FDA Warning Letters: October 2010

Friday, October 29, 2010

CP Pharmaceuticals, Ltd. 10/29/10


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

Warning Letter

WL: 320-11-002

October 29, 2010

Mr. Sirjiwan Singh
Managing Director
CP Pharmaceuticals, Ltd.
Ash Road North
Wrexham Industrial Estate
Wrexham, LL13 9UF, United Kingdom

Dear Mr. Singh:

During our July 22-29, 2010 inspection of your pharmaceutical manufacturing facility, CP Pharmaceuticals, Ltd., located at Ash Road North, Wrexham Industrial Estate, Wrexham, LL13 9UF, United Kingdom, 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.

We acknowledge your written responses, dated September 3, 2010, and September 24, 2010, to the Form FDA 483. However, because these responses were received more then 15 business days after the Form FDA 483 was issued, the responses have not been considered. We plan to evaluate your responses to the Form FDA 483, along with any other written material provided, as a direct response to this Warning Letter.

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

1. Your firm has not established separate or defined areas or such other control systems to prevent contamination during aseptic processing [21 C.F.R. § 211.42(c)]. For example,

a. There is no documentary evidence of in-situ air pattern analysis (e.g., smoke studies) conducted at critical areas to demonstrate unidirectional airflow and sweeping action over and away from the product under dynamic conditions. Your firm failed to demonstrate that the appropriate design and controls are in place to prevent turbulence and stagnant air in the critical area. It is essential that you evaluate airflow patterns for turbulence that can act as a channel for air contamination. The studies should be well documented with written conclusions, and should include an evaluation of the impact of aseptic manipulations (e.g., interventions) and the equipment design.

b. Your aseptic processing control systems and operations do not provide assurance that the production rooms and equipment maintain aseptic conditions. Additionally, your environmental monitoring practices do not include adequate routine examination of the facilities and equipment to ensure that possible contaminants can be detected.

The inspection documented mold contamination in the class 100 production room and poor conditions of a wall in the freeze dryer room, even though maintenance is conducted on the freeze dryer every (b)(4) months. An incident report, initiated in November 2009, identifies holes in the ceiling and visible light coming from the roof near the ventilation system, bubbling of the vinyl and disintegration of the wall under vinyl in the freeze dryer room, visible black mold on the wall, a poor drain system for the freeze dryer steam venting system, and a soft (spongy) wall.

c. Operators involved in the filling operations for the sterile drug products manufactured at your facility do not practice adequate aseptic techniques to prevent product contamination. The environmental monitoring performed at the end of the production run consist of sampling the chest and the hand most frequently used (right or left) of the employee's gown. Also, this procedure is performed by the gowned operator and is not monitored by a second qualified person (e.g., supervisor; quality unit personnel) to ensure the proper techniques are being applied. This practice is unacceptable. We expect that all operators who conduct operations within aseptic processing areas be properly trained and monitored to ensure that proper techniques are utilized during all operations, including aseptic filling operations and personnel sampling.

2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].

For example, your firm’s microbiology laboratory does not perform species identification on a routine basis of the yeast and molds detected in your production area. There was no identification raw data available for the media fill that failed in November 2009. Additionally, your firm does not perform challenge testing to the sterility media with environmental isolates from the environmental monitoring program.

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

For example, at the time of the inspection the validation data for several laboratory methods was incomplete or unavailable (i.e. total viable aerobic count for the API, total viable aerobic plate count of raw materials, and bacterial endotoxin testing for ((b)(4)). However, you approved the validation for these methods without the complete data in place.

In addition to the items listed above, the inspection uncovered deficiencies that increase our concerns regarding the quality of the sterile drug products manufactured at your facility. These issues include, but are not limited, to:

ô€‚ƒ Your firm failed to adequately address the increased adverse trends observed in the environmental monitoring trends for the period of August 2009 to May 2010; and, therefore, did not recognize that the environment did not appear to be under control.

ô€‚ƒ Your firm did not establish a schedule for the cleaning with an agent designed to kill spores, although mold continued to be found in the class 10,000 area. Our investigators observed that the mold contamination had not been eliminated at the time of the inspection in July 2010, almost a year after the initial discovery.

We are concerned that your firm has not properly evaluated the risk these deviations pose to the products that have been released and distributed. Your firm has not provided a scientific justification to ensure the product available in the United States (U.S.) market is in compliance with CGMP standards. Please provide a list of all the products and lots shipped to the U.S. that remain within expiration, and any additional corrective actions you plan to initiate. It is important that you take appropriate actions to address these deficiencies and notify us if any actions are planned for lots of sterile drug products manufactured by your Wrexham facility, and include your rationale.

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. If you wish to continue to ship your products to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.

Until all corrections have been completed and FDA has confirmed corrections of the violations and your firm’s compliance with CGMP, FDA may withhold approval of any new applications or supplements listing your firm as a drug product manufacturer. In addition, failure to correct these violations may result in FDA refusing admission of articles manufactured at CP Pharmaceuticals, Ltd., Ash Road North, Wrexham Industrial Estate, Wrexham, LL13 9UF, United Kingdom, into the United States. The articles are subject to refusal of admission pursuant to section 801(a)(3) of the Act [21 U.S.C. § 381(a)(3)], in that, the methods and controls used in their manufacture do not appear to conform to Current Good Manufacturing Practice within the meaning of section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct 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. Please identify your response with FEI # 3003369660.

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

U.S. Food and Drug Administration
Center for Drug Evaluation and Research
Division of Manufacturing and Product Quality
International Compliance Branch
White Oak, Building 51, Room 4224
10903 New Hampshire Ave
Silver Spring, MD 20993
Tel: (301) 796-3201
Fax: (301) 847-8741

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

CP Pharmaceuticals, Ltd. 10/29/10


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

Warning Letter

WL: 320-11-002

October 29, 2010

Mr. Sirjiwan Singh
Managing Director
CP Pharmaceuticals, Ltd.
Ash Road North
Wrexham Industrial Estate
Wrexham, LL13 9UF, United Kingdom

Dear Mr. Singh:

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

1. Your firm has not established separate or defined areas or such other control systems to prevent contamination during aseptic processing [21 C.F.R. § 211.42(c)]. For example,

2. Your firm has not thoroughly investigated the failure of a batch or any of its components to meet its specifications whether or not the batch has already been distributed [21 C.F.R. § 211.192].

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

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

Tuesday, October 26, 2010

Bay Island, Inc. 10/26/10


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) 758-7185 FAX: (612) 334-4142

October 26, 2010

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Refer to MIN 11 - 03

Robert G. Bolling
Owner and Chief Executive Officer
Bay Island, Inc.
10501 Bren Road East
Minnetonka, Minnesota 55343

Dear Mr. Bolling:

The Food and Drug Administration (FDA) conducted an inspection of your packaged food warehouse located at 2300 Highway 13, Burnsville, Minnesota, on July 23, 26, 27 and August 2, 2010. During the inspection, the FDA investigators documented serious violations of the Current Good Manufacturing Practice (CGMP) regulation for foods, Title 21, Code of Federal Regulations, Part 110 (21 CFR 110). These violations cause the food products produced in your facility to be 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 have been prepared, packed, or held under insanitary conditions whereby they may have become contaminated with filth or rendered injurious to health. You can find the Act and the FDA regulations through links on FDA's homepage at www.fda.gov.

Your significant violations are as follows:

1. Effective measures were not taken to exclude pests from your facility and to protect against the contamination of food on the premises by pests, as required by 21 CFR 110.35(c). Our investigator observed the following evidence of a lack of pest control:

On July 23, 2010:

• Two packages of finished product located along the northeast wall of the North warehouse were gnawed open with product missing.

• A minimum of 15 rodent excreta pellets (REPs) were located along the south portion of the wall that divides the North and South warehouses. Two holes along this portion of the wall had REPs in them.

• Two packages of finished product located in the north section of the South warehouse near a dock door and cardboard recycling area were gnawed pen on top of a cardboard box which fluoresced under blacklight, indicating the presence of rodent urine. Over 40 REPs were in this same area, some in the food package.

• Two dead mice were observed, one in the North warehouse near the southeast portion of the wall and the other observed in the old railway section that is adjacent to the South warehouse.

• Two packages of finished product located in the center area of the North warehouse were gnawed open with over 20 REPs in and around the packages.

On July 26, 2010:

• A box located on a pallet along the west wall of the North warehouse had 10 REPs on top of it, and an area of the box fluoresced under blacklight.

• Over 20 REPs were located on a pallet containing boxes of finished product. The pallet was located along the west wall of the North warehouse. Boxes of finished product that were loaded onto a trailer contained packages that were gnawed open. REPs and fluorescent stains were observed inside these boxes and on product packaging.

Additionally, you stated that you failed to provide pest control, such as employing the services of a pest control company, at your warehouse facility where packaged foods were stored from January 2010 to the time of our inspection in July 2010.

We acknowledge the corrections made during the inspection process, specifically that a pest control firm was observed by the inspectors on July 27, 2010, setting traps inside and outside the warehouse; however, we have not received documentation of pest control action by a licensed professional or a plan for ongoing pest control.

2. Adequate screening or other protection against pests was not provided, as required by 21 CFR 110.20(b)(7). The investigator observed the following on inspection dates July 23,26, and 27, 2010:

• Ten out of twelve dock doors located in the North warehouse leading to the exterior parking lot of the facility were fully open on all three inspectional days. There were no screens or other pest control measures, such as plastic strips, covering the doorways and, during the course of the three-day inspection, only one trailer was observed being loaded (on July 26, 2010).

• Two dock doors located on the southern half of the warehouse leading to the exterior of the building were open without screens at various times during the course of the inspection. These dock doors are located approximately 20 feet from an overgrown area of foliage.

• Dock doors were not securely fitted to create a seal, and brush plates were noted to be worn or absent on several of the dock doors.

• Three doorways located along the southern wall connecting your facility to an adjoining warehouse leased by another company lacked doors or screening. The dock door for the adjoining warehouse was observed to be open to the exterior of the facility.

We acknowledge the discussion about corrections that took place between Mr. Benson and the inspectors on August 2, 2010, and receipt of your written response on August 12, 2010, to the FDA-483, Inspectional Observations, issued to you at the close of the inspection. However, your response did not provide any documentation of the corrections or photographs of the improvements made to the building.

This letter may not list all the violations at your facility. You are responsible for ensuring that your food facility operates in compliance with the Act and the Current Good Manufacturing Practice regulations (21 CFR 110). You also have a responsibility to use procedures to prevent further violations of the Act and all applicable regulations.

Failure to implement lasting corrective action of these violations may result in enforcement action being initiated by FDA without further notice. For example, we may take further action to seize your products and/ or enjoin your firm from operating.

Additionally, our investigator found that you have failed to update required facility registration information, such as the facility address, within 60 days of any change, as required by 21 CFR 1.234. You have been operating at your current location since June 2009 but have not updated your registration to reflect this change in location. Please take prompt action to correct this required information.

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 and the specific steps you have taken to correct the noted violations. In your response, include, for example, documentation of actions performed by a licensed exterminator, documentation of other actions performed to control unauthorized entrance of pests, plans on how you plan to protect food products from possible contamination, photographs of corrective measures you have put in place and/or any other useful information that would assist us in evaluating your corrections. If you cannot complete all corrections before you respond, 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: Melissa I. Michurski, Compliance Officer, at the address listed in the heading of this letter. If you have questions regarding any issue in this letter, please contact Ms. Michurski at (612) 758-7185.

Sincerely,
/S/
Gerald J. Berg
Director
Minneapolis District

Thursday, October 21, 2010

Nobel Laboratories, LLC 10/21/10


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

October 21, 2010

2011-DAL-WL-001

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Fasprin Health, LLC / Nobel Laboratories, LLC
Attn: Edward J. Petrus, MD
President, Fasprin Health, LLC / Nobel Laboratories, LLC
3413 Spanish Oak Dr.
Austin, TX 78731

Dear Dr. Petrus:

This letter concerns "FASPRIN®" (Fasprin), which is marketed by your firm in quick dissolving tablet form as an over-the-counter (OTC) internal analgesic product. According to the package labeling, Fasprin is used for temporary relief of occasional headaches, minor aches and pains and for relief of fever (internal analgesic and antipyretic uses), as well as for various other uses. Fasprin's package label identifies aspirin as the active ingredient and each tablet contains 81 mg of aspirin. Other labeling identifies glucosamine, zinc salt and magnesium salt as active ingredients for other drug uses, as described below.

The labeling for Fasprin contains statements that cause the product to be a drug, as defined by section 201 (g) of the Federal Food, Drug, and Cosmetic Act (the Act) (21 U.S.C. § 321 (g)).

The following are examples of intended drug uses described in the labeling for this product:

From the package label

• "Purpose[:] Pain Reliever/Fever Reducer"
• ''The Easy Way to Maintain Your Daily Aspirin Regimen" directly above a vignette of an EKG and a heart
• "Clinical Studies Indicate Low-Dose Aspirin Therapy Helps Reduce The Risk Of Heart Attack Or Stroke"
• "Daily Use Of Low-Dose Aspirin is Recommended By The American Heart Association"
• "Take FASPRIN For Emergency Treatment. At First Signs Of Heart Attack Or Stroke Call 911, Take Two FASPRIN ...."

Additional labeling claims from your websites,
(http://www.nobellabs.com/pages/fasprin.html, http://www.fasprin.com and
http://www.fasprinhealth.com). and product brochure (available at http://www.fasprin.com/)
• "ideal for: Daily low dosage aspirin therapy
Usage at the onset of symptoms of stroke ...
Arthritis pain treatment."
• "with regular use ... reduces blood pressure and enhances blood flow in small vessels"
• "Additionally the FDA advises physicians to prescribe aspirin for patients with angina (chest pain), to reduce the risk of death in patients with a suspected acute heart attack, to prevent recurrent heart attacks, prevent stroke (blockage of blood flow to the brain), and treat transient ischemic attacks (mini-stroke)"
• "Every other day use of aspirin had a 44% reduction in the incidence of first myocardial infarction"
• After describing the process of a heart attack the website states "aspirin should be given within 1 hour of the start of heart attack symptoms."
• "Fasprin also contains glucosamine to protect the lining of the mouth and GI tract; a zinc salt to promote healing of any ulcerationsplus to help prevent tinnitus associated with salicylates, and a magnesium salt to buffer the aspirin and decrease acid production in the stomach."
• "Fasprin® incorporates glucosamine and a zinc salt to prevent any irritation."
• "Figures show that long-term use of aspirin may double the chance of living a healthy life into your 90s!"
• "Low dose aspirin can reduce the risk [of Deep Vein Thrombosis] by 36 percent"
• "Did you know that the daily use of aspirin • Reduces the risk of stroke by 30% • Reduces the risk of Alzheimer's disease by 50% • Reduces the risk of Parkinson's disease by 45%"
• "Aspirin use is linked to lower rates of cancer"
• "Low dose aspirin reduces the risk of colon cancer by 50-60%"
• "Aspirin use treats and prevents periodontal disease"
• "Aspirin use reduced vision loss in elderly"
• "Aspirin prevents gall stone formation"
• "Aspirin may improve cognitive function in Alzheimer's patients"

As labeled, Fasprin is a drug under section 201(g)(1)(B) of the Act (21 U.S.C. § 321 (g)(1)(B)), because it is intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease in man (e.g., cardiovascular-related diseases, arthritis, colon cancer, Alzheimer's disease, Parkinson's disease, gall stone formation, vision loss, periodontal disease, and longevity), and under section 201(g)(1)(C) of the Act (21 U.S.C. § 321 (g)(1)(C)), because it is intended to affect the structure or function of the body.

New Drug Violation

A. New indications for use, combination of active ingredients and dosage

Based on the combination of active ingredients and claims made for this product, Fasprin is a "new drug" within the meaning of section 201(p) of the Act (21 U.S.C. § 321(p)). Although the "Purpose" section of Fasprin's Drug Facts panel states that Fasprin is intended as a "Pain Reliever/Fever Reducer,¹Fasprin's labeling claims demonstrate that one of its primary marketed intended uses is for cardiovascular-related diseases and events, including heart attacks, strokes and deep vein thrombosis. As described in 21 C.F.R. § 343.80, certain claims for the
treatment or prevention of cardiovascular- and cerebrovascular-related diseases are permissible only in professional labeling for aspirin. According to the labeling, Fasprin is also intended for arthritis pain treatment; reducing the risk of Alzheimer's, Parkinson's disease and colon cancer; treating and preventing periodontal disease, reducing vision loss; preventing gall stone formation; and increasing longevity. Fasprin's uses for Alzheimer's disease, Parkinson's disease, colon cancer, periodontal disease, vision loss, gall stone formation, arthritis pain relief, and longevity are not covered by the tentative final monograph (TFM) for OTC internal analgesics (53 Fed. Reg. 46204, Nov. 16, 1988) or the final rule covering professional labeling for internal analgesics (63 Fed. Reg. 56802, Oct. 23, 1998). Moreover, we are not aware of evidence to show that Fasprin, as formulated and labeled, is generally recognized as safe and effective.

In addition, several of the above claims discuss Fasprin containing glucosamine, a zinc salt, and "a magnesium salt" intended for uses that represent and suggest they are active ingredients under 21 C.F.R. § 201.66(b)(2), based on the claims they are components intended to furnish pharmacological activity or other direct effect in the mitigation or treatment of disease or to affect the function of the body.² The Internal Analgesics TFM did not include the combination of aspirin, glucosamine, zinc salt, and "a magnesium salt" as a combination of active ingredients, nor was this combination of ingredients evaluated as part of the Food and Drug Administration's (FDA's) OTC Drug Review for any of the internal analgesic/pain relief uses found in the labeling for Fasprin.

Also, the labeled directions for adult analgesic use of Fasprin specify a 81 mg daily dosage of "1 tablet daily" which falls within the range of the dosage listed in the professional labeling for aspirin for cardiovascular-related indications (see 21 C.F.R. § 343.80), but is well below the dosages for pain and fever relief that were' considered in the Internal Analgesics TFM and OTC Drug Review. See 53 Fed. Reg. 46204 at 46257.

Therefore, based on the combination of active drug ingredients, dosage, and its labeled uses in mitigating, treating or preventing cardiovascular- and cerebrovascular-related diseases, Alzheimer's disease, Parkinson's disease, colon cancer, periodontal disease, vision loss, gall stone formation, arthritis pain relief, and longevity, as described above, Fasprin is a "new drug" within the meaning of section 201 (p) of the Act (21 U.S.C. § 321 (p)), as further described in 21 C.F.R. § 310.3(h), because it is not generally recognized as safe and effective for such labeled uses. Fasprin is not covered by FDA's OTC Drug Review because no product formulated with this combination of active ingredients and dosage, and labeled for these intended uses has previously been commercially marketed on or before the inception of that review, and the Agency has never proposed that such a product be included in that Review. Thus, the current marketing of Fasprin violates section 505(a) of the Act (21 U.S.C. § 355(a)), because it is a "new drug" and it is not the subject of an approved new drug application.

B. New dosage form and method of administration

In addition, Fasprin for the uses described above is in a dosage form that is not generally recognized as safe and effective. According to its package labeling, Fasprin is a tablet that "Dissolves In Your Mouth Not In Your Stomach[,]" is " • Fast Acting" and is " • Quick Dissolv[ing]." According to its websites (http://www.nobellabs.com/pages/fasprin.html and http://www.fasprin.com), Fasprin "melts in the mouth after contact with saliva on the tongue and is absorbed by the lining of the mouth, avoiding first-pass metabolism" and "Get[s] into the blood stream faster," such that, "[t]he protective action of aspirin is available within 5 minutes after absorption in the mouth." Fasprin's website "Q&A" goes on to explain "[s]ince Fasprin is absorbed by the lining of the mouth and carried with about 140 blood vessels, no tablet makes contact with the lining of the stomach to cause direct irritation."

FDA is not aware of any evidence demonstrating that a fast acting quick dissolve internal analgesic tablet absorbed by the lining of the mouth was marketed at the inception of or considered under the OTC Drug Review. Because the dosage form is intended to avoid first-pass metabolism and be absorbed by the lining of the mouth unlike the dosage form covered by the Internal Analgesics TFM, without review of safety and efficacy data, the agency cannot conclude that such a dosage form is suitable for dosing conditions established under that TFM. A product that is initially marketed after the inception of the OTC Drug Review and that does not fully meet conditions established under the procedural regulation established in the OTC Drug Review is ineligible for the OTC Drug Review and requires an FDA-approved drug application before it can be legally marketed in the U.S. 21 C.F.R. §§ 330.1, and 330.10(b); 21 U.S.C. §§ 321(p) and 355(a).

As a result, Fasprin's dosage form and method of administration are not generally recognized as safe and effective. 21 C.F.R. §§ 330.1, and 330.10(b). Therefore, Fasprin is a "new drug," as defined in section 201(p) of the Act (21 U.S.C. § 321 (p)). See also 21 C.F.R. § 310.3(h)(5). The current marketing of Fasprin in the United States violates section 505(a) of the Act (21 U.S.C. § 355(a)), because it is a "new drug" and it is not the subject of an approved new drug application.

Misbranding Violations

Furthermore, Fasprin is misbranded under section 502(f)(1) of the Act (21 U.S.C. § 352(f)(1)) because it does not bear adequate directions for its intended cardiovascular and arthritis use. "Adequate directions for use" is defined in 21 C.F.R. § 201.5 as "directions under which the layman can use a drug safely and for the purposes for which it is intended." Thus, if an indication requires the supervision of a practitioner licensed to prescribe drugs, adequate directions for use cannot be written for consumer directed OTC use. See U.S. v Articles of Drug, 625 F.2d 665, 672-673 (5th Cir. 1980). The directions are also inadequate under 21 C.F.R. §201.5 because the label does not include a "Uses" section as required by 21 C.F.R. § 201.66(c)(4) to identify the intended uses. In addition, Fasprin's direction to take one 81 mg tablet daily is inadequate with respect to the aspirin doses considered under the OTC Drug Review for pain and fever relief and thus it is misbranded under 502(f)(1).

Fasprin is also misbranded under section 502(a) of the Act (21 U.S.C. § 352(a)) because the labeling of Fasprin as "The Easy Way to Maintain Your Daily Aspirin Regimen" is misleading when juxtaposed with the ten and three day limitations for pain and fever use, respectively, as set forth under the "Do Not Use" section and with the "take 1 to 4 tablets and repeat hourly, not to exceed 20 tablets during a 24 hour period" included on Fasprin's website. The statements on the labeling send consumers a mixed message about the purpose of the product and the duration for which it can be safely used and as such the labeling is misleading. Additionally, because these labeled warnings are undermined by the inconsistent and incompatible language pertaining to the use as a daily regime with no time frame, Fasprin fails to bear adequate warnings against unsafe duration of administration and, therefore, is also misbranded under section 502(f)(2) of the Act (21 U.S.C. § 352(f)(2)).

Fasprin is also misbranded under 502(a) and 502(f)(2) because its immediate container, which is the blister card, does not contain the Reyes Syndrome warning as required for aspirin containing internal analgesic products under 21 C.F.R. § 201.314(h).

As previously discussed, Fasprin labeling claims that Fasprin contains glucosamine, a zinc salt, and "a magnesium salt" intended for uses that represent and suggest the ingredients are active ingredients under 21 C.F.R. § 201.66(b)(2). Accordingly, all three ingredients are required to be listed as active ingredients under 21 C.F.R. § 201.10 and 21 U.S.C. § 352(e)(1)(A)(ii). However, Fasprin's label only lists glucosamine (Glucosamine Sulfate-K) and a zinc salt (Zinc Gluconate) as inactive ingredients and does not list any magnesium salt ingredient. As a result Fasprin is misbranded under 502(a) and 502(e)(1)(A)(ii).

Fasprin is further misbranded under section 502(e)(1)(A)(ii) of the Act (21 U.S.C. § 352(e)(1)(A)(ii)) because it fails to list and declare the quantity of all active ingredients. As previously discussed the glucosamine, zinc salt and "a magnesium salt" contained in Fasprin are active ingredients under 21 C.F.R. § 201.66(b)(2). Also, based on the labeled claims, "a magnesium salt" is present in the formulation, as noted above. However, there are no magnesium-containing ingredients listed on the package labeling. As neither glucosamine, zinc salt nor magnesium salt is listed as an active ingredient of Fasprin, the product is misbranded under section 502(e)(1)(A)(ii) of the Act.

In addition to the above violations, Fasprin is also misbranded under section 502(c) of the Act (21 U.S.C. § 352(c)), because the product is not labeled in accordance with the "Drug Facts" labeling requirements described in 21 C.F.R. § 201.66. For example, there is no "Uses" section under the "Drug Facts" as required by 21 C.F.R § 201.66(c)(4).

Finally, the introduction or delivery for introduction of a misbranded drug into interstate commerce is prohibited under section 301 (a) of the Act (21 U.S.C. § 331 (a)). Therefore, the marketing of Fasprin in the United States violates this provision of the Act.

The violations cited in this letter are not intended to be an all-inclusive list of deficiencies regarding your products, nor are the arguments raised here regarding them exhaustive. You are responsible for investigating and determining the causes of these violations and for preventing their recurrence and the occurrence of other violations. It is your responsibility to assure that your firm complies 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.

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct the referenced violations. Include an explanation of each step being taken to prevent the recurrence of violations, as well as copies of related documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the time within which you will complete the correction.

Please send your reply to the Food and Drug Administration, Attention: Sherrie L. Krolczyk, Compliance Officer at the letterhead address. If you have questions regarding the content of this letter, please contact Sherrie L. Krolczyk at 214-253-5312.

Sincerely,

/S/

Reynaldo R. Rodriguez, Jr.
Dallas District Director

RRR/sik

---------

¹ Aspirin for use as a pain and fever reducing internal analgesic is addressed in the OTC Drug Review under the Tentative Final Monograph (TFM) issued on November 16, 1988 for OTC Internal Analgesics.

² The specific glucosamine and zinc salt listed on Fasprin's label are Glucosamine Sulfate-K and Zinc Gluconate, both of which are listed as inactive ingredients. While the labeling also discusses the use of a magnesium salt, there is no magnesium salt listed under either the active ingredient or inactive ingredient headers.

Hong Chang Corporation 10/21/2010


Department of Health and Human Services	Public Health Service Food and Drug Administration
	Los Angeles District 19701 Fairchild Irvine, California 92612-2506 Telephone (949) 608-2900 Fax (949) 608-4415

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

October 21, 2010

W/L 08-11

Ms. Hai Hua Li, President
Hong Chang Corporation, dba California Food International
10155 Painter Avenue
Santa Fe Springs, CA 90670-3017

Dear Ms. Li:

The Food and Drug Administration (FDA) conducted an inspection of your food storage and processing facility located at 10155 Painter Avenue, Santa Fe Springs, CA from July 7 - 23, 2010. During the inspection, FDA investigators documented serious violations of the Current Good Manufacturing Practice regulations for manufacturing, packing, or holding human food, Title 21, Code of Federal Regulations, Part 110 (21 CFR Part 110). The inspection revealed that food stored at your facility is 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)] because these food products have been prepared, packed, or held under insanitary conditions whereby they may have become contaminated with filth. You can find the Act and its associated regulations on the internet through links on the FDA web page at www.fda.gov.

The following significant violations were observed during the inspection:

1) You failed to take effective measures to exclude pests from your facility and to protect against the contamination of food on the premises by pests, as required by 21 CFR 110.35(c).

The conditions observed include the following:

• Rodent excreta pellets in the storage refrigerator at your facility;

• Rodent excreta pellets in your Compressor Pump Room, in Storage Room (b)(4) your Repacking/Packing Room, and on food processing equipment;

• Contaminated bags of Perilla Seeds in the storage refrigerator at your facility with rodent excreta pellets and rodent urine on the bags and evidence of rodent guawing on bags of these food products stored in the refrigerator;

• Rodent excreta pellets and urine on bags of Soy Bean products, boxes of Dried Radish Stem products, (b)(4) Bread Crumb products, bagged (b)(4) Rice products and bagged Green Pea products;

• Evidence of rodent gnawing on bagged (b)(4) Rice products, bagged Black Bean products, bagged Perilla Seed products, bagged Brown Rice Flour products, bagged Red Whole Chili products, and bagged Brown Rice Flour products;

• Rodent traps on a bag of (b)(4) Rice products and on a box containing Roasted Black Sesame Seed products;

• Bird feces on an outer box containing Perilla Seed products;

• Rodent excreta pellets on bagged Chili Powder products, on boxes of Dried Kelp products, Gagocha Powder products, bags of Perilla Seed products, bags of Mixed Rice products, Red Whole Chili products, bagged (b)(4) Rice products, bagged (b)(4) Rice products, bagged Evaporated Food Grade Salt products, boxes of Natural Sea Salt products, boxes of Tempura Mix Powder products, boxes of Cabbage Kimchi products, bags of Radish Leaf products, bags of Soy Bean products, and bagged Brown Rice Flour products;

• Moth-like insects on bagged (b)(4) Rice products, and on bagged Soy Bean products;

• Rodent urine on boxes of Natural Sea Salt products; and

• A gap of approximately 1/2 inch at the base of an exterior door to your film's facility serving as an entryway for rodents and pests.

We acknowledge that on July 9, 2010, your firm voluntarily destroyed 36,814 lbs. of food products, including the above referenced adulterated food products. We note that not all the food products in the facility were destroyed, and' harborage areas still exist under pallets of food products not removed, as well as elsewhere in the facility. In your response, dated August 4, 2010, you state that your firm hired a new pest control company to correct the rodent infestation at your facility, hired one full-time janitor to inspect the facility on a daily basis and to be responsible for "routine housekeeping," and made structural repairs to an exterior door. You provide photographs that demonstrate cleaning was performed in your warehouse, and show an exterior door without any visible gap.

However, cleaning the facility and hiring a new pest control company may not be sufficient to eradicate pests living in walls, under pallets of remaining food products, in mechanical areas, such as within refrigeration units, in areas above suspended ceiling systems, and other areas within your facility. Further, the documentation submitted does not indicate the specific steps taken to repair the above referenced gap in the exterior door. You should provide additional documentation of the steps taken to exclude pests from your facility.

2) Your firm failed to provide sufficient space for storage of materials as necessary for the maintenance of sanitary operations and the production of safe food, as required by 21 CFR 110.20(b)(1).

The inspection disclosed that Freezer (b)(4) lacks adequate space for sanitation inspections. There are stacked pallets of frozen products with no space in between the pallets for performing inspections.

In your response, dated August 4, 2010, you state that your firm emptied and re-organized Freezer #(b)(4) in a manner that now provides aisle space, allowing free movement and the ability to inspect the space. However, we are unable to determine from your response the adequacy and the extent to which this corrective action has been carried out to provide sufficient space for the maintenance of sanitary operations within the freezer area. You should provide additional documentation of your corrective action and steps taken to prevent recurrence.

The above items are 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. You should take prompt action to correct these violations. Failure to do so may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure and/or injunction.

Please notify this office in writing within 15 working days of receipt of this letter of the specific steps you have taken to correct the noted violations and to prevent recurrence. Include documentation of the corrective action, including those you have taken since your August 4, 2010 response. 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:

Mr. Blake Bevill
Director, Compliance Branch
Food and Drug Administration
19701 Fairchild
Irvine, CA 92612-2506

If you have any questions about the content of this letter please contact: Dr. William Vitale, Compliance Officer at 949-608-2919.

Sincerely yours,
/S/

Alonza E. Cruse
District Director

Hanover Foods Corporation 10/21/10


Department of Health and Human Services	Public Health Service Food and Drug Administration
	Baltimore District Office 6000 Metro Drive, Suite 101 Baltimore, Maryland 21215 TELEPHONE: 410-779-5455

WARNING LETTER

(b)(4)

October 21, 2010

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Mr. John A. Warhime, CEO/Chairman
Hanover Foods Corporation
P.O. Box 334
Hanover, Pennsylvania 17331

Dear Mr. Warhime:

The Food and Drug Administration (FDA) conducted an inspection of your produce manufacturing facility, located at 502 Factory Lane, Hanover, Maryland from April 6 to April 30, 2009 and from May 11 to May 27, 2010. During the inspection, FDA collected a number of samples. Laboratory analyses of these samples found the presence of the pathogen Listeria monocytogenes (L. mono) in environmental and in-line samples. In addition, FDA investigators documented serious violations of the Current Good Manufacturing Practice (CGMP) regulation for foods, Title 21, Code of Federal Regulations, Part 110 (21 CFR 110). These observations and the results of the laboratory analysis cause the foods manufactured at your facility to be adulterated under 402(a)(4) [21 U.S.C. 342(a)(4)] of the Federal Food, Drug and Cosmetic Act (the Act), in that they were prepared, packed, or held under insanitary conditions whereby they may have become contaminated with filth, or whereby they may have been rendered injurious to health. You may find the Act and FDA’s regulations through links in FDA’s home page at http://www.fda.gov.

During the inspection, FDA collected samples of in-line sliced mushrooms, and environmental swabs and sponges taken from throughout your processing facility, including the Individually Quick Frozen (IQF) room. Laboratory analysis of the samples confirmed the presence of L. mono in a sliced mushroom in-line sample and in an environmental sample from a food contact surface. The finding of L. mono in a sliced mushroom in-line sample, and on food contact surfaces in your facility indicates a high risk of finished product contamination.

L. mono is a pathogenic bacterium that is widespread in the environment and may be introduced into a food processing facility. L. mono can contaminate foods, resulting in a mild illness (called listerial gastroenteritis) or a severe, sometimes life-threatening, illness called invasive listeriosis. Listeriosis is an atypical foodborne illness of major public health concern because of the severity of the disease, a high case-fatality rate, a long incubation and a predilection for individuals with underlying conditions.

Our investigators documented a number of significant objectionable conditions relating to your facility’s compliance with the CGMP regulations. Significant deviations observed during the inspection include:

1. Your firm failed to take effective measures to protect finished food from contamination by ingredients or refuse, and failed to protect food transported by conveyor against contamination as required by 21 CFR 110.80(b)(6). Specifically, the following was observed during the inspection:

A. Ready-to-eat mushrooms were observed spilling from the hopper affixed to the conveyer belt in the IQF room onto an electrical panel accumulated with old food debris. After the mushrooms spilled onto the electrical panel accumulated with old food debris they bounced into a 40lb box containing ready-to-eat mushrooms.

B. Accumulated mushroom debris was observed caught between the conveyer belt and conveyer belt wheel. The accumulated mushroom debris was observed being sprinkled into open boxes containing ready-to-eat mushrooms in the IQF room.

C. Defrosted mushroom debris was observed accumulated on the following pieces of equipment during operation and coming in contact with the rotating conveyer belt carrying ready-to-eat mushrooms to be packed:

  a) Cross beam beneath the magnet as mushrooms exit from the IQF freezer.
  b) Scraper located beneath the magnet as mushrooms exit from the IQF freezer.
  c) Metal guide affixed to magnet as mushrooms exit from the IQF freezer.

2. Your firm failed to take effective measures to protect against the inclusion of metal or other extraneous material in food as required by 21 CFR 110.80(b)(8). Specifically, an accumulation of rust was observed on multiple bolts affixed to a grow rack containing wheat grass in the “Green Sprout Grow Room.” The bolts were observed to be dripping water that accumulated on them from the grow rack's watering system. The rusty bolts were located directly over multiple pans containing in-process (growing) wheat grass.

3. Your firm failed construct your facility in such a manner that drip or condensate from fixtures does not contaminate food as required by 21 CFR 110.20(b)(4). Specifically, two 55 gallon drums that contained ready-to-eat alfalfa sprouts were observed stored uncovered under a water hose reel that was affixed to the wall of the “Sprout Washroom.” The water hose reel was accumulated with water and water droplets were observed dripping into the drums that contained uncovered ready-to-eat alfalfa sprouts.

4. Your firm failed to provide adequate screening or other protection against pests as required by 21 CFR 110.20(b)(7). Specifically, the following was observed during the inspection:

A. The receiving door located on the western wall of the “Dry Warehouse” had three gaps leading to the exterior of the firm.

B. The northern wall of the “Green Bean Room” had a gap which led to the exterior of the firm.

C. The exit door on the southern wall of the “Green Bean Room” had a gap which led to the exterior of the firm.

We have reviewed your June 9, 2010 response letter to the FDA-483 from Bridget Dadds, QC Management. Although your letter states that a number of corrective actions have been completed, the actions outlined in your response letter have not fully addressed all our concerns. Please submit documentation which shows completion of corrections (i.e., revised SSOPs, photographs or receipts that verify equipment or other structural modifications, etc.) and steps you have taken to prevent contamination of finished products with L. mono. The adequacy and implementation of your corrective actions and will be assessed during our next inspection.

This letter may not list all the violations at your facility. You are responsible for ensuring that your processing plant operates in compliance with the Act, and the CGMP regulations (21 CFR Part 110). You should take prompt action to correct these violations. Failure to do so may result in regulatory action being initiated by the FDA without further notice, including 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 June 2010 correspondence, including any further specific steps that you have taken to correct 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: Randy F. Pack, Compliance Branch Director at the address above. If you have questions regarding any issues in this letter, please contact Mr. Pack at (410) 779-5417.

Sincerely,

/s/

Evelyn Bonnin
District Director

Wednesday, October 20, 2010

Vita-Herb Nutriceuticals, Inc. 10/20/10


Department of Health and Human Services	Public Health Service Food and Drug Administration
	Los Angeles District 19701 Fairchild Irvine, California 92612-2506 Telephone (949) 608-2900 Fax (949) 608-4415

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

October 20, 2010

W/L 07-11

Mohamed Bing Baksh, President/CEO
Vita-Herb Nutriceuticals, Inc.
1012 Segovia Circle
Placentia, CA 92870-1944

Dear Mr. Baksh:

On May 18th through June 29th, 2010, the U.S. Food and Drug Administration (FDA) inspected your firm located in Placentia, CA. Your film manufactures, packages, labels, and holds dietary supplements. The inspection identified significant violations of Current Good Manufacturing Practice (CGMP), 21 CFR Part III for the Manufacturing, Packaging, Labeling, or Holding for Dietary Supplements.

The inspection revealed that your (b)(4) Cod Liver Oil capsules, (b)(4) capsules, and (b)(4) Omega-3 DHA capsules products manufactured in your facility, are adulterated within the meaning of Section 402(g)(1) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. 342(g)(1)] in that the dietary supplements have been prepared, packed, or held under conditions that do not meet current good manufacturing practice regulations for dietary supplements. These observations were presented to you in a FDA-483 at the conclusion of our' inspection on June 29, 2010.

The inspection revealed the following deficiencies:

1. Your firm failed to conduct testing of each finished batch of dietary supplement to determine whether such dietary supplement met established product specifications for identity, purity, strength, and composition, as required by 21 CFR 111.75(c). You must establish product specifications for each dietary supplement you manufacture (21 CFR 111.70(e)), and determine whether these specifications are met (21 CFR 111.73) by testing the finished batch of dietary supplement in accordance with testing requirements in 21 CFR 111.75(c).

The inspection disclosed that batch records for the following released finished products lacked finished product testing to verify the identity, purity, strength, and composition:

i. (b)(4) Cod Liver Oil capsules, (b)(4)-count bottles), lots (b)(4) and (b)(4);

ii. (b)(4) Bombyx Mori capsules for male performance, lots (b)(4) (bulk packaged), (b)(4) (one-count blister cards), (b)(4) (one-count blister cards) and (b)(4) (bulk packaged +one-count blister cards);

iii. (b)(4) Omega-3 DHA capsules (b)(4)-count bottles), lot (b)(4).

Pursuant to 21 CPR 111.75(c)(1), you must either verify that every finished batch of these products meets your product specifications or you must identify a subset of finished batches to test using a sound statistical sampling plan.

We reviewed your response dated July 20, 2010, and have concluded that it is inadequate. Your letter stated that you will increase the scope of testing "to capture a wider slice of the products manufactured," but you did not provide documentation that the above batches had finished product testing conducted and did not provide documentation on how you plan to ensure finished product testing is conducted for future batches.

2. Your firm failed to conduct at least one appropriate test or examination to verify the identity of a dietary ingredient, prior to its use, to comply with 21 CPR 111.75(a)(1)(i).

Specifically, your firm uses a (b)(4) cod liver oil, (b)(4) vitamin (b)(4) oil, and (b)(4) oil in your (b)(4) Cod Liver Oil capsules; b) bombyx mod proprietary blend in your (b)(4) capsules; and c) DHA oil, (b)(4) oil and (b)(4) oil in your (b)(4) Omega-3 DHA capsules, but your firm does not perform an identity test or examination on any of the dietary ingredients used in such dietary supplements. Although your firm performs microbiological tests for these dietary ingredients, such testing is not appropriate to indicate the identity of such ingredients.

We reviewed your response dated July 20, 2010, and have concluded that it is inadequate. Your letter stated that you will increase the scope of testing, but you did not specify and submit supporting documentation on how you intend to ensure that you will verify the identity of each dietary ingredient used in these dietary supplements you manufacture.

3. Your film failed to approve and release from quarantine all components before they were used, as required by 21 CPR 111.120(e).

Specifically, your quality unit did not approve and release from quarantine the following dietary supplement ingredients before they were used in the manufacture of dietary supplement products.

i. (b)(4) Cod Liver Oil - Material#(b)(4) and (b)(4) was added to your (b)(4) product, Lot (b)(4) and (b)(4) on April 8, 2010 and April 19, 2010, respectively, before the ingredient was released on May 10, 2010.

ii. (b)(4) Beeswax - Material#(b)(4) was added to (b)(4) product, Lot (b)(4) on April 19, 2010, before the ingredient was released on May 10, 2010.

iii. Bombyx Mori Blend - Material#(b)(4) was added to your (b)(4) product, Lots (b)(4) and (b)(4) on January 7, 2010, before the ingredient was released on January 27, 2010.

iv. Bombyx Mori Blend - Material#(b)(4) was added to your (b)(4) product, Lot (b)(4) on April 6, 2010, before the ingredient was released on May 10, 2010.

v. DHA (b)(4) Oil - Material#(b)(4) and (b)(4)- Material#(b)(4) was added to your (b)(4) Omega-3 DHA product, Lot (b)(4) on December 9, 2009, before the ingredients were released on December 17, 2009 and December 29, 2009, respectively.

We reviewed your response dated July 20, 2010, and have concluded that it is inadequate. You have not committed to fully complying with the regulation by approving and releasing all components before they are used.

4. Your firm failed to include documentation, at the time of performance, in the batch production record, that quality control personnel approved and released, or rejected, the batch for distribution, including any reprocessed batch, to comply with 21 CPR 111.260(1)(3) and 21 CPR 111.123(a)(8). Specifically, our review of the following batch records for (b)(4) Bombyx Mori capsules for male performance indicate that your quality personnel did not document approval and release, or rejection, of the batch for distribution prior to release of the product for distribution.

Lot Number	Date Shipped	Date of QA Bill of Material	Date of QA Final Formula Review	Date of QA Final Record Review
(b)(4)	1/7/10	1/20/10	1/20/10	Bulk shipped, no packaging record for Final Record Review
(b)(4)	"1/19/09" printed, with actual ship date of 1/19/10	1/20/10	1/20/10	1/20/10
(b)(4)	4/6/10, 4/8/10, 4/14/10, 4/26/10	6/2/10	6/2/10	6/8/10
(b)(4)	5/11/10	No Bill of Material Review	No Final Formula Review	6/8/10

Your firm failed to include documentation, at the time of performance, in the batch production record, that quality control personnel approved and released, or rejected, the packaged and labeled dietary supplement, including any repackaged or relabeled dietary supplement, to comply with 21 CFR 111.260(1)(4) and 21 CPR 111.127(h). Specifically, our review of the following batch records below indicated that you only conducted a review of the batch records of finished dietary supplement products after the finished dietary supplements were released to your customers.

a.) (b)(4) Cod Liver Oil (b)(4)

Lot Number	Date Shipped	Date of QA Bill of Material Review	Date of QA Final Formula Review	Date of QA Final Record Review
(b)(4)	5/6/10, 5/10/10, 5/13/10	5/18/10	5/18/10	5/18/10
(b)(4)	4/28/10	5/18/10	5/18/10	5/18/10

b.) (b)(4) Omega-3 DHA

Lot Number	Date Shipped	Date of QA Bill of Material Review	Date of QA Final Formula Review	Date of QA Final Record Review
(b)(4)	12/28/09, 1/4/10	5/20/10	5/20/10	5/20/10

We reviewed your response dated July 20, 2010, and have concluded that it is inadequate. You have not committed to fully complying with the regulation because an "effort[] to decrease occurrences of this type" does not indicate that you will review the batch records and make a determination on the batch of product (e.g., approved and released or rejected) prior to it being released.

5. Lastly, our review of the inspection records collected during the inspection, specifically, the batch records for the DHA (b)(4) Capsules, Lot (b)(4), showed that you added (b)(4) per capsules of (b)(4) to the batch during blending to compensate for leaky capsules. However, your film failed to make and keep documentation of any material review and disposition decision and follow-up, as required by 21 CFR 111.140(b)(3). Specifically, you did not provide documentation of any material review and disposition decision and follow up for this deviation. Such documentation must meet the requirements of 21 CFR 111.140(b)(3), including an identification of the specific deviation or the unanticipated occurrence [21 CFR 111.140(b)(3)(i)] , a description of your investigation into the cause of the deviation from the specification or the unanticipated occurrence [21 CFR 111.140(b)(3)(ii); an evaluation of whether or not the deviation or unexpected occurrence has resulted in or could lead to a failure to ensure the quality of the dietary supplement [21 CFR 11.140(b)(3)(iii)]; the identification of the actions taken to correct, and prevent a recurrence of, the deviation or unanticipated occurrence [21 CPR 111.140(b)(3)(iv); an explanation of what you did with the component, dietary supplement, packaging, or label [21 CFR 111.140(b)(3)(v)]; and a scientifically valid reason for any reprocessing of a dietary supplement that is rejected or any treatment or in-process adjustment of a component that is rejected [21 CFR 111.140(b)(3)(vi)].

This letter is not an all-inclusive list of violations at your facility. It is your responsibility to ensure that your establishment and the products you market comply with the Act and its implementing regulations. Failure to promptly correct the violations specified above may result in enforcement action without further notice. Enforcement action may include seizure of violative products and/or injunction against the manufacturers and distributors of violative products.

Additionally, we note that there is 2 year expiration dating placed on product labels of (b)(4) Cod Liver Oil capsules and (b)(4) Omega-3 DHA capsules manufactured in your facility. Any expiration date you place on a product label should be supported by data. (See 72 FR 34752 at 34856; June 25, 2007). You should continue to work with your customers to provide supporting data for the expiration dates placed on the products you manufacture.

Please advise this office in wilting within 15 working days from your receipt of this letter of the specific steps you have taken to correct the violations noted above and to ensure that similar violations do not occur in the future. Your response should include any documentation necessary to show that correction has been achieved. If you cannot complete all corrections before you respond, state the reason for the delay and the date by which you will complete the corrections.

Your response should be sent to:

Director, Compliance Branch
Food and Drug Administration
Los Angeles District Office
19701 Fairchild
Irvine, CA 92612

If you have any questions about the content of this letter, please contact Mei-Chen (Jessica) Mu, Compliance Officer, at 949-608-4477.

Sincerely yours,
/S/
Alonza E. Cruse

District Director

Scott, David F., M.D.


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

WARNING LETTER

Oct 20, 2010

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Ref: 11-HFD-45-10-06

David F. Scott, M.D.
785 E Holland Avenue
Spokane, WA 99218-1257

Dear Dr. Scott:

Between March 15 and March 24, 2010, Dr. S. Lori Brown and Dr. Sunitha Rajaram, representing the Food and Drug Administration (FDA), conducted an investigation and met with you to review your conduct of the following clinical investigations:

• Protocol (b)(4), “(b)(4)” of the investigational drug (b)(4), performed for (b)(4).

• Protocol (b)(4), “(b)(4)” of the investigational drug (b)(4) performed for (b)(4).

This inspection is a part of FDA's Bioresearch Monitoring Program, which includes inspections designed to evaluate the conduct of research and to help ensure that the rights, safety, and welfare of the human subjects of those studies have been protected.

From our review of the establishment inspection report, the documents submitted with that report, and your written response dated April 6, 2010, we conclude that you did not adhere to the applicable statutory requirements and FDA regulations governing the conduct of clinical investigations and the protection of human subjects. We are aware that at the conclusion of the inspection, Drs. Brown and Rajaram presented and discussed with you Form FDA 483, Inspectional Observations. We wish to emphasize the following:

1. You failed to ensure that the investigations were conducted according to the signed investigator statements and the investigational plans [21 CFR 312.60].

a. Protocol (b)(4):

i. The protocol states, "Once the subject meets all of the inclusion criteria and none of the exclusion criteria, and the knee replacement surgery has been completed, the investigator or the investigator's designee will contact the IVRS to randomize the subject into the study." Ten subjects (Subjects 002, 003, 004, 005, 006, 008, 009, 010, 011, and 013) were randomized into the study before surgery, contrary to the protocol, prior to sponsor’s approval of your request for exemption, dated May 7, 2008.

ii. The protocol required a complete physical examination for each randomized subject at Day 10 (completion of study) or upon early termination, prior to venography, for the day that the venogram was to be performed (Day 10, Visit 7). You failed to perform this physical examination for any of the randomized subjects in this study.

iii. The protocol states, for visit 5: “Collect blood samples for Pharmacokinetic testing for subjects randomized to (b)(4) only. The samples should be collected at pre-dose, 2, 6, and 12 hours post-dose.” Pharmacokinetic (PK) data was a secondary endpoint of the (b)(4) study.

PK testing was not performed on 11 of the 13 subjects for whom it was required (002, 003, 004, 006, 010, 011, 013, 014, 015, 016, and 017). The (b)(4) laboratories document indicates that the sample was not received, and the eCRF indicates that PK collection was not performed.

iv. Eligibility criteria are designed specifically for each clinical investigation by the sponsor to optimize the interpretability of the data to the disease process under study and to minimize foreseeable harm to enrolled subjects due to comorbidities and possible interactions with concomitant medications.

Protocol exclusion criterion # 16 states, “The subject is taking aspirin > 162 mg/day.”

Source documents indicate that subject 4033017 was taking aspirin while participating in the study.

• Bufferin brand aspirin, with a dose of 325 mg, is listed in the case report form (CRF) under Concomitant Medication, with a start date of 2006 and an end date of (b)(6).

• In addition, Bufferin is included in the source documents (b)(6): Medical History dated (b)(6), under Current Medications).

• Documentation is also found in (b)(6), Medication Reconciliation, Admission Medication Orders: Aspirin (Bayer) 1-2 By Mouth As Needed (date: (b)(6)); and (b)(6), Medication Reconciliation, Admission Medication Orders: Aspirin (Bayer) 1-2 By Mouth As Needed, Last Taken: (b)(6).

v. The protocol indicates that a bilateral venography procedure was required at the End of Treatment or at Early Termination. Venography was not performed for 7 of 16 randomized subjects. For example:

Subjects 017, 018, and 019 did not have venography at the End of Treatment/Day 10 (Visit 7) due to scheduling conflicts and/or technical problems at the radiology clinic.

vi. The sponsor sent you a letter dated June 16, 2008, instructing you to suspend screening new subjects into the study. However, you screened Subject 4033021 into the study on July 23, 2008.

b. Protocol (b)(4):

i. The protocol requires a physical examination at Visit 6 (end of treatment) on the day of the venography procedure.

Subject 72001 had Visit 6 (end of treatment) on August 19, 2008. A physical examination was not conducted at this visit.

ii. The protocol requires a blood sample to be sent to the central laboratory for Liver Function Test (LFT) monitoring at Visit 5 or Day of Discharge. A blood sample for LFT was not drawn and sent to the central laboratory for Subject 72001 on July 25, 2008 (Visit 5) due to hospital error. Instead, these laboratory tests were performed in a local laboratory on August 08, 2008.

iii. The protocol requires a blood sample for laboratory evaluations at Visit 1/Screening Visit. Subject 72004 had Visit 1 on July 18, 2008, but blood samples were not collected until August 22, 2008.

Failure to perform study-related procedures jeopardizes subject safety and welfare, and compromises the interpretation and validity of the investigational endpoints.

2. You failed to obtain Institutional Review Board approval for changes in the research prior to implementing the changes [21 CFR 312.66].

Protocol (b)(4) required randomization of subjects after completion of the surgery. All of the subjects were randomized prior to surgery. After the randomization of 10 of the 16 subjects, sponsor approved your request for an exemption from this protocol requirement (dated May 7, 2008). You failed to obtain the IRB approval for this change.

Making changes in the research without IRB approval compromises the safety and welfare subjects enrolled in the clinical investigation.

3. You failed to maintain adequate and accurate case histories that record all observations and other data pertinent to the investigation on each individual administered the investigational drug or employed as a control in the investigation [21 CFR 312.62(b)].

a. For Protocol (b)(4), the Integrated Voice Response System (IVRS) site’s user manual states: “Complete call worksheets prior to contacting the IVRS; then file completed worksheets with each subject’s source documentation.” The IVRS worksheets were not kept in the subjects’ files or maintained at the site.

b. For Protocol (b)(4), subject eligibility forms in the source document were not filled out. The protocol states in Section 6.2.1, Visit 1: Screening period (Days -14 to Day -1), “Pre-Screen patient for eligibility by checking inclusion/exclusion criteria.” For example, source documents for Subjects 72003 and 72008 show that all the items in the exclusion criteria checklist are checked except for the exclusion criterion related to the history of thrombocytopenia, including heparin-induced thrombocytopenia, or a platelet count < 100,000 cells/micro liter. However, the eCRFs show that all the exclusion/inclusion criteria are checked.

Failing to maintain adequate and accurate case histories compromises the interpretation and validity of the investigational endpoints.

This letter is not intended to be an all-inclusive list of deficiencies with your clinical study of an investigational drug. It is your responsibility to ensure adherence to each requirement of the law and relevant FDA regulations. You should address these deficiencies and establish procedures to ensure that any ongoing or future studies will be in compliance with FDA regulations.

Within fifteen (15) working days of your receipt of this letter, you should notify this office in writing of the actions you have taken to prevent similar violations in the future. Failure to adequately and promptly explain the violations noted above may result in regulatory action without further notice.

If you have any questions, please contact Constance Cullity, M.D., M.P.H., at 301-796- 3397; FAX 301-847-8748. Your written response and any pertinent documentation should be addressed to:

Constance Cullity (formerly Lewin), M.D., M.P.H.
Branch Chief
Good Clinical Practice Branch I
Division of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
Building 51, Room 5354
10903 New Hampshire Avenue
Silver Spring, MD 20993

Sincerely yours,
{See appended electronic signature page}
Leslie K. Ball, M.D.
Director
Division of Scientific Investigations
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration
Reference ID: 2845789
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This is a representation of an electronic record that was signed electronically and this page is the manifestation of the electronic signature.
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/s/
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LESLIE K BALL
10/20/2010

Pacific Fishing Company Limited 10/20/10


Department of Health and Human Services	Public Health Service Food and Drug Administration
	College Park, MD

Warning Letter
I.D. # 120210

OCT 20 2010

VIA OVERNIGHT MAIL

Chandra Prakash
Pacific Fishing Company limited
P.O. Box 41
Beach Street
Levuka, Fj-Nota
Fiji

Dear Mr. Prakash:

In response to a request by the United States Food and Drug Administration for a copy of your firm’s HACCP plan and additional supporting documents including monitoring records for your tuna loins, your firm responded by email on June 4 through 6, 2010 (via 13 separate email messages) with the requested documents. Our evaluation of the HACCP plan you provided (dated May 18, 2010) and supporting documentation revealed serious deviations from the requirements of the seafood Hazard Analysis and Critical Control Point (HACCP) regulation, Title 21, Code of Federal Regulations, Part 123 (21 CFR Part 123).

In accordance with 21 CFR 123.6(g), failure of a processor of fish or fishery products to have and implement a HACCP plan that complies with this section or otherwise operate in accordance with the requirements of Part 123, renders the fish or fishery products 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). Accordingly, your tuna loins are adulterated, in that they have been prepared, packed, or held under insanitary conditions whereby they may have been rendered injurious to health. You may find the Act, the seafood HACCP regulation, and the Fish and Fisheries Products Hazards and Controls Guidance: 3rd Edition (the Hazard Guide) through links in FDA’s home page at www.fda.gov.

We note the following deviations:

1. You must conduct a hazard analysis to determine whether there are food safety hazard that are reasonably likely to occur and have a HACCP plan that, at a minimum, lists the critical control points, to comply with 21 CFR 123.6 (a) and (c)(2). A critical control point is defined in 21 CFR 123.3(b) as a “point, step, or procedure in a food process at which control can be applied and a food safety hazard can as a result be prevented, eliminated or reduced acceptable levels.” However, your firm’s HACCP plan for “Tuna Loins” does not list critical control point(s) at the pre-cook operation or at any subsequent steps following the pre-cook, (b)(4) as necessary critical control points to ensure control of exposures during the operations to control scombrotoxin formation.

Specifically, your firm identifies the operations leading up to the pre-cook step, (b)(4) as a critical control point; however, there is no indication in your HACCP plan to suggest that concerns with scombrotoxin formation end at the staging operation.

For example, the pre-cook step is a likely critical control point when the critical limits are sufficient to terminate further scombrotoxin formation. In this instance, the HACCP plan should include the pre-cook as a critical control point and should include all appropriate critical factors to achieve an adequate cook.

When the pre-cook step is not a controlling step for scombrotoxin formation, then the concern for temperature exposures above 70 ^oF are pertinent to exposures all the way from the beginning of the thawing operation right through to the bagged product entering the freezer…inclusive of the pre-cook, cooling, skinning/cleaning, and bagging steps.

2. Predetermined corrective action plans included in your HACCP plan, to be taken whenever there is a deviation from a critical limit, must be appropriate to comply with 21 CFR 123.7(b). However your HACCP plan lists inappropriate corrective actions at the “Receiving of frozen fish” CCP (CCP 1a). (b)(4)

You should respond in writing within thirty (30) working days from your receipt of this letter. Your response should outline the specific things you are doing to correct these violations and address the listed concerns. Your response should include documentation, such as: a copy of any revised HACCP plans; at least five (5) product days worth of monitoring records to demonstrate that you have implemented the revised plan; any verification records; and any other useful information that would assist us in evaluating your corrections. If you cannot complete all corrections within fifteen days, you should explain the reason for your delay and state when you will correct any remaining violations.

If you do not respond or if we find your response inadequate, we may take further action. For instance, we may take further action to refuse admission of your imported fish or fishery products under Section 801(a) of the Act (21 U.S.C. §381(a)), including placing them on detention without physical examination (DWPE). FDA’s DWPE is an administrative procedure whereby products offered for import into the United States may be detained without physical examination upon entry. DWPE information may be conveyed in FDA’s Import Alerts. For your information, an example of an Import Alert that conveys information specific to foreign firms that are not in compliance with the seafood HACCP regulation is Import Alert #16-120. This alert can be found on FDA’s web site at: http://www.fda.gov/ora/fiars/ora_import_ia16120.html.

This letter may not list all your deviations from the requirements of the Act or applicable regulations. You are responsible for ensuring that your processing plant operates in compliance with the Act, the Seafood HACCP regulation, and the Current Good Manufacturing Practice regulations (21 CFR Part 110). You also have a responsibility to use procedures to prevent further violations of the Act and all applicable regulations.

During our review, we also identified the following additional concerns:

1. Sample for Histamine Determinations

At the “Receiving of frozen fish” critical control point (CCP 1a), your firm lists monitoring procedures that include “[c]ollect a (b)(4) from the nape of each fish…” Studies by FDA in recent years have shown that the region of the fish being sampled by firms, i.e. the “nape” of the fish, is highly unlikely to reveal elevated histamine even in severely time-temperature abused fish that have become scombrotoxic. The studies show that the lower anterior loin of the fish is the more likely region to find elevated histamine. It is an ineffective use of resources and an inadequate control for scombrotoxin formation to sample and analyze the nape of the fish for histamine.

In addition, FDA recommends the sampling of a minimum of 250 grams of fish muscle from each fish for scombrotoxin controls, rather than the (b)(4) listed in your firm’s plan.

2. Applicability of Histamine Test Kit Used for Monitoring

Your firm identifies use of the (b)(4) test kit in the monitoring procedures for the “Receiving of frozen fish” critical control point (CCP 1a) for histamine testing of the incoming tuna. The (b)(4) test kit is a qualitative test, not a quantitative test. It is designed to indicate the presence of histamine equal to or greater than 50 ppm, not at your firm’s critical limit target of (b)(4). Please provide additional details regarding your use of the (b)(4) as an appropriate monitoring measure for histamine at (b)(4) including the preparation of positive and negative controls.

3. Receiving Fish by Various Modes; Application/Effectiveness of Primary Processor Controls

In various places within the plan, your firm refers to the receipt of tuna directly from (b)(4) Please provide clear descriptions of the physical vehicle or apparatus used to convey the fish as received, the typical contents of fish within, and the typical history of fish from the water to receipt, in each of these receiving modes or forms of conveyance. In those instances where your firm is not off-loading the fish directly from the individual harvest vessels, please 1) identify the suppliers of the fish (back to the primary processor if possible), and 2) identify the reasons for any confidence that your firm may have that the fish are processed in compliance with the seafood HACCP regulation by its suppliers.

In the HACCP monitoring records, it was noted that larger sample sizes are collected and analyzed for certain sample lots. However, your firm does not consistently identify the source of the fish in the monitoring records submitted and it is not evident what is triggering additional sampling in some cases.

4.(b)(4)

a. Your firm includes a (b)(4) critical control point (CCP3a and CCP3b) that includes histamine testing and organoleptic examination for evidence of decomposition. FDA would like more information about the makeup of the (b)(4) and its sources.

• Please provide a detailed description of the (b)(4) What ingredients does the tuna slurry consist of and how is it manufactured? Who produces the (b)(4) at each step starting from the raw fish?
• What does the “accompanying certificate of analysis” from “an accredited supplier” attest to or ensure with regard to the (b)(4)
• What is involved in a (b)(4) supplier becoming accredited?
• Provide an example certificate of analysis and the HACCP plans of your suppliers of the (b)(4) product, with trace back to the primary processor
• Please describe how the (b)(4) and other ingredients making up the (b)(4) is consistent with the standard of identity for canned tuna (21 CFR § 161.190) for which your product is intended.

b. In your HACCP plan, your firm describes a process related to the (b)(4) starting material along with other additives into the tuna (Figure 1, Process Flow Diagram; section C. Process Flow Diagram and Description; section D. Hazard Analysis, pages 10-11, and section E. Tuna Loins HACCP Plan, pages 19-20). Your firm’s hazard analysis suggests that other time and temperature control parameters are deemed necessary to control the scombrotoxin (histamine) hazard during the (b)(4) but dismisses the need for a critical control point because “[t]here is a program in place to monitor and document times and temperatures.” This monitoring and documentation is not part of the HACCP plan and such monitoring documentation was not included in the submission.

Whenever a hazard can be introduced in the absence of appropriate controls, then the controls should become part of the HACCP plan. If the processing of the (b)(4) component can introduce the hazard of scombrotoxin (histamine) formation or other hazards in the absence of time-temperature controls, then a critical control point with appropriate time-temperature controls should be included in the HACCP plan.

5. Corrective Action Procedures

a. At the “Receiving of Frozen Fish” critical control point (CCP 1b), your firm lists corrective action procedures, (b)(4)

The random sampling should also selectively include those fish that were found to be decomposed. Because scombrotoxin cannot reliably be detected by sensory analysis, and because sensory analysis is recommended only as a trigger to indicate time-temperature abuse in the lot, upon a finding of decomposed fish, a processor’s interest should be to determine if the time-temperature abuse detected also permitted scombrotoxin formation in the lot. Consequently, inclusion of those fish found to be decomposed in the samples to be tested for histamine will assist your firm in making that determination.

In addition, at CCP 1b, the listed corrective action procedures in (b)(4) state that decomposed fish will be rejected if histamine levels are found to be acceptable. The procedures should also specify that 100% of the lot will be inspected for decomposition when those conditions occur.

b. At the (b)(4) CCP (CCP2), the listed corrective action procedures do not ensure the cause of the critical limit deviation is corrected. (Note: the critical limit at this CCP should also more appropriately specify “less than 12 hours,” “maximum of 12 hours,” “not to exceed 12 hours” or something more descriptive than “12 hours.”)

Please send your reply to the Food and Drug Administration, Attention: Mildred Benjamin, Consumer Safety Officer, Office of Compliance, Division of Enforcement, Manufacturing and Storage Adulteration Branch (HFS-607), 5100 Paint Branch Parkway, College Park, MD 20740 U.S.A. If you have any questions regarding this letter, you may contact Ms. Benjamin by phone at (301) 436-1424 or via email at Mildred.Benjamin@fda.hhs.gov

Sincerely,

/s/

Jennifer Thomas
Acting Director
Office of Compliance
Center for Food Safety
and Applied Nutrition

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