, from January 28 through February 23, 2010. During the inspection, FDA collected environmental samples from various locations within your processing facility, as well as finished product samples. FDA laboratory analyses of the environmental samples (FDA sample numbers 584663, 584664 and 584665) found Salmonella in forty-three (43) areas within your manufacturing plant. Each of these positive subsamples was further serotyped and determined to be Salmonella senftenberg (s. senftenberg), with an indistinguishable Pulse-Field Gel Electrophoresis (PFGE) pattern. The discovery of an indistinguishable S. senftenberg serotype pattern from multiple locations within your manufacturing facility indicates that Salmonella may have become established in a niche environment in your facility. Further, FDA's finding of an indistinguishable PFGE pattern among isolates obtained from environmental swabs (collected from non-food contact surfaces, including a forklift wheel and gap in the processing floor) with a sample of finished product organic soy flour collected at your facility (FDA sample number 519231) is significant because it demonstrates the potential for Salmonella contamination in finished product.

Based on FDA's analytical results for environmental samples and inspectional findings documented during the inspection, we determined that your firm's soy grit and soy flour products were adulterated within the meaning of Section 402(a)(4) of the Federal Food, Drug and Cosmetic Act (the Act) [21 U.S.C. 342(a)(4)], in that they were prepared, packed, or held under insanitary conditions whereby they may have been rendered injurious to health. You can find the Act and its associated regulations on the internet through links on the FDA webpage at www.fda.gov.

As noted above, during the inspection, FDA also collected finished product samples, including a sample of "Organic Low - Fat Soy Flour" (FDA sample number 519231) manufactured at your facility. Our analysis of the soy flour revealed the product to be contaminated with S. senftenberg. Salmonella, including the S. senftenberg serotype, is a microorganism that is known to be pathogenic to humans. FDA's laboratory confirmation of S. senftenberg in your finished product soy flour causes the lot to be adulterated within the meaning of Section 402(a)(1) of the Act [21 U.S.C. 342(a)(1)], in that it bears or contains a poisonous or deleterious substance which may render the product injurious to health. FDA acknowledges that your firm initiated a voluntary recall of these soy products on February 25, 2010.

Appropriate control of Salmonella in a food processing environment requires expert knowledge of the unique characteristics of the organism. It is essential to identify the areas of the food processing plant where this organism is able to grow and survive (niche areas) and to take such corrective actions as necessary to eradicate the organism by rendering these areas unable to support the growth and survival of the organism.

Further, serious violations of the Current Good Manufacturing Practice (CGMP) regulation for foods, Title 21, Code of Federal Regulations, Part 110 (21 CFR 110), including violations that created possible routes of cross-contamination, were identified by our investigators and documented in the Form FDA-483, lnspectional Observations, issued to you, on February 23, 2010. We have reviewed your March 2, 2010, March 24, 2010, and April 8, 2010, response letters and have determined that additional information is needed in order to assess the adequacy of your completed and planned corrective actions. For example, your responses identify a number of planned corrections, including "working" with a third-party to decontaminate your facility, developing an "environmental control plan," and establishing various "cleaning procedures and/or Sop's" for decontaminating processing areas and equipment. However, your response letters do not include the details of your (1) decontamination plan, including the methods and sanitizing agents to be utilized, (2) ongoing environmental monitoring plan, and (3) revised sanitation standard operating procedures (SSOPs). In addition, your response letter should include information about your corrective action plan for addressing potential positive Salmonella findings in the future. Please submit copies of records to
support your planned and taken corrective actions.

This letter may not list all of the violations at your facility. You are responsible for ensuring that your processing plant operates in compliance with the Act and FDA regulations, including the CGMP regulation for foods. Failure to implement lasting corrective action of these violations may result in regulatory action being initiated without further notice. For example, we may take further action to seize your products and/or enjoin your firm from operating.

We request that you notify this office in writing, within 15 working days from your receipt of this letter, of the current status of your corrective actions, including any further specific steps that you have taken to correct the noted violations. If you cannot complete all corrections before you respond, we expect that you will explain the reason for your delay and state when you will correct any remaining violations.
 

Please send your reply to the Food and Drug Administration, Attention: Mr. Steven B. Barber, Director of Compliance, Detroit District Office, 300 River Place, Suite 5900, Detroit, Michigan 48207. If you have any questions regarding any issues in this letter, please contact Mr. Barber at 313-393-8110.

Sincerely,

/S/

Joann M. Givens
District Director
Detroit District Office
 

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North Memorial Medical Center 6/24/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	10903 New Hampshire Ave. Silver Spring, MD 20993-0002

 

June 24, 2010

WARNING LETTER

VIA UPS EXPRESS

David W. Cress
President and Chief Executive Officer
North Memorial Medical Center
3300 Oakdale North
Robbinsdale, MN 55422

Dear Mr. Cress:

This Warning Letter is to inform you of objectionable conditions observed during the Food and Drug Administration (FDA) inspection of your Institutional Review Board (IRB) from March 23, 2010 to March 30, 2010 by investigators from the FDA Minneapolis District Office. The purpose of this inspection was to determine whether your IRB is in compliance with applicable federal regulations. IRBs that review investigations of devices must comply with applicable provisions of Title 21, Code of Federal Regulations (21 C.F.R.) Part 56-Institutional Review Boards, Part 50-Protection of Human Subjects, and Part 812-Investigational Device Exemptions. This letter also requests prompt corrective action to address the violations cited.

The inspection was conducted under a program designed to ensure that data and information contained in requests for Investigational Device Exemptions (IDE), Premarket Approval (PMA) applications, and Premarket Notification submissions (510(k)) are scientifically valid and accurate. Another objective of the program is to ensure that human subjects are protected from undue hazard or risk during the course of
scientific investigations.

Our review of the inspection report prepared by the district office revealed several violations of Title 21, Code of Federal Regulations (21 C.F.R.) Part 56 -- Institutional Review Boards. At the close of the inspection, the FDA investigator presented an inspectional observation Form FDA 483 for review and discussed the observations listed on the form with Gary D. Hanovich, M.D., IRB Chair. The deviations noted on the Form FDA 483 and our subsequent review of the inspection report are discussed below:

Failure to have adequate written procedures governing the functions and operations of the IRB. [21 CFR 56.108(a) and (b)]

The IRB has no written procedure for ensuring prompt reporting to appropriate institutional officials and the Food and Drug Administration of any instance of serious or continuing noncompliance with FDA regulations or the requirements or determinations of the IRB. Serious and unexpected adverse events were repeatedly not reported promptly to the IRB for the study entitled “Genentech AVF 4096g: A Phase II, Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial Evaluating the Efficacy and Safety of Bevacizumab in Combination with Carboplatin and Paclitaxel Chemotherapy for the First-Line Treatment of Patients with Metastatic Melanoma. (03/07/55).”

a) Serious and unexpected adverse events that occurred on 6/26/2009 and 9/3/2009 were not reported to the IRB until 1/27/2010.

b) Serious and unexpected adverse events that occurred on 5/1/2008, 9/21/2008 and 10/9/2008 were not reported to the IRB until 04/14/2009.

c) Serious and unexpected adverse events that occurred on 7/28/2008 and 1/12/2009 were not reported to the IRB until 03/09/2009.

Failure to review proposed research at convened meetings at which a majority of the members of the IRB are present, including at least one member whose primary concerns is in nonscientific areas. [21 CFR 56.108(c)]

The IRB reviewed and voted on FDA-regulated research when less than a majority of the members were present and granted initial approval. Examples of this failure include, but are not limited to, the following:

a) The IRB roster for 2009 consists of 14 voting members. Minutes for the IRB meeting held on September 9, 2009, identified seven (7) members present, in which the IRB approved continuation the FDA regulated study entitled, "(b)(4)."

b) The IRB roster for 2008 consists of 15 voting members. Minutes for the IRB meeting held on April 9, 2008, identified six (6) members present, in which the IRB reviewed the FDA regulated study entitled, "Protocol GOG 0214, Phase II Double-Blind, Randomized Trial Evaluating the Biologic Effect of Levonorgestrel on the Ovarian Epithelium in Women at High Risk for Ovarian Cancer."

c) The IRB roster for 2007 consists of 20 voting members. Minutes for the IRB meeting held on December 12, 2007, identified seven (7) members present, in which the IRB reviewed the FDA regulated study entitled, "Protocol GOG 0209, Randomized Phase III Trial of Doxorubicin/Cisplatin/Paclitaxel and G-CSF versus Carboplatin/Paclitaxel in Patients with Stage III & IV or Recurrent Endometrial Cancer."

Failure to prepare and maintain adequate documentation of IRB activities. [21 CFR 56.115(a)(2) and (5)]

An IRB must prepare and maintain adequate documentation including minutes of IRB meetings which shall be in sufficient detail to show the number of members voting for, against, and abstaining on actions taken by the IRB. Such documentation also must include a list of IRB members identified by name, earned degrees, representative capacity, indications of experience sufficient to describe each member’s chief anticipated contributions to IRB deliberations; and any employment or other relationship between each member and the institution. Examples of this failure include, but are not limited to, the following:

a) The IRB meeting minutes for 2007, 2008, 2009 and 2010 describe voting actions as “passed unanimously” and do not identify the number of members voting for, against, and/or abstaining.

• Minutes for the IRB meeting held on January 13, 2010 indicate that the IRB reviewed and approved the FDA regulated study entitled "TAXUS Liberte Post-Approval Study: A U.S. Post-Approval Study of the TAXUS Liberte Paclitaxel-Eluting Coronary Stent System." However, the minutes lack details of the votes on its actions, including the number of members voting for, against, and/or abstaining.

b) The list of IRB members for 2010 shows only the member’s name, place of employment and phone number. The list does not adequately identify scientific, non-scientific, and community members; voting members from non-voting members; or whom each alternate is designated to represent and in what capacity.

The violations described above are not intended to be an all inclusive list of problems that may exist at the IRB. The IRB is responsible for ensuring compliance with the Act and applicable regulations.

During the inspection it was noted that the IRB has used compassionate use review for some FDA regulated studies. Please note that information with reference to compassionate use of devices can be found in Chapter III of the guidance document entitled Guidance on IDE Policies and Procedures. This guidance document can be found at the following website address:
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/ucm080202.htm.

Please note your response dated April 21, 2010 was received, however, it was not received within the established timeframe for submission of post-inspection responses. The Agency will review your written response and will respond to you in a subsequent letter.

Within fifteen (15) working days of receiving this letter, please provide written documentation of the actions you have taken or will take to correct these violations and prevent the recurrence of similar violations. Failure to respond to this letter and take appropriate corrective action could result in the FDA taking regulatory action without further notice to you.

Your response should reference “CTS# EC100214/E001” and be sent to:

Attention: Kathy Weil
Food and Drug Administration
Center for Devices and Radiological Health
Office of Compliance
Division of Bioresearch Monitoring
10903 New Hampshire Avenue
Building 66, Room 3451
Silver Spring, Maryland 20993-0002.

A copy of this letter has been sent to the Minneapolis District Office, 250 Marquette Ave., Suite 600, Minneapolis, MN 55401. Please send a copy of your response to that office.

The Division of Bioresearch Monitoring has developed introductory training modules in FDA regulated device clinical research practices, which are available on the FDA website. The modules are for persons involved in FDA regulated device clinical research activities. These modules are located at the following website address: http://www.fda.gov/Training/CDRHLearn/ucm162015.htm.

If you have any questions, please contact Kathy Weil at (301) 796-6054 or via e-mail at Kathy.Weil@fda.hhs.gov.

Sincerely yours,

/S/

Michael E. Marcarelli, Pharm.D., M.S.

Director

Division of Bioresearch Monitoring

Office of Compliance

Center for Devices and Radiological Health

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Blountys, LLC

Department of Health and Human Services	Public Health Service Food and Drug Administration
	10903 New Hampshire Avenue Silver Spring, MD 20993

JUN 23 2010

Via United Parcel Service

Warning Letter

Paul Blount
Blountys LLC
6312 NW 99th Avenue
Doral, Florida 33178

RE: NightForm Infant Positioning Mattress

Dear Mr. Blount:

Refer to GEN0900704 when replying to this letter.

The Food and Drug Administration (FDA) has learned that your firm is marketing the NightForm Infant Positioning Mattress in the United States (U.S.) without the required marketing clearance or approval, in violation of the Federal Food, Drug, and Cosmetic Act (the Act).

The NightForm Infant Positioning Mattress is a device within the meaning of section 201 (h) of the Act Because it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body, 21 U.S.C. 321(h). The Act requires that manufacturers of devices that are not exempt obtain marketing approval or clearance for their products from the FDA before they may offer them for sale. This helps protect the public health by ensuring that new devices are shown to be both safe and effective or substantially equivalent to other devices already marketed in this country for which approval is not required.

A review of our records indicate that we cleared a premarket notification (510(k) for this device, K041996, on August 3, 2004, with an indication "for healthy infants 0-9 months to aid in the prevention of skull deformities that can rise from consistent back-sleeping postures, namely the condition known as deformational (or positional) plagiocephaly." We did not clear this device for use in the prevention of sudden infant death syndrome (SIDS).

The Office of Compliance (OC) in the Center for Devices and Radiological Health (CDRH) reviewed your website (most recently on June 14, 2010), located at http://www.blountys.com/Nightform-Infant-Positioning-Matress-Pink-p/nf1001pink.htm for the NightForm Infant Positioning Mattress. According to your website:

" ...NightForm Infant Positioning Mattress... is designed to address the dual risk of SlDS and of sleep-related skull flattening (deformational plagiocephaly)...

Promotion of this device for SIDS causes a significant change in the intended use of the device that requires the submission of a new 510(k). 21 CFR 807.81(a)(ii). Because of the SIDS claims, the device is adulterated under section 501(f)(1)(B) of the Act, 21 U.S.C. 351(f)(1)(B). because you do not have an approved application for premarket approval (PMA) in effect pursuant to section 515(a) of the Act, 21 U.S.C. 360e(a), or an approved application for an investigational device exemption (IDE) under section 520(g) of the Act, 21 U.S.C. 360j(g). This device is also misbranded under section 502(o) of the Act 21 U.S.C. 352(o), because you did not submit to FDA a notification respecting the changes to the intended use of the device, as required by section 510(k), 21 U.S.C. 360(k), and 21 CFR 807.81 (a)(3)(ii).

The device is also misbranded under section 502(a) of the Act, 21 U.S.C. 352(a), in that the labeling of the device, namely your website located at www.blounty.com contains statements that are misleading in accordance with 21 CFR 807.97, because such statements create an impression of official approval of a device due to clearance of a premarket notification submission. Specifically, the labeling states, with respect to the NightForm Infant Positioning Mattress

"Is it safe to use?
... It is the only FDA-approved infant sleep positioner product on the market today."

''How is NightForm different from other sleep wedges on the market?
...It has been clinically tested and it is approved by the FDA as a regulated medical device. No other device can claim these medical qualifications."

This device was not approved by the FDA, but was determined to be substantially equivalent within the meaning of section 513(i)(1)(A) of the Act, 21 U.S.C. 360c(i)(1)(A).

This device is also misbranded under section 502(o) of the Act 21 U.S.C. 352(o), because it was manufactured, prepared, propagated, compounded, or processed In an establishment not duly registered under section 510 of the Act, 21 U.S.C. 360; and it was not included in a list as required by 510(j) of the Act, 21 U.S.C. 360(j).

The Office of Compliance requests that Blountys LLC immediately cease marketing the NightForm Infant Positioning Mattress for unapproved/uncleared uses such as those described above. You should take prompt action to correct these violations. Failure to promptly correct these violations 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, injunction, and/or civil money penalties.

Please submit a written response to this letter within 15 working days from the date you receive this letter, describing what steps you have taken to correct the problem and how you plan to prevent this from happening again. Please list all promotional materials for NightForm Infant Positioning Mattress containing claims for unapproved/uncleared uses such as those described above, and explain your plan for discontinuing such claims. Please direct your response to George Kroehling at the Food and Drug Administration. 10903 New Hampshire Avenue, W066-3512, Silver Spring, MD 20993 or via facsimile at (301) 847-8137. We remind you that only written communications are considered official.

The violations discussed in this letter do not necessarily constitute an exhaustive list. It is your responsibility to ensure that NightForm Infant Positioning Mattress complies with each applicable requirement of the Act and FDA implementing regulations.

Sincerely yours,

/S/
Timothy A. Ulatowski
Director
Office of Compliance
Center for Devices and
   Radiological Health

Cc:
Paul Blount
10162 Northwest 87th Court
Miami, FL 33178

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Basic Food Flavors, Inc.

Department of Health and Human Services	Public Health Service Food and Drug Administration
	San Francisco District 1431 Harbor Bay Parkway Alameda, CA 94502-7070 Telephone: 510/337-6700

 

Via UPS

WARNING LETTER

June 23, 2010

Mr. Kanaiyalal N. Patel

Basic Food Flavors, Inc.

3950 East Craig Road

North Las Vegas, NV 89030-7504

Dear Mr. Patel:

The Food and Drug Administration (FDA) conducted an inspection of your food manufacturing facility located at 3950 East Craig Road, North Las Vegas, NV, from February 12, 2010 through March 4, 2010. This inspection revealed that hydrolyzed vegetable protein (HVP) processed by your facility is adulterated within the meaning of section 402(a)(1) and (a)(4) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 342(a)(1) and (a)(4)]. You can find the Act and its associated regulations on the internet through links on the FDA web page at www.fda.gov.

During the inspection, FDA collected a sample of HVP (b)(4) processed at your facility. Laboratory analysis of the HVP product revealed the presence of Salmonella tennessee

(S. tennessee). Salmonella, including the S. tennessee serotype, is a microorganism that is known to be pathogenic to humans. Foods containing Salmonella pose a danger to health and are adulterated within the meaning of Section 402(a)(1) of the Act, in that the products contain a poisonous or deleterious substance which may render them injurious to health. FDA notes that your firm subsequently voluntarily recalled all powdered and paste HVP manufactured on or after September 17, 2009.

In addition, FDA analyzed environmental samples collected from various locations within your fum's processing facility during the inspection. Laboratory analysis of these environmental samples found Salmonella in nine separate subsamples. The positive subsamples were further serotyped and S. tennessee, S. senftenberg, and S. westhampton were isolated from the environmental samples. It was further determined that six of the subsamples to be S. tennessee, the same serotype with an indistinguishable Pulsed-Field Gel Electrophoresis (PFGE) pattern as isolated from the samples of finished product. The recovery of indistinguishable S. tennessee serotype patterns from multiple processing locations, including direct food contact surfaces, within your facility indicates that Salmonella may have become established in a niche environment in your facility. Further, finding Salmonella on direct food contact surfaces and other areas very near to where food is exposed indicates a high risk of product contamination. Based on our analytical and inspection findings, we determined that your firm's HVP products were adulterated within the meaning of Section 402(a)(4) of the Act, in that they were prepared, packed, or held under insanitary conditions whereby they may have been contaminated with filth or may have been rendered injurious to health.

Appropriate control of Salmonella in a food processing environment requires expert knowledge of the unique characteristics of the organism. It is essential to identify the areas of the food processing plant where this organism is able to grow and survive (niche areas) and to take such corrective actions as necessary to eradicate the organism by rendering these areas unable to support the growth and survival of the organism.

FDA's inspection also revealed serious violations of the Current Good Manufacturing Practice (CGMP) regulation for foods, Title 21, Code of Federal Regulations, Part 110 (21 CFR 110). We reviewed your firm's written response from (b)(4) dated March 12, 2010, to the Form FDA-483, in which you state you have corrected or promise to correct the deficiencies listed. In addition to the voluntary recall of HVP manufactured on or after September 17, 2009, your promised corrections include (b)(4); implementation of new procedure, including training, to minimize the potential of microbial contamination of food products; revising and updating your (b)(4); revising and updating your (b)(4) program, including (b)(4) and reviewing and amending as appropriate your (b)(4) program. Please submit documentation which shows implementation of your completed corrections including (b)(4) and contract work to (b)(4), detailed information on how you will minimize movement of personnel/material/equipment in the primary Salmonella control areas, how you intend to monitor the (b)(4), information about your (b)(4) program, and specifically, your intended corrective actions should include (b)(4) monitoring detect a possible sanitation failure. Your submission should also include revise (b)(4) and operating procedures related to (b)(4) as well as training materials you have developed for employees to minimize microbial contamination. The adequacy of your corrective actions and their implementation will be assessed during our next inspection.

The above violations are not meant to be an all-inclusive list of deficiencies in your facility. It is your responsibility to ensure that all of your products are in compliance with the Act and applicable FDA regulations. Failure to correct violations of the Act and applicable regulations may result in regulatory action without further notice, such as seizure and/or injunction.

We request that you notify this office in writing, within 15 working days from your receipt of this letter, of the current status of your corrective actions since your March 12, 2010 correspondence, including any additional documentation and further specific steps that you have taken to correct the noted violations. If you cannot complete all corrections before you respond, we expect that you will explain the reason for your delay and state when you will correct any remaining violations.

Please send your reply to the Food and Drug Administration, Attention: Russell A. Campbell, Compliance Officer, 1431 Harbor Bay Parkway, Alameda, CA. If you have questions regarding any issue in this letter, please contact Russell Campbell at (510) 337-6861.

Sincerely,

/S/

Gerald J. Berg

Acting District Director

San Francisco District

U. S. Food and Drug Administration

Glenn D. Savage, REHS

Environmental Health Director

Southern Nevada Health District

P.O. Box 3902

Las Vegas, Nevada, 89127

State of Nevada

Department of Health and Human Services

Health Division

4150 Technology Way

Carson City, NV 89706

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Nanjing Pharmaceutical Factory Company Limited 6/22/10

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Rockville MD 20857

JUN 22 2010

WARNING LETTER

Via UPS

Ms. Li Qing, Plant Manager
Nanjing Pharmaceutical Factory Company Limited
Nanjing Chemical Industry Park
No.9, Fangshui East Road
Nanjing, China (Mainland) 210047

Dear Ms. Li Qing:
 

This letter is regarding the U.S. Food and Drug Administration (FDA) inspection of your active pharmaceutical ingredient (API) manufacturing facility located at Nanjing Chemical Industry Park, No.9, Fangshui East Road, Nanjing Chemical Industry Park, Nanjing, China, conducted by FDA Investigators, Jose Hernandez and Chemist Felix Maldonado, on September 21 - 25, 2009. A pre-approval/current Good Manufacturing Practice (cGMP) inspection of your API manufacturing facility was performed covering the processing of the API Praziquantel intended for animal drug use. Due to the significant observations uncovered, the inspection was expanded to also cover the API Sucralfate, intended for human drug use only.

We have completed our review of the Establishment Inspection Report (EIR) for the inspection. The inspection revealed significant deviations from the cGMPs in the manufacture of APIs. These deviations were listed on an Inspectional Observations form (Form FDA483) issued to you at the conclusion of the inspection.

These cGMP deviations cause your APIs 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). This section of the Act states that drugs, as defined in the Act, are adulterated when they are not manufactured, processed, packed, and held in conformity with current good manufacturing practices. You can find the Act and its associated regulations on the internet through links on the FDA's web page at www.fda.gov. No distinction is made between animal and human drugs, and the failure of either to comply with cGMP constitutes a failure to comply with the requirements of the Act.

We have also received your written responses to the Form FDA 483 inspectional observations, dated January 18, 2010 and April 20, 2010. We note that you state that many corrections have been, or soon will be implemented. However, your responses do not adequately address some of the deficiencies as further discussed below. Specific areas of concern include, but are not limited to:

Current Inspectional Findings:

1. Failure of your firm's Quality Unit to complete its essential responsibilities.

For example,

a. Your quality unit failed to discover, document, and investigate the data altering practices and lack of adequate cGMP documentation practices at your facility.

Specifically, the practice of scraping off or erasing original data from production batch records is pervasive throughout your facility. Our investigators documented over 30 production batch records (approximately 80% of the records reviewed) that contained evidence of original data such as dates, signatures, temperatures, test results, weights, volumes, and times being removed, and new data written. This data alteration was done without an explanation of why the data was changed, or the signature or initials of the person making the changes. Interviews conducted with an operator revealed that this practice is so common that the operator made a special tool to scrape off entries in production batch records, so that new data or information can be recorded in its place.

Additionally, you acknowledged during the inspection that the GMP Controller makes entries into the production batch records associated with the manufacturing steps. However, there is no documentation of his/her signature to acknowledge the entries recorded. The operator responsible for conducting the manufacturing step includes only his or her signature or initials to information completed by the GMP Controller.

During an interview with the Quality Assurance (QA) Manager, he stated that management has been aware of the data alteration practices since September 2007. Your quality unit failed to document, investigate, and prevent the recurrence of these deviations. Provide in your response, the actions taken to correct these deviations and prevent their recurrence.

b. Your quality unit failed to ensure that effective systems are in place for the calibration and maintenance of critical equipment and instrumentation.

Specifically, there was no chromatography data (chromatograms) for the calibrations of High Pressure Liquid Chromatography (HPLC) and Gas Chromatography (GC) systems completed by the (b)(4). Also, your firm had no record of the procedure that the (b)(4) used to complete the yearly qualifications of your HPLC and GC instrumentation. In addition, there was no chromatography data (chromatograms) for the qualification of the Headspace GC completed by (b)(4), who was used as a contract service vendor.

Additionally, not all of your analytical laboratory instrumentation had written and approved calibration procedures. There were no calibration procedures for melting point apparatus (b)(4)), analytical balances (b)(4)), or (b)(4)

Furthermore, you had no records of the calibration of the vacuum drier's (b)(4)) chamber thermometer and the actual parameters used during the qualification of this vacuum drier (b)(4) was incomplete).

Instrument and equipment calibrations should be conducted according to approved, written procedures and established frequencies. All raw data and associated records, such as procedures, standard certificates, etc., should be maintained. An assessment of all current calibration of equipment and instrumentation should be done to ensure required information is available, and adequate corrective actions have been implemented.

c. Your QCD failed to review and approve all quality related documentation.

For example, blank production batch records are printed by an outside company. These printed production batch records are not reviewed by the QCU prior to being issued. Your Standard Operating Procedure (b)(4) effective date July 1, 2009) includes the instructions for the printing and issuance of batch production records, but does not include instructions on reviewing and approving the blank batch production records. Provide updated procedures for the quality review and approval of all quality related documentation.

2. Failure of the operator to document all quality related activities at the time they are performed.

For example, review of batch records (specifically (b)(4) and (b)(4)) and interviews with operators revealed that operators are not recording their own observations (batch record required entries) into production batch records. The entries (including observations) are being entered by the "GMP Controller" and not by the operator at the time they are performed. This is a cGMP deviation and is inconsistent with your written procedures, specifically (b)(4), effective date July 1, 2009).

A comprehensive investigation into this deviation should be conducted, including why this behavior was not discovered by the quality unit during production batch record review.

3. Failure to have an adequate stability testing program designed to monitor the stability characteristics of APIs.

For example, at the time of the inspection, you did not have an approved stability protocol for the two APIs manufactured for the U.S. market, Praziquantel and Sucralfate. You should establish an ongoing testing program of APIs to monitor its stability characteristics.

Your stability testing protocols should include as a minimum, representative sampling, storage conditions, testing time-points, adequate analytical testing methods, and specifications. You should review all available stability data to determine if the testing is adequate, timely, and includes a representative number of samples. If any inconsistencies are discovered, a justification or explanation should be included.

4. Failure to appropriately store stability. samples under controlled conditions to evaluate the thermal stability and moisture sensitivity of the API.

You do not store the stability samples under controlled conditions. The stability room currently in use for long term stability conditions is not designed to control temperature and humidity adequately. The room's temperature is controlled by a (b)(4) unit located on one side of the room. The back-up cooling and heating unit in use is not capable of controlling relative humidity. This room also contains a large, clear glass window that is not completely sealed, and a standard office type entry door that is not sealed. The temperature and relative humidity is not continuously recorded.

Provide with your response, the corrective actions to ensure stability samples are stored at the required controlled conditions. Also, provide justification of current retest or expiry dates assigned to your APIs using data from this stability room.
 

5. Failure to have an adequate number of personnel qualified by education, training, experience, or a combination thereof, to ensure the APIs are manufactured in accordance with cGMP.

Complete training records are not maintained for operators. The training records associated with operators do not identify the SOPs the operators were trained on. As a result, there is no way to confirm if operators were trained on SOPs concerning raw data and batch record documentation (b)(4), effective date July 1,2009) that are a required part of their responsibilities.

Additionally, the QA Manager stated that numerous temporary employees were used in 2007 for the manufacture of APls that were inadequately trained. The QA Manager admitted to knowing about the errors the temporary employees had made, but did not document, investigate, or prevent the recurrence of these errors via training.

Please indicate in your response when the employees will receive external cGMP or Q7A "Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients" training.

6. Failure to completely validate analytical equipment used for quality testing of APIs, such as in-process, release, and stability.

For example, the electronic formulas used to calculate results for assay, related compounds, and residual solvents associated with HPLC and GC tests for Praziquantel and Sucralfate USP APls, have not been verified for accuracy. This observation is considered a repeat of an observation made during the October 2005 inspection of your facility when your laboratory was cited for the failure to validate calculations used in the laboratory.

All electronic formulas used at your facility during testing should be verified for accuracy as a part of a validation. Please provide documentation of these efforts and include how the security of these calculations will be controlled to ensure these formulas are not altered.

Please specify in your response how your firm will improve procedures and training, and all actions you are taking to ensure raw materials are sampled in a manner to prevent their contamination and contamination of other materials.

7. Failure to evaluate all changes that may affect the production and control of manufactured APls, specifically, assuring current analytical methods are used to test USP APIs.

For example, you used an obsolete USPINF (ASIAN edition) version from 2005 for the testing of the two USP products (Praziquantel and Sucralfate) manufactured at your facility.

In your response, provide a complete assessment of the adequacy of the methods used to test the APIs you manufacture. The differences between the current USP methods and that of the 2005 version used at your site should be identified, and their potential impact evaluated.

The violations cited in this letter or on the Form FDA 483 issued to your firm are not intended to be an all-inclusive list of violations that exist at your facility. You are responsible for investigating and determining the causes of the violations identified above and for preventing their recurrence and the occurrence of other violations. If you wish to ship APIs to the United States, it is the responsibility of your firm to ensure compliance with all FDA standards for cGMP and all other applicable U.S. laws and regulations.

Please respond in English to this letter within thirty (30) days of receipt and identify your response with FEI # 3004674350. Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firm's compliance with cGMP, these offices may recommend withholding approval of any new applications or supplements listing your firm as an API manufacturer. Until these deviations are corrected and a FDA inspection confirms your facilities to be compliant with the cGMP, FDA will continue to deny entry of articles manufactured at Nanjing Chemical Industry Park, No.9, Fangshui East Road, Nanjing, China 210047 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). Additionally, you should consider obtaining the services of an organization or person known by FDA to have knowledge and experience in FDA rules and regulations to certify the firm as in compliance prior to any future inspection by FDA personnel. You should also consider obtaining the services of an organization or individual known to possess keen knowledge in cGMP or Q7 "Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients" to provide training to all employees and management.

We remind you that your firm shall comply with the drug establishment registration and drug listing requirements as codified in Title 21, Code of Federal Regulations, section 207.40 (21 C.F.R. 207.40). in order to export drugs to the U.S.A. You can find pertinent information on-line at the following internet website: http://www.fda.gov/cder/drls/registration_listing.htm.

Please note that a guidance document entitled "Q7 Good Manufacturing Practice Guidance for Active Pharmaceutical Ingredients" (ICH CGMP Guidance), prepared under the auspices of the International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), describes current good manufacturing practice (cGMP) for the manufacturing of APIs. The guidance is intended to help ensure that all APIs meet the standards for quality and purity they purport or are represented to possess. Although the ICH CGMP guidance does not impose requirements, FDA considers its recommendations, as well as alternatives intended to accomplish the same goals and provide an equivalent level of quality assurance, in determining whether a firm's APIs have been manufactured, processed, packed, and held according to current good manufacturing practice under section 501 (a)(2)(B) [21 U.S.C. 351(a)(2)(B)] of the Act. To obtain the ICH CGMP guidance document for your reference, please refer to the following website: http://www.fda.gov/cder/guidance/4286fnl.htm.

Please contact Jonathan R. Bray, Compliance Officer, at the following address and telephone number if you have any questions related to animal drugs:

U.S. Food & Drug Administration
Center for Veterinary Medicine (CVM)
Office of Surveillance & Compliance
Division of Compliance
Enforcement & Regulatory Policy Team (HFV-232)
7519 Standish Place
Rockville, MD 20855 U.S.A.
Phone: (240) 276-9228
Fax: (240) 276-9241

Or, please contact Brian L. Belz, Compliance Officer, at the following address and telephone number if you have any questions related to human drugs:

U.S. Food & Drug Administration
Center for Drug Evaluation and Research (CDER)
Division of Manufacturing and Product Quality
International Compliance Branch (HFD-325)
10903 New Hampshire Avenue
Silver Spring, MD 20993 U.S.A.
Tel: (301) 796-4279
Fax: (301) 847-8743

To schedule are-inspection of your facility, after corrections have been implemented and your firm is in compliance with cGMP requirements, send your written request to:

Director
U.S. Food & Drug Administration
Office of Regulatory Affairs
Office of Regional Operations
Division of Field Investigations (HFC-130)
5600 Fishers Lane
Rockville, MD 20857 U.S.A.

You can also contact that office by telephone at (301) 827-5655 or by fax at (301) 443-6919.

 

Sincerely yours,
/S/
Neal Bataller, ME, DVM,
Director,
Division of Compliance
Office of Surveillance & Compliance
Center for Veterinary Medicine
 

 

/S/

Richard L. Friedman MS
Director,
Division of Manufacturing and Product Quality
Office of Compliance
Center for Drug Evaluation & Research

 

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