Mayne Pharma Pty., Ltd. 21-Nov-02

Departmentof Health and Human Services            PublicHealth Service

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Food and Drug Administration
Rockville, MD 20857

Warning Letter

WL: 320-02-01

November 21, 2002

Mr. Alexander B. Bell

Vice President Technical Operations

Mayne Pharma Pty., Ltd.

1-23 Lexia Place

Mulgrave North, Melbourne, VIC 3170

Australia

Dear Mr. Bell,

This letter is in response to an inspection of your pharmaceutical manufacturingfacility in Melbourne, Australia, by the United States Food and Drug Administration(FDA) on, April 8-16, 2002. This inspection revealed significant deviationsTom U.S. Current. Good Manufacturing Practices (CGMP) Regulations (Title 21CFR, Parts 210 and 211) in the manufacture of sterile drug products. At thecompletion of this inspection, you were issued a 46-item Inspectional Observations(FDA-483) form. These CGMP deviations cause your drug products to be adulteratedwithin the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and CosmeticAct.

Our review also included your May 21, 2002, August 22, 2002 and October 11,2002 written response letters to the FDA-483 observations. We acknowledge thecommitments to correct the deficiencies; however, the response lacks sufficientdetails, explanations, and documentation to address the deviations observedduring the April 2002 inspection.

In addition, we have the following concerns that include, but are not limited to:

1. In the last two years there were 11 product sterility failures involvingthe organism [redacted]. The investigations into these routine results foundno assignable cause or the sterility failures. Some of the failures involved[redacted] sterilized products that included [redacted]. There were no correctiveactions identified in these investigations and the batches were released onthe basis of the survivor test. [21 CFR 211.192]

The production department conducted no investigations, although the productionsystem could not be ruled out as the potential cause of the product contamination.The response stated that no probable cause was identified in four investigations,i.e., no conclusive evidence that the failure was due to either laboratory orproduction error therefore corrective action could not be documented. In threeinvestigations the most probable cause for the sterility positives was deemedto be laboratory error. Further, you acknowledged at a minimum retraining ofboth production and laboratory staff should have taken place, as a correctiveaction. The response also indicated that extended review of trends for sterilityfailures was not undertaken, but will be considered as a corrective action inany future investigations.

In not addressing probable causes and not initiating corrective actions thefirm failed to identify the cause of the contamination and neglected to insurethat this type of problem would not recur. Furthermore, the drug products thatwere released failed to meet their established standards or specifications andhad no assurance to be free of objectionable microorganisms.

In the three investigations for which the sterility positives were deemed tobe laboratory errors, the investigations failed to identify the type of errorsor relate them to laboratory errors. In these three cases, the firm identifiedthe sterility positives as laboratory errors only because the product was [redacted]sterilized. The firm failed to implement any corrective actions to insure thatthe laboratory errors would not occur in the future.

2. The test methods used for sterility testing are inadequate. [21 CFR 2 11.165]There is a lack of data to demonstrate that the methods are capable of recoveringlow levels of organisms that would be found in a typical non-sterile drug product.The study summaries and raw data lacked any counts for the inoculated controlsand samples, and there is insufficient data to interpret whether the productinhibits growth of organisms. The reproducibility of the method was not demonstrated.For example, only one result following a negative recovery was used to validatethe [redacted] Method.

It was also noted that you have not completed [redacted]

Validation for 7 of 15 products with [redacted]

In the August 22, 2002 response, it states that the methodology complies withthe requirements of USP Sterility Test [redacted] Validation for [redacted].It clarified that the counts used to initially inoculate the test and controlsamples are quantified, but you don?t explain how the procedure is done. Italso states that an update to the validation requirement such that three validationtests will be performed in order to comply with the requirements of Validationof [redacted] from Pharmacopeial Articles [redacted].

Further, the response included a commitment to repeating the Validation for [redacted] testing three times for any new formulations/presentations. The validation will be performed twice on existing products the next time the batches are manufactured. As to the products requiring [redacted] inclusion in the validations, this will be scheduled for the next production batches being produced.

Until this validation is completed, the sterility test methods used are inadequatein that there is no documentation, which demonstrates the accuracy and repeatabilityfor [redacted] from Pharmacopeial Articles. Also there is no assurances thatthe sterility positive &Its identified as errors were accurate assessmentsbecause of the inadequacy of the test methods.

3. written procedures designed to prevent microbiological contamination ofsterile drug products were inadequate and resulted in: [21 CFR 211.113]

• inadequate monitoring of differential air pressures between clean rooms


• inadequate support of changes for the movement of walls and HVAC modifications made to the [redacted] facility

• inadequate controls and procedures for gowning


• inadequate validation of the sterilization process in no microbiological qualification or determination of the resistance of the biological indicator challenge system was performed for [redacted]

The responses and commitments made by the firm to correct these deficienciesin item #3 appear adequate. However, this raises concerns about the QualityControl Unit. We remind you of their responsibilities in reviewing and approvingail procedures related to production, quality control, and quality assuranceto assure the procedures are adequate for their intended use.

The CGMP deviations identified above or on the FDA-483 issued to your firmare not to be considered an all-inclusive list of the deficiencies at your facility.FDA inspections are audits, which are not intended to determine all deviationsfrom CGMPs that exist at a firm. If you wish to continue to ship your productsto the United States, it is the responsibility of your firm to assure compliancewith all U.S. standards for Current Good Manufacturing Practices.

Failure to correct these deficiencies may result in FDA denying entry of articlesmanufactured by your firm into the United States. The articles could be subjectto refusal of admission pursuant to Section 801(a)(3) of the Act in that themethods and controls used in their manufacture do not appear to conform to CurrentGood Manufacturing Practices within the meaning of Section 501(a)(2)(b) of theAct.

Please respond to this letter within 30 days and provide documentation regardingcorrections of the above deviations. Your response should include data collectedin your corrections to the deficiencies cited as well as copies of proceduresnot already included.

Please identify your response with CFN 9610999. Until FDA can confirm compliancewith CGMP?s and correction to the most recent inspection deficiencies, thisoffice will recommend disapproval of any new applications listing your firmas the manufacturer of sterile drug products.

Please contact Anthony A. Charity, Compliance Officer, at the address and telephonenumbers shown below, if you have any questions, written response or concernsregarding these decisions:

U.S. Food & Drug Administration

CDER HFD-322

7520 Standish Place

Rockville, MD 20855-2737

Tel: (301) 827-0062; FAX (301) 594-1033

To schedule a re-inspection of your facility, after corrections have been completedand your firm is in compliance with CGMP requirements, send your request to:International Operations Branch, HFC-132, 5600 Fisher?s Lane, Rockville, MD,20857. You can also contact that office by telephone at (301) 827-5655 or byfax at (301) 443-6919.

Sincerely,

/s/

Joseph C. Famulare

Director

Division of Manufacturing and Product Quality

Center for Drug Evaluation and Research

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Youth Light 2010 Inc 18-Nov-02

Departmentof Health and Human Services	Public Health Service Food and Drug Administration
	555 Winderley PI., Ste. 200 Maitland, Fl 32751

VIA CERTIFIED MAIL

WARNING LETTER

FLA-03-10

November 18, 2002

William Donaldson, President
Youth Light 2010, Inc,.
150 E. Sample Road
Pompano Beach, Florida 33064

Dear Mr. Donaldson

We are writing to you because during an inspection of your establishment located in Pompano Beach, Florida on July 10-16, 2002, Food and Drug Administration (FDA) investigators Michelle S. Dunaway and Prince Brown determined that your establishment is a specification developer and distributor of the Youth Light 2010 Intense Pulse Light System. As a specification developer, you are considered to be a manufacturer in accordance with Title 21, Code of Federal Regulations (CFR), Section 807.20(a)(1).

Under a United States law, the Federal Food, Drug, and Cosmetic Act (the Act), the Youth Light 2010 is considered to be a medical device because it is intended to be used to diagnose or treat a medical condition or to affect the structure or function of the body. The law requires that manufacturers of medical devices obtain marketing clearance for their products from the FDA before they may offer them for sale. This helps protect the public heath by ensuring that newly introduced medical devices are safe and effective or substantially equivalent to other devices already legally marketed in this country.

The inspection determined that you promote and distribute the Youth Light 2010 device for structure/function claims including the treatment of wrinkles, lines and folds, age spots and sun damage, coarse skin and large pores, and for the promotion of collagen production.

Our records do not show that you obtained marketing clearance before you began offering your product for safe. The kind of information you need to submit in order to obtain this clearance is described on FDA's medical device website at .http://www.fda.gov/cdrh/devadvice. FDA will evaluate this information and decide whether your product maybe legally marketed

Be cause you do not have marketing clearance from the FDA, marketing your product is a violation of the law. In legal terms, the product is adulterated under section 501(f)(1)(B) and misbranded under section 502(o) of the Act. Your product is misbranded under the Act because you did not submit a section 510(k) premarket notification that shows your device is substantially equivalent to other devices that are legally marketed.

Until you submit a section 510(k) premarket notification and FDA reviews it and notifies you that you may market your device, your product is also adulterated under the Act because the law requires, and you do not have, an approved premarket approval application that shows your device is safe and effective.

The above-stated inspection revealed that the device is adulterated under Section 501(h) of the Act, in that the methods used in, or the facilities or controls used for manufacturing, packing, storage, or installation are not in conformance with the current Good Manufacturing Practice (CGMP) requirements of the Quality System Regulation.

1. Your firm's management with executive responsibility failed to establish its policy and objectives for, and commitment to, quality as required by 21 CFR 820.20(a),(c), and (e). For example, you do not have any written procedures documenting any of your firm's management activities and no quality audits or management reviews have been conducted (FDA 483, Item #11, 2, and 13).

2. Your firm failed to establish procedures for quality audits and to conduct such audits to assure that the quality system is in compliance with the established quality system requirements and to determine the effectiveness of the quality system as required by 21 CFR 820.22. For example, no quality audits have been conducted and none are scheduled to assure the quality system is effective (FDA 483, Item #12).

3. Your firm failed to establish and maintain procedures to control the design of the device in order to ensure that specified requirements are met as required by 21 CFR 820.30 (f),(g), and (j). For example, no design verification confirmed that the design outputs meet design input requirements, design validation did not ensure that devices conform to defined user/patient needs and intended uses, and a design history file was not established or maintained.(FDA 483, Item #s 8,9, and 10).

4. Your firm failed to maintain records of complaint investigations by a formally designated unit as required by 21 CFR 820.198(e). Your firm received several complaints that were not documented (FDA 483, Item #11).

5. Your firm failed to establish and maintain device master records (DMRs)which include specifications (appropriate drawings composition, and/or component specifications), for maintenance and service of equipment, for production or process operations, for quality assurance, for packaging and labeling operations, and the DMR does not include or refer to the location of these records as required by 21 CFR 820.181 (a), (b), (c), and (d). For example, there are no production and process procedures/specifications, no quality assurance procedures/specifications, no packaging and labeling procedures, and there was no reference as to where these records are maintained (FDA 483, Item #s 3, 4; 5, 6, and 7).

This letter is not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure adherence to each requirement of the Act and regulations. Mr. William Chappie promised to respond in writing documenting corrective actions taken covering the observed deviations listed on the Inspectional Observations (FDA 483) and verifying that distribution of the device had been discontinued. As of this date, no response has been received.

You should know that this serious violation of the law may result in FDA taking regulatory action without further notice to you. These actions include, but are not limited to, seizing your product inventory, obtaining a court injunction against further marketing of the product, or assessing civil money penalties. Also, Federal agencies are informed about the Warning Letters we issue, such as this one, so that they may consider this information when awarding government contracts. Additionally, no requests for Certificates for Products for Export will be approved until the violations related to the subject devices have been corrected.

It is necessary to take action on this matter now. Please let this office know what steps you have taken to correct the problem within fifteen (15) working days from the date you received this letter, including: (1) the time frames within which the corrections will be completed, (2) any documentation indicating the corrections have been achieved, and (3) an explanation of each step being taken to identify and make corrections to any underlying systems problems necessary to assure that similar violations will not recur. Please adviseyour intentions to cease distribute. If you need more time, let us know why and when you expect to complete your correction. Please direct your response to Mr. Timothy J. Couzins, Compliance Officer, Food and Drug Administration, 555 Winderley Place, Suite 200, Maitland, Florida 32751, (407) 75-4728.

 

Sincerely,

/s/

 

Emma Singleton
Director, Florida District

 

 

 

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Abbott Laboratories, Inc. 24-Sep-02

Departmentof Health and Human Services            PublicHealth Service

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Chicago District
550 West Jackson Blvd., 15^th Floor
Chicago, Illinois 60661
elephone: 312-353-5863

September 24, 2002

WARNING LETTER

CHI-25-02

CERTIFIED MAIL

RETURN RECEIPT REQUESTED

Mr. Miles D. White

Chairman & CEO

Abbott Laboratories, Inc.,

One Abbott Park Road, Bldg AP6

Abbott Park, IL 60064

Dear Mr. White:

An inspection of Abbott?s pharmaceutical manufacturing operations in BuildingAP- 16,located at Abbott Park, IL, was conducted from June 18 through July 24,2002,: Theinspection covered the production of [redacted]. During the inspection,our investigators documented significant violations of current Good ManufacturingPractice (cGMP) regulations listed Title 21, Code of Federal Regulations (CFR),in your firm?s production of [redacted]. These violations cause this productto be adulterated within the 501(a)(2)(B) of the Federal Food, Drug, and CosmeticAct (the Act).

1. Failure to conduct a thorough investigation when a batch or any of its components fail to meet specifications [21 CFR 211.192]. For example:

During the production of [redacted] lot#79298AF00, black, magnetic particulateswere observed in the granulation. The corrective action taken was to reconditionthe granulation by [redacted] that were expected to eliminate the particles.No validation study was performed to establish that this procedure would successfullyeliminate all of the particles.

During processing, lot #79298AF00 was stored in containers numbered from 1-153. After finding metal particulate contamination in tablets held in container #153, your firm?s investigation covered the tablets held in container# 152 only. No additional inspection of tablets held in containers #l-151 was conducted

During the production of Erythrocin Stearate Tablets, lot #81420AF00, a metalparticle was observed on the surface of one tablet held in container was heldin a total of nine containers numbered from 1 to 9. After the remaining tabletsheld in container #9 were destroyed, your firm visually the tablets held incontainer #8 and no re-examination of the tablets held in containers #1-7 wasperformed.

2. Failure to have adequate written procedures for procedures and process controlto assure that drug products have the identity, strength, quality and puritythey purport or are represented to possess [21 CFR 211.100(a)]. For example:

[redacted] tablet lot #79298AF00 was one of the batches included in the process validation study for this product. This lot was not produced using the manufacturing process discussed in the validation study protocol. Lot #79298AF00 was subjected to several reconditioning steps, due to particulate contamination, that were not listed in the master batch record. Some of the actions taken with respect to this lot, such as the hand pouring of the granules from a drum and [redacted] were steps that were performed for the production of the two additional [redacted] lots used in the validation study.

The master batch manufacturing instructions for the production of [redacted] differ from the procedures used in manufacturing the batches produced in the validation study. The drying process for the tablet granulation component used in the validation batches used a different type of dryer and different time and temperature parameters from the procedures directed in the master batch manufacturing.

3, Failure to clean, maintain and sanitize, at appropriate intervals, equipment and utensils used in the manufacture, processing, packing, or holding of a drug product [21 CFR 211.67(a)]. For example:

Your firm determined that black particles found in tablet granulations was due to the disintegration of the mill?s drive damper and grease seals. Your firm also determined that metal particles clinging to the surface of one tablet was due to the tablet press turret rubbing the upper guard, caused by a worn Neoprene mounting pad. In both examples, there was no established schedule for inspecting or replacing these parts.

At the conclusion of the inspection, our investigators issued the FDA 483, List of Inspectional Observations, to Kay E. Peel, Vice President, Quality Assurance, PPD. A copy of the FDA 483 is enclosed.

This letter and the FDA 483 are not intended to be an all-inclusive list ofdeficiencies at your facility. It is your responsibility to ensure that thedrug products you manufacture are in compliance with the Act and the regulationspromulgated under it. Federal agencies are routinely advised of Warning Lettersissued so that they may take this information into account when consideringthe award of government contracts.

You should take prompt action to correct deficiencies at your facility. Failureto implement corrective measures may result in further regulatory action withoutnotice. These actions may include seizure of your products or injunction.

You should notify this office in writing, within 15 working days of receipt of this letter, of the specific steps you have taken to correct the deficiencies at your firm and prevent their recurrence. Your reply should be directed to the attention of George F. Bailey.

We have received Ms. Peel?s written response, dated August 6, 2002, regarding inspectional observations on the FDA 483. We note that, in response to FDA 483 item #2, Abbott has committed to running three additional validation batches of [redacted] and that a target date for completion of this activity is scheduled for October 31, 2002. Please notify this office when you have completed the additional validation batches. With regard to that commitment and the other corrective steps Ms. Peel indict underway or have been completed, we will consider your FDA 483 response in conjunction with any response to p Warning Letter and will determine the acceptability of your responses during a subsequent follow-up inspection.

Sincerely,

/s/

Arlyn H. Baumgarten

District Director

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21st Century Sports Nutritionals, Inc. 13-Jun-02

Departmentof Health and Human Services            PublicHealth Service

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Food and Drug Administration
Rockville, MD 20867

WARNING LETTER
June 13, 2002

President/Owner
21^st Century Sports Nutritionals, Inc
745 Hollywood Blvd., N.W.
Fort Walton Beach, Florida 32548

Ref: 02-HFD-312-05

Dear Sir or Madam

This letter is written in reference to your firm?s marketing of the products,Phenylkinetics, Libido Magic for Men, and Libido Magic for Women. Accordingto your Internet web site, http://www.2lcenturysports.com, Phenylkinetics contains,among other ingredients, norephedrine HCI, Libido Magic for Men contains, amongother ingmdiellts, 1R, 2s norephedrine HCI, and Libido Magic for Women contains,among other ingredients, 1R, 2s not-ephedrine HCI. Statements on your Internetweb site, indicate that these products are intended for stimulating sexual interestand function and/or for weight loss.

Although your web site represents these products as dietaty supplements, forexample by statements such as, " . . .Energy Supplements.. .?* and ".. .sports supplements.. . *?, they cannot be so considered because the norephedrineHCI used in your products appears to be a synthetic compound that is not derivedfrom any botanical source. Synthetic norephedrine HCI is not plant-derived andcannot, therefore, be considered a constituent or extract of a botanical source.Consequently, FDA has determined that synthetic ephedrine alkaloids am not ?dietaryingredients" as defined in the Federal Food, Drug and Cosmetic Act [theAct, Section 201(ff)(1)].

Therefore, products containing synthetic ephedrine alkaloids do not fall underthe dietary supplement regulatory scheme. Based on their intended uses, to affectthe structure or function of the body, these products are drugs within the meaningof Section 201(g) of the Act. Such products are considered drugs when theirintended use is established by structure injunction claims, such as those thatappear on your web site. Some of the claims on your Internet web site, http://www.21centurysports.com,from which these products may be ordered, state, for example, ". . Phenylkinetics..designed to promote weight loss through rapid metabolization of stored fat withoutcausing that bouncing off the walls? feeling?. , .?*, ". , . Libido Magicfor Men.. .increased sexual function by raising testosterone levels and enhancingblood circulation needed to support firmer, longer lasting erections...,? and" . . Libido Magic for Women.. . stimulate female sexual desire, intensifyorgasm strength and longevity while heightening sexual satisfaction.. .".

As drugs, the labeling claims made for these products subject them to the requirements for new drugs [Section 201(p) of the Act] because there is no evidence that these products are generally Page 2 - 21" Century Sports Nutritionals recognized as safe and effective for their claimed uses.

Under Section 505(a) of the Act, a "new drug" may not be introducedor delivered for introduction into interstate commerce unless an FDA-approvednew drug application is in effect for such drug. Because your products are notthe subjects of approved NDA?s, they may not be marketed in the United Statesand their continued distribution violates Section 505 of the Act.

This letter is not intended to be an all-inclusive review of your Internet web site nor all labeling and products your firm markets. The violation of the Act described above is not intended to be an all-inclusive list of violations concerning your firm and its products. It is your responsibility to ensure that all products marketed by your firm, including other synthetic ephedrine alkaloid products, are in compliance with the Act and its implementing regulations.

We request that you take prompt action to correct these violations. Failure to promptly correct violations may result in enforcement action being initiated by the FDA without further notice. The Act provides for the seizure of illegal products and for injunction against the manufacturer and/or distributor of illegal products.

Please notify this office within fifteen (15) working days of receipt of this letter as to the specific steps you have taken to correct the stated violations. You should also include an explanation of each step being taken to identify and make corrections to assure that similar violations will not recur. 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 implemented.

Your reply should be sent to the attention of Ms. Vesna Stanoyevitch, Compliance Officer, at the Food and Drug Administration, Center For Drug Evaluation and Research, Office of Compliance (HFD-310). Metropark North I, 7520 Standish Place, Rockville, MD 20855.

Sincerely yours,

/s/

David J. Horowitz, Esq.
Acting Director
Office of Compliance
Center for Drug Evaluation and Research
Food and Drug Administration

 

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A. Friscia Seafoods Inc 23-Apr-02

DEPARTMENT OF HEALTH & 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 FEDERAL EXPRESS

Our Reference: 2945025

April 23, 2002

WARNING LETTER

Anthony S. Friscia, President

A. Friscia Seafoods, Inc.

555 Francisco Street

San Francisco, California 94133

Dear Mr. Friscia:

On November 19-20 and December 3, 2001, we inspected your seafood processingfacility, located at 555 Francisco Street, San Francisco, CA. We found thatyou have serious deviations from the seafood HACCP regulations in Title 21,Code of Federal Regulations, Part 123 (21 CFR 123). These deviations cause yourAhi, Mahi, Tombo Tuna, and Cooked Crab to be adulterated within the meaningof Section 402(a)(4) of the Federal Food, Drug, and Cosmetic Act (the Act),in that the fishery products have been prepared, packed, and held under insanitaryconditions whereby they may be rendered injurious to health. You may find theAct and the seafood HACCP regulations through links in FDA? s home page at www.fda.gov.See attached handout, which gives information on how to obtain the Fish &Fisheries Products Hazards & Controls Guidance, 3ti edition, June 2001.

Your serious HACCP deviations are as follows:

1. You must have a HACCP plan that lists the critical limits that must be metto comply with 21 CFR 123.6(c)(3). However, your firm? s HACCP plans for Ahi,Mahi, and Tombo Tuna list critical limits, "Cooler temp not to exceed [redacted]degrees F for more than 4 hours in a 24 hour period. Cooler temp not to exceed[redacted] degrees F control cumulative," at the receiving critical controlpoint that is not adequate to control histamine formation.

FDA recommends that either:

All lots received are accompanied by transportation records (e.g., temperaturerecording chart) that show the fish were held at or below 40?F throughout transit

OR

For fish held under ice or other cooling media at the time of delivery--thereis an adequate quantity of ice or other cooling media to completely surroundthe product

OR

For fish delivered with a total transit time of 4 hours or less, the internaltemperature of a representative number of fish in the lot at the time of deliveryis not more than 40?F.

2. You must have a HACCP plan that lists the critical control points to complywith 21 CFR 123.6(c)(2). However,

1. Your firm?s HACCP plans for Ahi, Mahi, and Tombo Tuna do not list the critical control point of storage for controlling the food safety hazard of scombrotoxin formation. FDA recommends that refrigerated seafood products be held at 40?F or less and that the temperature be monitored continuously by means of a temperature data recorder or by using an alarm system.


2. Your firm?s HACCP plan for Cooked Crab does not list the critical control point of storage for controlling the food safety hazard of bacterial pathogen growth. FDA recommends that refrigerated seafood products be held at 40?F or less and that the temperature be monitored continuously by means of a temperature data recorder or by using an alarm system.

3. Since you chose to include corrective actions in your HACCP plan, your describedcorrective actions must be appropriate to comply with 21 CFR 123.7(b). However,your corrective action plan for Cooked Crab at the cooking critical controlpoint is not appropriate. Your corrective action plan does not address the correctiveaction to be taken when your time-temperature critical limit is not met (i.e.,[redacted]minutes at [redacted] degrees F). Your corrective action plan should also addresscorrecting the cause of the deviation and ensuring that unsafe product (i.e.,under-processed product) does not reach consumers.

4. You must maintain sanitation control records that document the monitoringand corrections applied to the following to comply with 21 CFR 123.1l(c):

• Safety of water


• Condition and cleanliness of food-contact surfaces


• Prevention of cross-contamination


• Maintenance of hand-washing, hand-sanitizing, and toilet facilities


• Protection from adulterants


• Labeling, storage, and use of toxic compounds


• Employee health conditions


• Exclusion of pests

5. You must have a HACCP plan that lists the food safety hazards that are reasonablylikely to occur, to comply with 2 1 CFR 123.6(c)( 1). However, your firm?s HACCPplan for Cooked Crab does not list the food safety hazard of natural toxins.

6. You must adequately monitor sanitation conditions and practices during processing,to comply with 21 CFR 123.1 l(b). However, your firm did not monitor the followingareas of sanitation with sufficient frequency to ensure control:

a. Your firm failed to monitor the condition and cleanliness of food contactsurfaces as evidenced by our investigator observing an employee using a telephonewhile wearing latex gloves and subsequently handling ready-to-eat crabmeat withoutwashing and sanitizing the gloves.

b. Your firm failed to prevent cross-contamination from insanitary object tofood or food-packaging material as evidenced by our investigator observing employeesroutinely packing ready-to-eat crabs into recycled boxes that were previouslyused to package fresh and frozen crabs.

At the conclusion of the inspection, the deviations were listed on Form FDA483 and discussed with you. A copy of this form is enclosed for your ready reference.This list is not meant to be an all-inclusive list of violations. You are responsiblefor ensuring that your processing facility operates in compliance with the Act,the seafood HACCP regulations, and the Good Manufacturing Practice regulations(21 CFR 110).

We may take further action if you do not promptly correct these violations.For instance, we may take further action to seize your products and/or enjoinyour firm from operating.

Please respond in writing within fifteen (15) working days of receipt of thisletter. More than four months have elapsed since FDA inspection. Please providethis office with information on what progress you have made in achieving FDAcompliance with the seafood HACCP regulations. You may wish to include in yourresponse documentation that would assist us in evaluating your corrections.If you cannot complete all corrections before you respond, we expect that youwill explain the reason for your delay, and state when you will correct anyremaining deviations.

Your response should be directed to: Ms. Harumi Kishida, Compliance Officer,U.S. Food and Drug Administration, 143 1 Harbor Bay Parkway, Alameda, CA 94502-7070.

If you have any questions regarding any issue in this letter, please contactMs. Kishida at (510) 337-6824.

Sincerely,

Dennis K. Linsley

District Director

San Francisco District

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A-Vox Systems, Inc. 18-Apr-02

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration

Dallas District

4040 North Central Expressway

Dallas, Texas 75204-3145

April 18, 2002

Ref: 2002-DAL-WL-13

WARNING LETTER

CERTIFIED MAIL

RETURNED RECEIPT REQUESTED

Mr. Albert P. Shepherd, President

A-VOX Systems, Inc.

28267 Ruffian Drive

Fair Oaks Ranch, Texas 78015-4809

Dear Mr. Shepherd:

On March 12 through 14, 2002, our FDA investigator conducted an inspectionof your device manufacturing facility located at 12001 Network Blvd., BuildingF, Suite 210, San Antonio, Texas. Our investigator determined that your firmmanufactures several models of oximeters, which are used for whole blood measurementof total hemoglobin, oxyhemoglobin, carboxyhemoglobin, methemoglobin, and oxygencontent, and disposable cuvettes. These products are medical devices as definedin Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act).

At the conclusion of the inspection, our investigator issued a list of InspectionalObservations (Form FDA-483) to you listing significant deviations from CurrentGood Manufacturing Practices (CGMP). Your devices are adulterated within themeaning of Section 501(h) of the Act in that the methods used in, or the facilitiesor controls used for their manufacturing, packing, storage, or installationare not in conformance with the CGMP requirements of the Quality System Regulation,as specified in Title 21, Code of Federal Requlation (CFR), Part 820. SignificantCGMP deviations include, but are not limited to, the following:

1. Failure to maintain device history records to demonstrate the devices aremanufactured in accordance with the device master record [21 CFR 820.184].

For example, your firm did not keep test records [Individual Device Records]as required by your procedures for the six oximeter devices cited in FDA-483item 1.

2. Failure to establish and maintain procedures to control product that doesnot conform to specified requirements [21 CFR 820.90]. For example, your firmfailed to maintain the non-conforming reports (NCR) as required by your proceduresfor the four oximeter devices cited in FDA-483 Item 5.

3. Failure to establish and maintain procedures for implementing correctiveand preventive action [21 CFR 820.100]. For example, your firm had not investigatedand documented the device failure causes or completed the corrective actionreports (CAR) for the non-conforming oximeter devices listed in FDA-483 Items1, 2, and 5 in order to identify the actions needed to prevent recurrence ofthe device failures.

4. Failure to maintain procedures to ensure all purchased or otherwise receivedproducts and services conform to specified requirements [21 CFR 820.50] seealso 820.80]. For example, your firm failed to ensure that the supplier of themain computer board (i.e., [redacted] Main Board) documented all of the requiredtest results to indicate the supplier?s quality acceptance of the [redacted]computer boards manufactured and delivered to your firm.

5. Failure to establish and maintain schedules and maintenance activities forthe adjustment, cleaning, and other maintenance of manufacturing equipment [21CFR 820.70(g)(l)]. For example, your firm does not have a maintenance documentationof maintenance activities for the [redacted] and the [redacted] [FDA-483 items3 and 4].

Your firm orally promised our investigator that it would correct FDA-483 Items1, 2, 5, and 6 and placed FDA-483 Items 3 and 4 under consideration. You havenot provided a written response confirming your promise and outlining specificsteps your firm has taken or will take to correct the above GMP deficiencies(although your firm stated its intention to respond in writing to the FDA-483within one month of the inspection, to date we have not received such a response).

This letter is not intended to be an all-inclusive list of deficiencies atyour facility. It is your responsibility to ensure adherence to each requirementof the Act and the regulations. The specific violations noted in this letterand in the FDA-483 issued at the close of the inspection may be symptomaticof serious underlying problems in your firm?s manufacturing and quality assurancesystems.

You are responsible for investigating and determining the causes of the violationsidentified by the FDA. If the causes are determined to be systems problems,you must promptly initiate permanent corrective actions.

Federal agencies are advised of the issuance of all Warning Letters about devicesso that they may take this information into account when considering the awardof contracts.

You should take prompt action to correct these violations. Failure to promptlycorrect these violations may result in regulatory action being initiated bythe Food and Drug Administration without further notice. These actions include,but are not limited to, seizure, injunction, and/or civil penalties.

Please provide this office in writing within 15 working days of receipt ofthis letter a report of the specific steps you have taken, or will take to identifyand correct any underlying systems problems necessary to assure that similarviolations will not recur. If corrective action cannot be completed within 15working days, state the reason for the delay and the time frame within whichthe corrections will be completed. Your reply should be directed to Thao Ta,Compliance Officer, at the above letterhead address.

Sincerely,

Michael A. Chappel

Dallas District Director

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Abbott Laboratories, Inc. 30-Jan-02

DEPARTMENT OF HEALTH & HUMAN SERVICES

Food and Drug Administration

Denver District Office

Building 20 - Denver Federal Center

P.O. Box 25087

Denver, Colorado 802250087

TELEPHONE: 303-236-3000

January 30, 2002

WARNING LETTER

CERTIFIED MAIL

RETURN RECEIPT REQUESTED

Ref. # - DEN-02-10

Mr. Miles White

Chairman and Chief Executive Officer

Abbott Laboratories, Inc.

100 Abbott Park Road

Abbott Park, Illinois 60064-3500

Dear Mr. White:

An inspection of your firm located at 4455 Atherton Drive, Salt Lake City, Utah was conducted between November 5 - 20, 2001, by Investigators Nicholas R. Nance and Ricki A. Chase-Off. This inspection determined that your firm manufactures sterile and non-sterile critical-care catheters, monitoring systems, auto-transfusion and infusion accessories, and custom surgical kits. These catheters, monitoring systems, and accessories are devices as defined by Section 201(h) of the Federal Food, Drug and Cosmetic Act (the Act).

The inspection revealed that these devices are adulterated within the meaning of Section 501(h) of the Act, in that the methods used in, or the facilities or controls used for manufacturing, packing, storage, or installation are not in conformance with the Quality System/Good Manufacturing Practice (QS/GMP) for Medical Devices Regulation, as specified in Title 21, Code of Federal Regulations (21 CFR), Part 820. The deviations are as follows:

Failure to establish CAPA procedures that assure all relevant information on identified quality problems, as well as corrective and preventive actions, are submitted for management review, as required by 21 CFR 820.100(a)(7). F or example, procedures do not assure that all sources of quality data are identified, reviewed, tracked or trended. Such sources of product non-conformance/quality data include production travelers, Device History Records (DHR), and Quality Tracking Reports.

Failure to establish and maintain procedures for corrective and preventive actions (CAPA) to include requirements to assure corrective actions are implemented and changes in methods and procedures to correct and prevent identified quality problems are recorded, as required by 21 CFR 820.100(a)(5). F or example, your CAPA procedure does not provide specific guidelines/timeframes in which corrective action reports (CAPARs) are to be closed. Several CAPARs were found to be open over a year after they had been initiated. Also, although your firm instituted corrective actions in May 2000 to eliminate/minimize catheter balloon failures, our inspection found that this change was not implemented in all catheters approved under this design control project manufactured since that time. There was no justification as to why this change was not incorporated in all devices.

Failure to establish adequate CAPA procedures in that your procedures lack verification or validation to ensure that such action is effective and does not adversely affect the finished device, as required by 21 CFR 820.100(a)(4). F or example, there is no evidence that CAPAR #[redacted], initiated to correct catheter balloon bursts and tears, was evaluated for efficacy. Complaints of balloon failures continue to be received.

Failure to establish and conduct adequate procedures to control the design of the device in order to ensure that specified design requirements are met, as required by 21 CFR 820.30. Your firm manufactured and distributed Thennodilution (TD) catheters with new design changes even though all aspects of design controls had not been approved and finalized. For example, lot #[redacted] was the first-lot-to-stock to be manufactured incorporating new design changes. Production of this lot began on February 10, 2000, and was released for distribution on April 27, 2000. The design transfer was partially signed and approved May 4, 2000, after release of this lot. The design inputs and design validation were not finalized until April 25, 2000, and the design history file was not signed and approved until November 20, 200l.

Failure to control nonconforming product to assure that it is identified, evaluated, segregated and disposed of according to procedures, as required by 21 CFR 820.90(a), and failure to establish and maintain adequate written procedures for rework, to include re-testing and re-evaluation of the nonconforming product after rework, to ensure that the product meets its current approved specifications, as required by 21 CFR 820.90(b). F or example, the disposition of in-process scrap or rejected material noted on Restrictions and DHRs is not always noted. Complaints alleging heparin occlusion occurred in several lots of catheters that had been previously re-worked for occlusions and subsequently distributed.

Failure to establish and maintain written procedures for changes to a specification, method, process, or procedure and to verify or validate that change before implementation, as required by 21 CFR 820.70(b). For example, there is no evidence that the rework procedure for TD catheters involving the balloon removal and reapplication, de-heparinization and re-heparinization, has been validated. Records documenting the " [redacted] procedure show inconsistencies from the protocol.

The protocol stated that the validation lot was to be lot # [redacted]. However, the validation summary page indicates that lot # [redacted] was used to complete the testing. Records from the DHR for lot #[redacted] indicate that it was scrapped in total due to extrusion problems. Records for lot [redacted] show that it was released for distribution on April l8, 2000.

Documentation is inadequate to indicate which lot was used for validation and testing. This discrepancy was not detected by your company upon review of the validation, prior to its release.

Failure to establish sampling plans based on a valid statistical rationale and to ensure that

sampling methods are adequate for their intended use, as required by 21 CFR 820.250(b). For example, our inspection revealed that in-process sampling data is recorded on the Quality Tracking Records. There is no evidence of the statistical rationale used for this sampling. Also, procedures require that all catheters are tested for resistance and conductivity; however, only the test results from the first twenty catheters manufactured per lot each day are maintained in the DHR. There is no rationale for this practice.

The above identified deviations are not intended to be an all-inclusive list of deficiencies at your facility. It is your responsibility to ensure that each of your facilities is in compliance with all requirements of the Federal regulations. The specific violations noted in this letter and in the Form FDA-483 issued at the conclusion of the inspection (a copy of which is included for your information) may be symptomatic of serious underlying problems in your establishment?s quality system. You are responsible for investigating and determining the causes of the violations identified by the FDA. You also must promptly initiate permanent corrective and preventive action to your Quality System at this and at all your other locations. Continued distribution of violative devices may result in regulatory action without further notice. These actions include, but are not limited to seizure, injunction, and/or civil penalties.

Federal agencies are advised of the issuance of all warning letters regarding medical devices so that they may take this information into account when considering the award of contracts.

We are in receipt of your correspondence dated December 11,200l in response to the FDA 483 issued at the end of the November 5 - 20^th inspection. With regards to your response, we have the following comments:

Observation 1 - You must assure that you are capturing, tracking and trending all sources of quality data and not just the specific items noted in our observations. The fact that there is evidence of continuing defects found after you have instituted corrective actions is indicative that the systems in place are inadequate to identify the source of these problems (i.e., balloon failures and heparin occlusions).

Observation 2 - Regarding your proposed changes to the CAPA procedures, your response does not indicate how the effectiveness of a corrective action will be determined and defined. Besides defining effectiveness, your procedures need to also state the time period over which corrective actions will be tracked, prior to their implementation.

Observation 3 - Your response appears adequate; however, you must assure the implementation of your corrective actions. The adequacy will be evaluated at the next inspection of your facility.

Observation 4 - We disagree with your response regarding design controls. Although your response refers to the lay-flat design change as a product improvement initiative, documentation noted throughout the design history file for this change indicate that the purpose was to make the tip diameter smaller, thus minimizing the likelihood of being caught on the introducer or contamination sheath. The sole purpose of this change was to minimize or eliminate balloon tears and damage and is therefore a corrective action.

Although your response states that design validation was established based on design verification data, the Design Validation Checklist in the Design History File indicated that design validation was based on the process validation of the lay-flat tip. There is no indication that Design Validation was based on the first-lot-to-stock, or on any other verification data.

Observation 5 - When our investigators asked why the design change was not applied to all TD catheters approved under the design control project, they were given two different explanations: Mr. Gilbreath, Engineering Manager stated that tooling issues somehow prevented implementation, and Mr. Cole Tims, Plant Quality Assurance Manager, attributed it to "low throughput," that is, Abbott was limited in its ability to manufacture these catheters. Mr. Tims stated that the new design was not to be manufactured on the remaining lists until new equipment was purchased to increase production. The document provided with your response was never supplied to our investigators or discussed at the close-out of the inspection. Nevertheless, it is essential that if your firm determines that a design change is warranted, the decision to implement or not to implement must be made using a risk-based assessment. That is, a risk-based assessment of the impact on patients? health should be performed prior to determining whether or not to implement the change.

Observation 6 - Your response appears adequate; however, we would like to remind you that you need to assure all BOPs define the methods for rework and that all steps taken are properly validated. The rationale for any decision not to validate rework on an EPWO must be also documented. Although your response indicated that all rework procedures were validated, our inspection found no evidence of the validation of the rework for ink removal and partial heparinization of TD catheters.

Observations 7 and 8 - Your responses appear adequate; however, you must assure the

implementation of your corrective actions. The adequacy will be evaluated at the next inspection of your facility.

Observation 9 - In response to the observation of lack of validation of the re-work of TD

catheters, your response states that validation was supported by document [redacted]".

Our review indicates that this document is the protocol used for the validation, but is not the actual validation results. We also note that this protocol is dated 1993; you must assure that any process changes which may have occurred since 1993 have been

addressed in order to assure re-validation is not necessary. Although your response states that the BOP for the Opticath catheter rework is appropriate for the TD catheters, our inspection revealed that your firm was only using part of this BOP for the rework. There is no justification for the partial use of the BOP in the addendum to the validation that your firm wrote on December 10, 200l.

Regarding validation [redacted used to support the rework of lots [redacted] and [redacted] our investigators reviewed Restriction [redacted], dated September 19, 2000. The restriction stated that the purpose was "to re-work this lot ([redacted] ) for a second sterilization the catheters need to be re-ballooned and re-heptined. The re-heparinization process needs to be validated. As a result test report [redacted])([redacted] will be run in parallel with the re-work of this lot of product." The EPWO, with re-work instructions, was dated September 27, 2000; however the validation (test report [redacted]) shows it originated December 4, 2000. Furthermore, the records for the lot indicate it was reworked and released to the sterilizer on December 6, 2000. This lot was not

received back until December 9, 2000, whereas the validation is signed off on December 7, 2000, before the product completed sterilization and before you could assure the process was indeed successful. This lot was later the subject of at least one complaint of heparin occlusion (PER # [redacted]).

You should notify this office in writing within 15 working days of receipt of this letter, of any additional steps you have taken to correct the noted violations, including an explanation of each step being taken to prevent the recurrence of similar violations. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time frame within which the correction will be completed.

Your reply should be sent to the Food and Drug Administration, Denver District Office, P.O. Box 25087, Denver, CO 80225-008, Attention: Regina A. Barrell, Compliance Officer. If you have any further questions, please feel free to contact Ms. Barrel1 at (303) 236-3043.

Sincerely,

B. Belinda Collins

Acting District Director

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