A La Carte Foods, Inc. 30-Oct-07

Department of Health and Human Services	Public Health Service Food and Drug Administration
	New Orleans District 404 BNA Drive Building 200 - Suite 500 Nashville, TN 37217 Telephone: (615) 366-7801 FAX: (615) 366-7802

 

October 30, 2007

WARNING LETTER NO. 2007-NOL-03

FEDERAL EXPRESS
OVERNIGHT DELIVERY

Darrel J . Rivere, Owner
A La Carte Foods, Inc.
278 Ideal Street
Paincourtville, Louisiana 70391

Dear Mr. Rivere:

We inspected your seafood processing facility, located at 278 Ideal Street, Paincourtville, Louisiana on July 24 - 26, 2007 . We found you have serious violations of the seafood Hazard Analysis and Critical Control Point (HACCP) regulation, Title 21, Code of Federal Regulations (21 CFR), Part 123, and the Current Good Manufacturing Practice (CGMP) regulation for foods, 21 CFR 110. In accordance with 21 CFR 123.6(g), failure of a processor of fish or fishery products to have and implement a HACCP plan, complying 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 United States Code (USC) 342(a)(4)]. Accordingly, your "Not Fully Cooked and Not Shelf Stable", "Heat Treated but not Shelf Stable", and your "Heat Treated but Not Fully Cooked-Not Shelf Stable" seafood products are adulterated, because 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 Product Hazards & Controls Guidance through links in FDA's Internet home page at www. fda.gov.

Your significant violations were as follows:

1. You must conduct a hazard analysis to determine whether there are food safety hazards which are reasonably likely to occur and have a HACCP plan which, 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 to acceptable levels." However, your firm's HACCP plan for products "Not Fully Cooked and Not Shelf Stable", which includes crab cakes and crab kickers, and your HACCP plan for products "Heat Treated but Not Fully Cooked-Not Shelf Stable," which includes crabmeat au gratin, do not list the critical control point of refrigerated storage of cooked seafood ingredients for controlling the food safety hazard of pathogen growth and toxin formation. The hazard of pathogen growth and toxin formation is associated with pasteurized canned crabmeat, an ingredient of some of the products manufactured under these HACCP plans. FDA recommends implementing controls which assure the product has not been exposed to temperatures above 40°F while in storage. These recommendations include monitoring the adequacy of the ice surrounding the product or continuous temperature monitoring of ambient temperature to control the growth of pathogens and toxin formation in cooked seafood products.

2. You must have a HACCP plan which, at a minimum, lists monitoring procedures and their frequency for each critical control point, to comply with 21 CFR 123 .6 (c) (4). However, all your firm's HACCP plans for products "Heat Treated but Not Fully Cooked", "Heat Treated but not Shelf Stable" and "Not Fully Cooked-Not Shelf Stable" list a monitoring procedure of "Temperature in each box", at receipt of refrigerated, cooked seafood products which is not adequate to control the hazard of pathogen growth and toxin formation during transit. FDA recommends implementing controls which assure the product has not been exposed to unsafe conditions while in transit. These recommendations include monitoring the adequacy of the ice surrounding the product or continuous temperature monitoring of ambient temperature during transit to control the growth of pathogens and toxin formation in cooked seafood products.

3. You must have a HACCP plan which, at a minimum, lists the critical limits which must be met, to comply with 21 CFR 123.6(c)(3). A critical limit is defined in 21 CFR 123 .3(c) as "the maximum or minimum value to which a physical, biological, or chemical parameter must be controlled at a critical control point to prevent, eliminate, or reduce to an acceptable level the occurrence of the identified food safety hazard." However, your firm's HACCP plans for multiple types of cooked seafood products list critical limits "[redacted] degrees F", "[redacted] degrees F", and "[redacted] degrees F" which are not adequate to control the hazard of pathogen survival through cooking. There is no indication as to whether these temperatures represent product temperatures (i.e. internal) or temperatures of the cooking apparatus. Furthermore, there is no "time" component listed in conjunction with the critical temperature limits. Please be advised when monitoring internal end-product temperatures, the Fish and Fisheries Products Hazards and Controls Guidance: 3rd Edition recommends employing a process authority to validate a process schedule to assure you are controlling the hazard of pathogen survival through processing and to ensure each piece in each batch receives an adequate cook process.

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

Please respond in writing within fifteen (15) working days from your receipt of this letter outlining the specific things you are doing to correct these violations. You should include in your response documentation, such as HACCP and verification records, or other useful information which would assist us in evaluating your corrections. If you cannot complete all corrections before you respond, state the reason for your delay and when you will correct any remaining violations.

We noted you have a HACCP plan for products which are not fully cooked and are not shelf stable. Please be advised FDA recommends manufacturers provide a cook adequate to control the pathogen(s) of concern to their products if the product might reasonably be consumed without a thorough cooking by the end user.

This letter may not list all the violations at your facility. You are responsible for ensuring your processing plant operates in compliance with the Act, the seafood HACCP regulation (21 CFR 123) and CGMP regulation (21 CFR 110). You also have a responsibility to use procedures to prevent further violations of the Act and all applicable regulations.

Please send your reply to the U.S. Food and Drug Administration, Attention: Karl L. Batey, Compliance Officer, at the above address. If you have questions regarding any issues in this letter, please contact Ms. Batey at (615) 366-7808.

Sincerely,

/S/

H. Tylhornburg
District Director
New Orleans District

Enclosure: Form FDA 483

 

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4 D Cattle 09-Oct-07

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Denver District Office Bldg. 20-Denver Federal Center P.O. Box 2508 7 6th Avenue & Kipling Street Denver, Colorado80225-0087 Telephone: 303-236-3000 FAX: 303-236-3100

 

October 9, 2007

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Mr. Dennis D. Luce
Owner
4 D Cattle
Route 1, Box 98
Fort Sumner, NM 88119
 

Ref. #: DEN-08-03

Dear Mr. Luce:

An investigation of your dairy operation located at 1262 Lande View Road, Fort. Sumner,, New Mexico, conducted by a representative of the U.S. Food and Drug Administration (FDA) on May 31 - June 2, 2007, confirmed that you offered an animal for sale for slaughter as food that was adulterated under sections 402(a)(2)(C)(ii) [21 U.S.C. § 342 (a)(2)(C)(ii)] and 402(a)(4) [21 U.S.C. § 342 (a)(4)] of the Federal Food, Drug, and Cosmetic Act (the Act) . The inspection also revealed that you caused the new animal drugs Tilmicosin and Phenylbutazone to become adulterated within the meaning of section 501(a)(5) of the Act [21 U.S.C. § 351(a)(5)] and unsafe under section 512 of the Act [21 U.S.C. § 360b]. You can find the Act and its associated regulations on the Internet through links on the FDA's web page at www.fda.gov.

On January 10, 2007, you sold a Holstein steer, identified with back tag [redacted] for slaughter as food to [redacted]. This animal was slaughtered by [redacted] United States Department of Agriculture, Food Safety and Inspection Service (USDA/FSIS) analysis of tissue samples collected from that animal identified the presence of 18.6 parts per million (ppm) Tilmicosin in the liver tissue, and 7.5 ppm Tilmicosin in the muscle tissue. In addition, the USDA/FSIS analysis identified 8888 ppm Phenylbutazone in the kidney tissue.

A tolerance of 1.2 ppm has been established for residues of Tilmicosin in the liver tissue of cattle, and 0.1 ppm in cattle muscle tissue, as codified in Title 21, Code of Federal Regulations, Section 556.735, (21 CFR 556.735). The presence of this drug in the edible tissues of this animal in amounts exceeding the tolerance set out in 21 CFR 556.735 causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act [21 U.S.C. § 342(a)(2)(C)(ii)].

No tolerance has been established for residues of Phenylbutazone in edible tissues of cattle. Phenylbutazone injection is only approved for use in dogs and horses, as set out in 21 CFR 522.1720. The presence of this drug in the edible tissues of this animal causes the food to be adulterated within the meaning of section 402(a)(2)(C)(ii) of the Act [21 U.S.C. § 342(a)(2)(C)(ii)].

Our investigation also found that you hold animals under conditions that are so inadequate that medicated animals bearing potentially harmful drug residues are likely to enter the food supply. You lack an adequate system to ensure that animals medicated by you have been withheld from slaughter for appropriate periods of time to permit depletion of potentially hazardous residues of drugs from edible tissues. For example, you failed to maintain and review complete treatment records, and you lack an adequate inventory system for determining the quantities of drugs used to medicate your animals. Food from animals held under such conditions is adulterated within the meaning of section 402(a)(4) of the Act [21 U.S.C. § 342(a)(4)].

In addition, you adulterated Tilmicosin and Phenylbutazone within the meaning of section 501(a)(5) [21 U.S.C. § 351 (a)(5)] of the Act when you failed to use the drugs in conformance with their approved labeling. "Extra-label use," i.e., the actual or intended use of a drug in an animal in a manner that is not in accordance with the approved labeling, is only permitted if the use is by or on the lawful order of a licensed veterinarian within the context of a valid veterinarian/client/patient relationship. The extra-label use of approved .veterinary or human drugs must comply with sections 512(a)(4)and (5) of the Act [21 U.S.C. §§ 360b(a)(4), (5)] and 21 C.F.R. Part 530.

For example, you administered Tilmicosin without-following the withdrawal period set forth in the approved labeling and you did so without the supervision of a licensed veterinarian, in violation of 21 C.F.R. 530.11(a). In addition, you administered Phenylbutazone to a species not approved on the labeling. Furthermore, your extra-label use resulted in illegal drug residues, in violation of 21 C.F.R. 530.11(c). Because your extra-label use of these drugs did not comply with 21 CFR Part 530, the drugs were unsafe under section 512(a) of the Act [21 U.S.C. § 360b(a)], and your use caused them to be adulterated within the meaning of section 501(a)(5) of the Act [21 U.S.C. § 351(a)(5)]. The above is not intended to be an all-inclusive list of violations. As a producer of animals offered for use as food, you are responsible for ensuring that your overall operation and the foods you distribute are in compliance with the law.

You should take prompt action to correct the above violations and to establish procedures whereby such violations do not recur. Failure to do so may result in regulatory action without further notice such as seizure and/or injunction.

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

Your response should be sent to U.S. Food and Drug Administration, P.O. Box 25087, Denver, Colorado 80225-0087, Attention: William H. Sherer, Compliance Officer. If you have any questions about this letter, please contact Mr . Sherer at (303) 236-3051.

Sincerely,

/S/

B. Belinda Collins
Denver District Director
 

cc:
Ronald K. Jones, D.V.M.
Denver District Manager
USDA/FSIS
PO Box 25387
DFC, Bldg 45
Denver, CO 80225

I. Miley Gonzalez, Ph.D.
Secretary
New Mexico Department of Agriculture
New Mexico State University
P.O. Box 300005, MSC 3189
Las Cruces, NM 88003-8005

Lee C. Jan, D.V.M.
Director
Texas Department of Health
Meat Safety Assurance Unit
1100 West 49th Street
Austin, TX 78756-7466
 

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Genzyme Corporation 19-Sep-07

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Center for Biologics Evaluation and Research 1401 Rockville Pike Rockville MD 20852-1448

SEP 19 2007

CBER-07-011

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Henri A. Termeer
Chairman, President and CEO
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
USA

Dear Mr. Termeer:

The Food and Drug Administration (FDA) conducted an inspection of Genzyme Polyclonals S.A.S. located at 1541 Avenue Marcel F-69280 Marcy L'etoile, Lyon, France between June 6 and June 19, 2007. During the inspection, the FDA investigator documented significant deviations from current good manufacturing practice (CGMP) in the manufacture of Thymoglobulin Formulated Bulk lots (bulk lots). These deviations from CGMP include deviations from the applicable requirements of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as well as requirements of your biologics license application approved under section 351(a) of the Public Health Service Act (PHS Act) and Title 21, Code of Federal Regulations (21 CFR) Part 601.

At the close of the inspection, FDA issued a Form FDA 483, Inspectional Observations, which described a number of significant deviations in the manufacture of your Thymoglobulin Bulk lots that are used to formulate your Thymoglobulin [Anti-thymocyte Globulin (rabbit)] product. Specific areas of concern include, but are not limited to:

PRODUCTION AND PROCESS CONTROLS

1. At least three [redacted] manufactured in 2006 exceeded your endotoxin action limit of [redacted] EU/ml. Three [redacted] that exceeded the endotoxin action limit were blended with [redacted] that did not exceed your action limit and were used in the formulation of final product lots TH173 and TH174 that were shipped to and distributed in the United States.

2. On several occasions you continued to use components and intermediates that failed your in-process limit for bioburden and presence of pathogenic microorganisms and you did not conduct sufficiently comprehensive investigations of these failures. For example, a Too Numerous to Count TNTC bioburden result with the presence of Pseudomonas fluorescens was obtained for [redacted] lot [redacted] Additionally, a bioburden result of >200 CFU/ml with the presence of Enterobacter cloacae was obtained for [redacted] lot [redacted] after the [redacted] step.

We also note that it is unclear what your "TNTC" designation represents in terms of bioburden. Because of this, it is also unclear how your assay is used to determine whether or not certain limits have been exceeded. For example, as stated in deviation report N2006-210, you have established an action limit of [redacted] and [redacted] for [redacted] yet you described TNTC at this step as [redacted] Please provide additional information regarding your use and application of the TNTC designation.

We acknowledge that the final Thymoglobulin product resulting from the bulk lots and intermediates referenced in items 1 and 2 met all specifications. However, based on FDA's experience, there is a high probability that the observed CGMP deviations, if not corrected, would substantially increase the risk of future product failures. Of particular concern is that you continued to use components and intermediates that did not meet your internal in-process limits and you did not fully investigate these deviations and implement appropriate corrective and preventive actions. Adequate process control and correcting and preventing deficiencies in the process before they result in product failures are underlying principles of CGMP.

3. You failed to control the Purified Water System used in the manufacture of bulk lots. For example;

a) From July 19, 2005 to July 27, 2005, purified water monitoring results exceeded the action limit of [redacted] for distribution points [redacted] and [redacted] of highly purified water loop [redacted]

b) On May 5, 2004 and October 26, 2006, purified water monitoring results exceeded the action limit of [redacted] in that pathogenic organisms Burkholderia cepacia and Enterobacter cloacae were isolated from various sampling points.

INVESTIGATION OF FAILURES

4. Your investigation into the deaths of two [redacted] during safety and potency tests [redacted] and the associated lack of investigation regarding Adverse Events THYM11145 and THYM11146 are inadequate. The relationship between the [redacted] deaths and the Adverse Event reports, which all implicated Thymoglobulin bulk lot #06TMG0080, should have triggered a comprehensive, in-depth investigation into all areas of the production process including manufacturing records and any associated deviations that occurred.

BUILDINGS AND FACILITIES

5. Your disinfectant effectiveness study # FR039-01 dated September 20, 2004, is incomplete.
The study did not evaluate the effectiveness of the disinfectants in use on fungi and spore forming microorganisms. Spore forming microorganisms have been routinely isolated in your manufacturing facility and accounted for 17% of total isolates in 2004 and 2005; 14% in 2006 and 7% in 2007, at the time of the inspection. We note that this is a repeat observation from our 2004 inspection.

The deficiencies described in this letter are indicative of your quality control unit not fulfilling its responsibility to assure the quality and purity of your components/in-process materials. Please describe in detail how Genzyme will attain CGMP compliance with regard to bulk lot production and process controls. Please include in that description how Genzyme will use all the relevant information to conduct thorough investigations, to ensure that adequate steps are taken to evaluate whether deviations impact product, and to implement effective corrective and preventive actions.

We acknowledge receipt of your written response dated July 30, 2007 which addresses the inspectional observations on the Form FDA 483 issued at the close of the inspection. We have reviewed the contents of your response. Corrective actions addressed in your letter may be referenced in your response to this letter; however, we believe that your response did not provide sufficient detail to fully assess the adequacy of the corrective actions. Our comments and request for further information regarding corrective action are detailed below. The items correspond to the observations listed in the Form FDA 483.

FDA 483 observation # 1

Your response indicates that rabbit pyrogen testing is performed on [redacted] finished vial lot as required by the product release specifications for Thymogloulin. We agree that [redacted] finished product testing is required as part of CGMP. However, in-process controls are also needed to further monitor the performance of the manufacturing process and to ensure that it remains within validated limits. When such limits are exceeded, it is an indication that the process is not in a state of control and a full investigation is warranted to determine appropriate corrective and preventive actions.

You stated in your overall response that "it is not always possible to have the final endotoxin results available prior to the initiation of the next process step." Please provide further details as to how your commitments will allow detection of endotoxin in a more timely manner and whether or not this will require process changes.

FDA 483 observations # 4/8

Please provide a copy of your Water System Summary Report as well as any conclusions and associated timelines for implementing any improvements identified during your assessment.

FDA 483 observation # 5, 6, 7

While we acknowledge the details of the investigations outlined in your response, we believe that more in-depth investigations, including batch record review and a review of associated adverse events (AE), were warranted. Please provide details as to how you plan to address the inadequacies in your AE investigations in the future.

FDA 483 observations #9/10

Your responses indicate that you will conduct an additional stud to evaluate the effectiveness of your disinfectants, as well as perform cleaning validation of the [redacted] laminar flow hood. Please be advised that the completion date of Q1/2008 for these activities appears excessive. We remind you that the failure to adequately evaluate your disinfectants is a repeat observation from our 2004 inspection. We recommend that you re-evaluate your proposed timeframe for completion of both studies.

Neither this letter nor the list of inspectional observations (Form FDA 483) is meant to be an all-inclusive list of deficiencies that may exist at your facility. It is your responsibility as management to assure that your establishment is in compliance with the provisions of the FD&C Act, PHS Act, and applicable federal regulations. Federal agencies are advised of the issuance of all Warning Letters about drugs so that they take this information into account when considering the award of contracts.

You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in FDA initiating regulatory action without further notice. Such action may include license suspension and/or revocation.

Please notify us in writing, within 15 working days of receipt of this letter, of any additional steps you have taken or will take to correct the noted violations and to prevent their recurrence. Include any documentation necessary to show that correction has been achieved. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.

Your reply should be sent to me at the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Suite 200N, Rockville, Maryland 20851-1448. Additionally, we acknowledge your request for a meeting. In order to facilitate your meeting request, please contact Robert McElwain at (301) 827-6196 to discuss an appropriate time for the meeting or if you have any questions regarding this matter.

Sincerely,

/S/

Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

Cc: Mark Bamforth
Senior Vice President
Corporate Operations and Pharmaceuticals
Genzyme Corporation
500 Kendall Street
Cambridge, MA 02142
USA

Henry Darnell
VP Quality
Genzyme Polyclonals
C4-C5 Buildings
1541, Avenue Marcel Merieux
69280 Marcy L'Etoile, France

 

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Kunshan Chemical and Pharmaceutical Co., Ltd. 06-Sep-07

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

Warning Letter

Via Fed Ex

WL: 320-07-02

SEP 6 2007

Mr. Su Weng Xing, General Manager
Kunshan Chemical and Pharmaceutical Co., Ltd.
No. 60, 339 Provinicial Highway
Kunshan City, Jiangsu
China

Dear Mr. Su,

We have completed our review of the Establishment Inspection Report (EIR) for the inspections conducted at your active pharmaceutical ingredient facilities on Kun Tai Road and Provincial Highway in Kunshan City, China, by FDA Investigator Robert C. Horan, Ph.D, in April 2007. These inspections revealed significant deviations from U.S. Current Good Manufacturing Practice (CGMP) in the manufacture of Active Pharmaceutical Ingredients (API). These deviations were listed on an Inspectional Observations form (FDA-483), issued to you at the close of the inspections.

These CGMP deviations cause your APIs to be adulterated within the meaning of section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act(the Act) [21 U.S.C. 351(a)(2)(B)]. This section of the Act states that drugs are adulterated when they are not manufactured, processed, packed, and held according to current good manufacturing practice. Failure to comply with CGMP constitutes a failure to comply with the requirements of the Act.

We have also reviewed your written response to the FDA-483 observations, dated 5/29/2007. We note that many corrections have been, or will soon be implemented. However, your response does not adequately address some of the deficiencies, as further discussed below. Specific areas of concern. include, but are not limited to:

1. Batch production records do not include complete information relating to the production and control of each API batch.

Both the Kun Tai Road (Old Site) and Provincial Highway (New Site) facilities show a pattern of non-compliance with CGMP documentation and records requirements. Refer to Observation #1 for the Kun Tail Road site (Old Site) and Observations #5 and #6 for the Provincial Highway site (New Site). Deficiencies included the lack of contemporaneous documentation of production steps in batch records, inadequate instructions in batch records, and improper completion of production steps. These same types of deficiencies were also observed during the inspection at the Kun Tai Road site (Old Site) in May 2002. Your response to the FDA 483 related to that inspection, dated June 2002, promised corrections and retraining. Observations from the current inspections indicate that unacceptable practices continued at the Kun Tai Road site (Old Site). We also noted that these poor practices were adopted during your initial validation operations at the. Provincial Highway site (New Site). Therefore, it does not appear that the corrections and retraining were effective.

Your current response again indicates that deficiencies will be corrected with revised SOPs and retraining of employees. Ensuring that each production step is completed and documented according to the instructions in the batch record is critical to the quality of the API. Without this assurance, there is insufficient confidence in the identity, quality, and purity characteristics of the APIs manufactured by your firm. A re-inspection will be necessary to evaluate these corrective actions.

2. Method validation documentation did not include appropriate data to verify that the analytical method produced accurate and reliable results.

Your response to Observation #2 for the Provincial Highway (New Site), regarding the [redacted] method for related substances, does not include method validation documentation to support that the proposed specification for [redacted] can be achieved as part of the extended system suitability requirement. You should also consider [redacted] of the "proven sample" throughout the [redacted] to ensure that the system suitability is consistent throughout the run.

3. Production equipment was not adequately cleaned and was not maintained in a good state of repair.

Regarding Observation #2, we note that you recognized this deficiency and plan to cease production at the Kun Tai Road site (Old Site). However, we also note that you have continued to export [redacted] to the U.S. from this site.

4. Laboratory equipment calibration was not adequately documented.

Regarding Observation #7, we noted that calibration documentation for [redacted] equipment lacked sufficient detail identifying the individual components of the system or specific parameters that were evaluated. The corrections described in your response appear satisfactory, and the adequacy of calibration documentation for [redacted] and other equipment will be evaluated during the next inspection.

Based on the previous and current inspectional observations, FDA has concluded that production of APIs at the Kun Tai Road site (Old Site) was not conducted under current Good Manufacturing Practice. In addition, your written response to the FDA-483 observations admits that "the focus on quality s stems was somewhat laxed [sic] at the old site after the last [redacted] US product production run was completed in August 2006."

It has come to our attention that products from the Kun Tai Road site (Old Site) are still being shipped to the U.S. During the inspection of the Kun Tai Road site (Old Site), it was reported to Investigator Horan that production of [redacted] API was intended for non-U.S. markets. Furthermore, your written response to the FDA-483 observations states that, "the old site is now used for the production of [redacted] intended for non-US markets." However, our databases indicate that your firm has made several shipments of [redacted] to U.S. firms, as recently as March 2007. Please provide us with a complete list of all products (including date, quantity, and consignee) that were manufactured at the Kun Tai Road site (Old Site) and shipped to the U.S., by you or any third party, since 2005.

Please respond to this letter within 30 days of receipt and identify your response with FEI# 3006255265. Any future shipments of APIs manufactured at the Kun Tai Road site (Old Site) will be denied entry into the United States. These articles are subject to refusal of admission pursuant to Section 801(a)(3) of the FD&C 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)]. Until all corrections have been completed and FDA can confirm compliance with CGMPs, this office will continue to recommend disapproval of any new applications or supplements listing your firm as the manufacturer of active pharmaceutical ingredients.

Please note that a guidance document entitled "Q7A Good Manufacturing Practice Guidance of Active Pharmaceutical Ingredients" (ICH CGMP Guidance), prepared under the auspices of the International nConference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH), describes current good manufacturing practice (CGMP) for manufacturing of APIs. The guidance is intended to help. ensure that all APIs meet the standards for quality and purity they purport or are represented to possess. Although the ICH CGMP Guidance does not impose requirements, FDA considers its recommendations, as well as alternatives intended to accomplish the same goals and provide an equivalent level of quality assurance, in determining whether a firm's APIs have been manufactured, processed, packed, and held according to current good manufacturing practice under Section 501(a)(2)(B) of the Act. To obtain the ICH CGMP Guidance for your reference, refer to the following website: http://www.fda.qov/cder/guidance/4286fnl.htm

Please contact Douglas A. Campbell, Compliance Officer, at the address and telephone numbers shown below, if you have any questions, further information, or further proposals regarding this letter.

U.S. Food & Drug Administration
Center for Drug Evaluation and Research, HFD-325
11919 Rockville Pike
Rockville, MD 20852
Tel: (301) 827-9049
FAX (301) 827-8909

To schedule a re-inspection of your facility, after corrections have been completed and your firm is in compliance with CGMP requirements, send your request to: Director, Division of Field Investigations HFC 130, 5600 Fisher's Lane, Rockville, MD 20857. You can also contact that office by telephone at (301) 827-5655 or by fax at (301) 443-6919.

Sincerely,

/S/

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

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MedImmune, Inc. 24-May-07

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Center for Biologics Evaluation and Research 1401 Rockville Pike Rockville MD 20852-1448

May 24, 2007

CBER-07-010

WARNING LETTER

CERTIFIED MAIL
RETURN RECEIPT REQUESTED

Mr. David M. Mott
President and Chief Executive Officer
Medlmmune, Inc.
One Medlmmune Way
Gaithersburg, MD 20878

Dear Mr. Mott:

The Food and Drug Administration (FDA) conducted an inspection of Medlmmune U.K. Ltd, a subsidiary of Medlmmune, Inc. (hereinafter "MedImmune" or "your firm"), Plot 6 Renaissance Way, Boulevard Industry Park, Speke, Liverpool L24 9JW, United Kingdom, between March 21 and March 29, 2007. During the inspection, FDA investigators documented significant deviations from current good manufacturing practice (CGMP) in the manufacture of FluMist bulk monovalent lots used to manufacture In fluenza Virus Vaccine Live, Intranasal. These deviations from CGMP include deviations from the applicable requirements of Section 501(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (FD&C Act), as well as requirements of your biologics license application approved under Section 351(a) of the Public Health Service Act (PHS Act) and Title 21, Code of Federal Regulations (21 CFR), Part 601.

At the close of the inspection, FDA issued a Form FDA 483, Inspectional Observations, which described a number of significant deviations in the manufacture of your bulk monovalent lots that are used to formulate In fluenza Virus Vaccine Live, Intranasal, FluMist. Specific areas of concern include, but are not limited to:

INVESTIGATION OF BIOBURDEN EXCURSIONS

1. As a condition of the December 22, 2005, approval of a supplement (pursuant to 21 CFR 601.12(b)) to your Biologics License Application (BLA) for In fluenza Virus Vaccine Live, Intranasal (STN 125020/12), you committed to FDA to agreed-upon interim bioburden alert and action limits, to investigate any excursions from those limits under defined conditions, and to re-evaluate the interim limits based on data from the 2006/2007 campaign. During the 2006/2007 campaign, five out of [redacted] FluMist bulk monovalent lots manufactured between February 2006 and April 2006 exceeded the [redacted] virus harvest interim bioburden action limit of [redacted] cfu/ml and/or the [redacted] virus harvest interim bioburden action limit of [redacted] cfu/ml. Three of the five FluMist bulk monovalent lots that exceeded the interim bioburden action limits were used in the formulation of final product (lots 600147, 600153, and 600157). We acknowledge that the subsequently filtered monovalent lots and the final vaccine product resulting from those lots met all specifications. However, based on FDA's experience, there is a high probability that the observed CGMP deviations, if not corrected, would substantially increase the risk of product failures. Of particular concern are your inadequate investigations into such excursions, and your lack of implementation of appropriate corrective and preventive actions, coupled with deficiencies in: aseptic practices by personnel, cleaning validation of equipment and effectiveness of the cleaning and disinfection processes used in your manufacturing facility and by your personnel. Adequate investigations and correcting deficiencies in the process before they result in product failures are underlying principles of CGMP.

The investigations that your firm performed for the interim bioburden action limit excursions did not adequately satisfy your December 2005 commitment to the agency which was incorporated into you BLA through the approval of your supplemental application (STN 125020/12). In addition, your investigations were not performed in accordance with CGMP because they were inadequate, and because corrective and/or preventive actions were neither identified nor implemented to prevent recurrence.
Specifically:

a) Your firm generally concluded that all isolates from the interim bioburden action limit excursions were associated with eggs. However, some microorganisms identified included those commonly associated with the environment and/or water (e.g., Brevibacterium ssp, Pseudomonas stutzeri, Staphylococcus aureus), in addition to those commonly associated with eggs (e.g., Enterococcusfaecalis, Escherichia coli). We also note that the microorganisms you have identified as being associated with eggs have also been identified during environmental monitoring of your manufacturing facility and your personnel (see item c below). No corrective actions have been proposed or implemented to control microbial contamination of the eggs or to minimize the introduction of microbial contamination from the manufacturing facility or personnel, all of which are important in ensuring the quality of your product.

b) For any of the action limit excursions you identified as being associated with eggs, your firm did not perform a review of the flock from which the eggs were obtained and/or make a determination as to whether the flock should be used for future production of vaccine. You committed to perform such a review for each action limit excursion in your December 8, 2005 correspondence to the agency, which was incorporated into your BLA through the approved supplemental application. Such a review should also include an evaluation of your egg suppliers' sanitation and handling practices to determine whether any corrective actions could be implemented to minimize microbial contamination of eggs.

c) Your firm's conclusions after investigations conducted into the interim bioburden action limit excursions, which your firm repeated in its response to the agency, arecontradicted in many cases by documentation collected during our inspection. For example:

During the manufacture of A/Wisconsin lot 600157, two of the [redacted] sub-lots exceeded the [redacted] virus harvest interim bioburden action limit of [redacted] cfu/ml: 1.25 x 104 and 9.4 x 103 cfu/ml, respectively. Deviation Report 3463, initiated for those interim bioburden action limit excursions for A/Wisconsin lot 600157, concluded that that "the root cause investigation conducted has not determined any anomlies [anomalies] or deviations associated with either the QC testing or manufacture of batch 600157 that could have resulted or contributed to the bioburden excursion observed . . . ." The report also stated: "Environmental control was maintained throughout. It is likely that the contamination originated from the eggs and were [was] present before use within manufacturing." The product impact assessment concluded that there are not "product implications" and includes the following reasons: "Environmental control was maintained throughout the critical and non-critical manufacturing stages," and "No deviations or anomalies were identified from the manufacturing review which could have resulted in the bioburden excursion."

We also note that the deviation reports associated with the interim bioburden action limit excursions generally contain the very same conclusions.

Contrary to those conclusions - that nothing in the environment or personnel could have contributed to the high bioburden in the monovalent sub-lots - your firm's records reveal environmental and personnel monitoring excursions directly associated with the manufacture of this lot during harvest and downstream processing operations. The isolates identified from the environment and personnel included the same microorganisms identified in the interim bioburden action limit excursions (e.g. Staphylococcus aureus, Escherichia coli, Brevibacterium spp., and Enterococcus faecalis.) Consequently, your firm should have investigated the possibility that the bioburden in the lots came, at least in part, from your facility's environment and/or personnel. In addition, according to your own firm's Quality Assurance review, you used some [redacted] and the [redacted] pipette controllers to manufacture this lot before your firm finished pre-cleaning that equipment. Clearly, several potential sources could have contributed to the lot's high bioburden, and your firm should have investigated those potential sources thoroughly.

d) Your firm's investigations also did not include review of the cleaning validation status for the [redacted] the [redacted] incubators, the dispensing and Biological Safety Cabinets, or the silicon rubber housing of the candling lamps (see Item 6) or the effectiveness of your cleaning and disinfection processes used in your manufacturing facility and by your personnel (see Item 4).

We acknowledge that you did re-evaluate the interim limits based on data from the 2006/2007 campaign and that you set bioburden limits for the 2007/2008 campaign, inaccordance to your commitment. Based on the data, the [redacted] virus harvest alertand action limits were increased to [redacted] cfu/ml and [redacted] cfu/n 1, respectively, and the [redacted] virus harvest alert and action limits were decreased to [redacted] cfu/m1 and [redacted] cfu/ml, respectively.

At the time of the inspection, two of the [redacted] bulk monovalent lots that had been produced for the 2007/2008 campaign exceeded the adjusted bioburden action and/or alert limits that you established based on your own data from last season. You must investigate those excursions thoroughly, as you committed to the agency to do, and as your BLA now requires. Your investigations into these excursions were ongoing at the time of the inspection.

PRODUCTION AND PROCESS CONTROLS

2. You failed to ensure that operators performing setup, sterile filtration and/or aseptic dispensing use proper aseptic techniques to prevent microbial contamination of monovalent lots. Specifically:

a) Operators were observed wearing safety glasses allowing for skin to be exposed and, therefore, increasing the opportunity for contamination.

b) On March 28, 2007, an operator was observed removing his/her safety glasses, then removing and cleaning his/her prescription type glasses, thus allowing for skin to be exposed.

c) Also, an operator was observed sampling his/her fingers onto an agar touch plate and without sanitizing or changing his/her gloves, mixing the sterile filtered monovalent.

3. Master and batch production records lack specificity. This issue was discussed with senior management at your firm during the March 6 to March 9, 2006, inspection and correction was promised, but has not been achieved. For example:

a) Master Production Record for B/Malaysia/2506/04 Batch Number: 600169 entitled "The Decontamination and Disassembly of the Ultracentrifuge within the Downstream Processing Room" does not document the maximum soiled hold time limit you established for the [redacted] Ultracentrifuge rotor. Such documentation is important to ensure that subsequent cleanings are performed within validated timeframes. It is important to clean within the validated timeframes to ensure complete removal of product related material and microorganisms.

b) Master Production Record for B/Malaysia/2506/04 Batch Number: 600169 entitled "Filter Preparation, Sterile Filtration and Dispensing of Monovalent Bulk" does not include an established time limit for the aseptic dispensing step.

BUILDINGS AND FACILITIES

4. You have failed to establish the effectiveness of the cleaning and disinfectionprocesses used in your manufacturing facility and by your personnel. For example:

a) From April 14- May 3, 2006, there were numerous environmental monitoring excursions for mold in Downstream Processing Room [redacted] Deviation report 3089 discusses the isolation of mold from the curtains around the laminar flow units after cleaning; from an operator's hand during filter connection activities in the Biological Safety Cabinet; from the ceiling Heating, Ventilation and Air Conditioning (HVAC) vent; and from the filter integrity tester, in addition to other locations. During this time, monovalent lots 600156 and 600157 were processed in room [redacted]. One of the conclusions of your firm's root cause analysis was as follows, "A number of environmental monitoring excursions investigations have come to the conclusion that the cleaning performed in UK-1 [Medimmune's manufacturing site] may not always be effective." However, there is no indication that you reviewed the effectiveness of the cleaning or disinfecting agents used.

b) In addition, other microorganisms were found in the egg incubator, on a harvesting room operator's hand, on the harvest room table, and on a downstream processing room operator's hands. These microorganisms, including Staphyloccoccus aureus, Escherichia coli, and Enterococcus faecalis are the same isolates found in sub-lots of monovalent 600157. There is no indication that you reviewed the effectiveness of the cleaning or disinfecting agent used.

c) The November 2003 disinfectant effectiveness validation study of [redacted] used to disinfect your facility, did not meet your established [redacted] log reduction acceptance criterion for [redacted] set forth in your validation study protocol. [redacted] is the study microorganism used to
evaluate the effectiveness of cleaning agents on fungi and mold.

d) There is no assurance that the disinfectant [redacted] is effective against mold, since it did not meet your established recovery rate acceptance criterion in the December 2001 "Disinfectant Validation and Efficacy Study [redacted] of by the Surface Test Method" study.

e) There has been no evaluation of whether the [redacted] solution, used to decontaminate outer egg shells during the virus harvest step, is ettective in the manner used by your firm.

5. Your firm failed to establish separate or de fined areas or other control systems for your operations to prevent contamination or mix-ups. For example:

a) There is no procedure in place regarding controlled access to the Medlmmune offsite warehouse used for receipt and storage of raw materials known as [redacted]

b) Rejected materials were observed stored with released and un-released raw materials.

CLEANING AND MAINTENANCE OF EQUIPMENT

6. Cleaning validation for the [redacted] the [redacted] incubators, the dispensing and Biological Safety cabinets, and the silicon rubber housing of the candling lamps has not been performed.

The deficiencies described in this letter are indicative of your quality control unit not fulfilling its responsibility to assure the identity, strength, quality, and purity of your components/in-process materials. Please describe in detail how Medtmmune will attain CGMP compliance with regard to monovalent bulk failure/deviation investigations. Please include in that description how Medlmmune will use all of the relevant information to conduct a root cause analysis, to ensure that adequate steps are taken to evaluate whether deviations impact product, and to implement effective corrective and preventive actions.

We acknowledge receipt of your written response dated April 27, 2007, which addresses the inspectional observations on the Form FDA 483 issued at the close of the inspection. Corrective actions addressed in your letter may be referenced in your response to this letter; however, we believe that your response did not provide sufficient detail to fully assess the adequacy of the corrective actions. Our comments and requests for further information regarding corrective action are detailed below. The items correspond to the observations listed on the Form FDA 483:

Production system, items 1-2
We agree with your response that excursions above alert or action limits do not necessarily mean that product should be rejected and we also agree with your statement that comprehensive investigations should be performed when alert and/or action limits are exceeded. We also acknowledge your previous discussions with CBER regarding the establishment of interim bioburden action/alert limits.

However, as described in this letter, Medlmmune has not performed adequate and complete investigations into the deviations, as required by section 501(a)(2)(B) of the FD&C Act and by your biologics license application that FDA approved under section 351 of the PHS Act, as supplemented pursuant to 21 C.F.R. §601.12(b). Although your firm did perform investigations for the interim bioburden action limit excursions, the investigations were not performed in accordance with CGMP in that they were inadequate, and that corrective and/or preventive actions were not identified or implemented to prevent recurrence. In addition, the investigations did not satisfy your December 2005 commitment to the agency, which was incorporated into your BLA, to investigate the root cause and determine approp riate corrective actions when interim bioburden action/alert limits were exceeded.

Please provide all investigation reports for the bulk monovalent lots produced for the 2007/2008 campaign which exceeded the bioburden action and/or alert limits

Production system, item 4a-b
Your response states that relevant [redacted] Standards were used in the study protocols to set the criteria for disinfectant [redacted] effectiveness and that although the results did not meet the stated [redacted] Standard acceptance criterion, the study demonstrated that the disinfectant was reasonably effective in fungal inactivation. Your response also states that a disinfectant [redacted] effectiveness study was performed and that preestablished recovery rate acceptance criterion was not consistently met during the execution of the protocol. Based on the environmental monito ring results mentioned above, we recommend that you perform disinfectants effectiveness studies in which all your acceptance criteria are met.

We also note that beginning in 2007 the European Union banned the use of [redacted] and [redacted] disinfectants. Please provide us your plans for the replacement of these disinfectants and their validation.

Facility and Equipment systems, items 8b and 9b-c
Your response indicates that microbiological control of non-product contact surfaces, including equipment and ISO classified rooms is validated for cleaning effectiveness utilizing the standard IQ, OQ, and environmental monitoring PQ approach. However, based on the documentation collected during our inspection, there is no assurance that your cleaning is effective, since microorganisms associated with eggs have also been identified during environmental monitoring of your manufacturing facility and your personnel.

Neither this letter nor the list of inspectional observations (Form FDA 483) is meant to be an all-inclusive list of deficiencies that may exist at your facility. It is your responsibility as management to assure that your establishment is in compliance with the provisions of the FD&C Act, PHS Act, and applicable federal regulations. Federal agencies are advised of the issuance of all Warning Letters about drugs so that they may take this information into account when conside ring the award of contracts.

You should take prompt action to correct these deviations. Failure to promptly correct these deviations may result in FDA initiating regulatory action without further notice. Such action may include license suspension and/or revocation.

To facilitate your remediation effort we request a meeting with you and other senior management at Medlmmune to further discuss the issues cited in this letter and your proposed responses to address them. Given the potential contributions of safe, pure and potent influenza virus vaccine to the public health, we encourage regularly scheduled and frequent interactions between your technical staff and FDA in an effort to help Medlmmune move forward with corrective actions as rapidly as possible.

Please notify us in writing, within 15 working days of receipt of this letter, of any additional steps you have taken or will take to correct the noted violations and to prevent their recurrence. Include any documentation necessary to show that correction has been achieved. If corrective actions cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.

Your reply should be sent to me at the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Suite 200 N, Rockville, Maryland 20852-1448. If you have any questions regarding this letter, please contact Mr. Robert A. Sausville, Director, Division of Case Management, at (301) 827-6201.

Sincerely,

/S/

Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research

Cc: Mike Austin
Senior Director, Site Operations
Medlmmune U.K., Ltd.
Plot 6 Renaissance Way
Boulevard Industry Park
Speke, Liverpool, L24 9JW
United Kingdom

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Abbott Laboratories, Inc. 13-Mar-07

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

 

March 13, 2007

 

Ref: 2007-DAL-WL-11

WARNING LETTER

CERTIFIED MAIL
RETURNEDRECEIPT REQUESTED

Mr. Miles D. White
Chairman of the Board and Chief Executive Officer
Abbott Laboratories, Inc.
100 Abbott Park Road
Abbott Park, Illinois 60064

Dear Mr. White:

During an inspection of your firm (Abbott Diagnostics Division - Dallas ADD)  located at 1921 Hurd Drive, Irving, Texas 75038, from October 30 through November 17, 2006, the United States Food and Drug Administration (FDA) determined that your firm manufactures, distributes, a installs automated clinical chemistry and immunoassay analyzers for the diagnosis of diseases. Under section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) (21U.S.C. § 321(h)), these products are devices because the are intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or are intended to affect the structure or function of the body.

This inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Act, 21 U.S.C. § 351(h), in that the methods used in, or the facilities or controls used for, their manufacture, packing, storage, or installation are not in conformance with the Current Good Manufacturing Practice (CGMP) requirements of the Quality System (QS) regulation found at Title 21, Code of Federal Regulations (CFR), Part 820. Your devices are also misbranded under section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), because your firm submitted several late MDR reports.

We received your firm's responses, dated December 14, 2006, January 15, and February 14, 2007, responding to our investigators' observations noted on the Form FDA 483, List of Inspectional Observations, which was issued to your firm (copy enclosed) on November 17, 2006. At your firm's request, on January 25, 2007, representatives of the FDA's Dallas District Office held a meeting with the management team from the Dallas ADD and Chicago Corporate Office to discuss your firm's quality system improvements. Your firm responded that its corrective actions are ongoing and that your firm will implement a more robust, comprehensive corrective action plan to correct compliance and quality issues globally across your product lines and update the FDA of the progress of your firm's corrective actions in subsequent progress reports.  Although the Agency recognizes your firm's commitment to improving product quality and compliance with the Quality System Regulation, the Agency is not satisfied with the pace and the results of your firm's past corrective actions as they have not been effectively, timely, and globally implemented for your entire family of analyzers. The current inspection documented repeat inspectional observations in your firm's CAPA System, Production and Process Control System, and MDR reporting. Your firm responded that it is still collecting and analyzing various quality sources and conducting engineering studies to determine potential root causes of the failures of the pressure monitors and pumps in the i2000, i2000SR, and ci8200 analyzers in order to implement effective corrective actions. Abbott Laboratories must timely and effectively implement permanent and substantial actions to correct systemic noncompliant issues at its Irving, Texas manufacturing site. Your firm's responses are incomplete until your firm adequately corrects recurring inspectional observations, specific issues cited in this warning letter, and various quality issues in all of your analyzers in a systemic manner; submits the progress reports your firm promised; and meets the Agency's requirements that call for the audits and certifications by an outside expert consultant and the certifications by your firm's Chief Executive Officer in the specific timeframes outlined in this warning letter. FDA follow-up inspections will be required to assure that corrections are adequate.

These violations include, but are not limited to, the following:

Quality System Violations

1.  Failure of the management with executive responsibility to ensure that an adequate and effective quality system has been fully implemented and maintained at all levels of the organization, as required by 21 C.F.R. § 820.20. For example, your firm's management has not effectively implemented adequate and global corrective actions in a timely manner to correct quality issues across your analyzer product lines. The FDA's current inspection involved the issuance of an 11-item FDA-483 to your firm. Your firm made incomplete corrections as some of the current inspectional observations were repeat observations from the previous inspections of 2003 and 2004. 

2.   Failure to establish and maintain adequate management review procedures and conduct adequate management reviews to meet the requirements of the Quality System Regulation and the manufacturer's established quality policy and objectives, as required by 21 C.F.R. § 820.22(c). Your firm's management failed to review all quality sources and take appropriate corrective actions to address various quality issues or document their adequate justification for not taking corrective actions. For example, your Dallas ADD's site management used a "dollar value" as the alert level for part replacements as a measure of malfunctions of the analyzers upon installation at their user sites to determine whether or not to further evaluate, conduct investigations, or take actions to address potential quality issues with your analyzers. If the cost of the replacement parts or "bad installs" did not exceed a "dollar" alert level, there was no investigation conducted. See your firm's Quality Metrics Report "The Installation and Performance Metrics for the c8000, i2000, i2000SR analyzers" that characterized at a number of the analyzers were found DOA (dead on arrival) upon installation in each month from 10/2004 through 9/2006.

3. Failure to establish and maintain procedures for the analysis of all sources of quality data to identify existing and potential causes of nonconforming product or other quality problems, as required by 21 C.F.R § 820.100(a)(1), and failure to document the results of corrective action activities, as required by 21 C.F.R. § 820.100(b). For example, your firm failed to collectively analyze all sources of quality data (e.g. defective parts rejected during incoming and factory testing, defective parts rejected during initial installation of the analyzers at user sites, and defective parts replaced during service calls of the analyzers) to identify potential quality issues and their root causes at the component level or the analyzer level, and document the results of your analysis. Your firm's responses stated that your firm had not analyzed service calls for parts being replaced in the past. To remedy this situation, among the issues explained in your responses, you stated that our firm will analyze critical components at a minimum of [redacted] every [redacted] collect failed part returns for further evaluation, and conduct investigations into the causes of failed parts during field services of your analyzers. Your firm's responses are not adequate as your firm should conduct analyses of all quality data on a more frequent basis to timely identify quality issues and their root causes, and therefore, implement timely corrective actions. Regardless of the assigned classification for each analyzer component (e.g. critical, major, and minor parts), your firm must take appropriate actions to improve product quality (reliability) as each defective part could use your analyzer to stop working and result in the delay of testing patient samples, transmitting patient test results to their physicians, or could cause aberrant test results.

4.  Failure to identify the action(s) needed to correct and prevent recurrence of nonconforming product and other quality problems, as required by 21 C.F.R. § 820.100(a)(3). For example, at the time of the inspection your firm had not initiated and implemented adequate actions to address potential quality issues with your analyzers despite the fact that from November 2004 through October 2006, your firm received 612 worldwide complaints of pressure monitor failures, factory nonconforming reports documenting 313 pressure monitors and 306 pumps that failed factory testing, 58 out-of-box failures of the pressure monitors upon installation of analyzers at user sites, field service calls to replace these components and other components and the DD005 Metrics Report identifying that the pressure monitors an pumps were two of the top ten defective parts. Your firm's responses concluded that your firm is still conducting additional investigations and/or analysis in order to understand the causes of the part failures.

5. Failure to establish and maintain procedures for verifying and validating the corrective and preventive action to ensure that such action is effective and does not adversely affect the finished devices, as required by 21 C.F.R. § 820.100(a)(4). Your firm's DD005 Metrics Report entitled "i2000SR Arrive Alive," dated April 2005, documented that the pressure monitors were susceptible to freezing when exposed to cold temperatures and that a correction would be implemented with Software Version [redacted] This information was not elaborated further in the subsequent September 2006, DD005 Metrics Report or was not included in your firm's responses to verify the effectiveness of this software change. Additionally, your responses indicated that the majority of the factory failures of the pressure monitors [redacted] %) were due to "erratic/no results" and the other failures [redacted]%) were due to "aspiration errors" and that your firm did not investigate each failure individually. Regarding the pumps, your firm's responses confirmed that the majority of their factory failures and field replacements were due to motor step loss errors but that their failure causes were not well understood. In short, your firm's action which was to simply replace malfunctioned pressure monitors and pumps, or any other defective components during factory testing, site installation, and subsequent service calls of analyzers is not an effective solution, and cannot be effectively verified nor validated without investigating all possible hardware and software fault conditions occurring during factory testing and field clinical use of the analyzers.

6. Failure to establish and maintain adequate procedure for finished device acceptance to ensure that each production run, lot, or batch of finished devices meets acceptance criteria prior to releasing the devices for distribution, as required by 21 C.F.R. §820-80(d). Your factory testing failed to adequately detect and reject defective device components, including the pressure monitors and pumps, and nonconforming device functions prior to releasing the analyzers for site installation. According to your firm's DD005 Metrics Report for the period of November 2004 through October 2006, many analyzers were characterized as "bad installs" at the user sites and their components had to be replaced. For example, this report stated that in April 2005, out of the [redacted] installations of the i2000SR analyzers, [redacted] analyzers were "Dead On Arrival" and that the "Arrive Alive" percentage was 76%.

7. Failure to establish and maintain adequate procedure to ensure that all purchased or otherwise received product and services conform to specified requirements, and to include evaluation of supplier, contractors, and consultants, as required by 21 C.F.R. § 820.50. For example, your firm rejected defective components during incoming and finished device testing, documented nonconforming material reports for rejected components, and then sent supplier corrective action reports to your suppliers to notify them of quality issues. However, your firm failed to collectively se these sources of information to re-evaluate the overall quality rating your suppliers as required by your procedures. Additionally, despite the fact that your firm documented negative quality data for the pressure monitors and pumps, your firm has not adequately evaluated the ability of the two suppliers to meet your firm's requirements.

8. Failure to establish and maintain adequate procedures for acceptance or rejection of incoming product, and for documenting the results of acceptance or rejection, as required by 21 C.F.R. § 820.80(b). For example, your Inspection Quality Assurance (IQA) unit did not follow your firm's inspection procedures in that your IQA staff used incorrect sampling plans, released components that failed acceptance criteria for production without documenting adequate justification, and did not completely document the types of inspection and secondary checks by peer review.

9.  Failure to establish and maintain adequate procedures for review and disposition of nonconforming product, and for documenting adequate justification for use of nonconforming product, as required by 21 C.F.R. § 820.90(b)(2). Your firm allowed the production use of components that did not meet your approved specifications. Your firm simply documented "the impact assessment rating is low per procedure S05.015" without providing adequate narrative details to justify the risk for using nonconforming product. For example, defective pumps were returned to your supplier for reprocessing or repair and sent back to your firm for use. During your factory testing, the motors of the reprocessed pumps were found to be ceased. Your firm nether adequately documented any adverse effect of the [redacted] of the reagents in the pumps when these pumps were replaced during field service calls and returned to their supplier for reprocessing nor evaluated the reliability of reprocessed pumps for reuses. See Supplier Corrective Action Report (SCAR) and Exception Report (ER) Report 168285.

Medical Device Reporting (MDR) Violation

The inspection also revealed that your devices are also misbranded under Section 502(t)(2) of the Act, 21 U.S.C. § 352(t)(2), in that your firm failed to furnish any material or information respecting the devices that is required by or under Section 519 of the Act, 21 U.S.C. § 360i, and 21 C.F.R. Part 803 - Medical Device Reporting (MDR) regulation. For example, your firm submitted to FDA several MDR reports that exceeded the 30-day timeframe of becoming aware of medical adverse events.

Audit Certifications

We are requesting that you submit to this office on the schedule below, certification by an outside expert consultant that he/she has conducted an audit of your establishment's manufacturing and quality assurance systems relative to the requirements of the device's QS regulation (21 C.F.R Part 820) and the MDR regulations (21 C.F.R. Part 803). You should also submit a copy of the consultant's report, and certification by the establishment's Chief Executive Officer (if other than yourself) that he or she has reviewed the consultant's report and that the establishment has initiated or completed all corrections called for in the report. The initial certifications of audit and corrections and subsequent certifications of updated audits and corrections should be submitted to this office by the following dates:

• Initial certifications by consultant and the establishment's Chief Executive Officer are due on August 15, 2007, approximately six months after issuance of this warning letter.

• Next certifications by consultant and the establishment's Chief Executive Officer are due in May of 2008 and 2009. FDA may conduct follow-up inspections anytime between August 2007 and May 009.

Response to the Warning Letter

You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in regulatory action being initiated by the FDA without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil penalties. Also, federal agencies are advised of the issuance of all Warning Letters about devices so that they may take this information into account when considering the award of contracts. Additionally, premarket approval applications for Class III devices to which the QS regulation deviations are reasonably related will not approved until the violations have been corrected. Requests for Certificates to Foreign Governments will not be granted until the violations related to the subject devices have been corrected.

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

Your response should be sent to Thao Ta, Compliance Office DAL-DO, Food and Drug Administration, HFR-SW140, 4040 N. Central Expressway, Suite 300, Dallas, TX 75240. If you have any questions about the contents of this letter, please contact Mr. Ta at 214-253-5217.

Finally, you should know that this letter is not intended to be an all-inclusive list of the violations at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violations noted in this letter and in the Form FDA-483 issued at the closeout of the inspection may be symptomatic of serious problems in your firm's manufacturing and quality assurance systems. You should investigate and determine the causes of the violations, and take prompt actions to correct the violations and to bring your products into compliance.

Sincerely,

/S/

Michael A. Chappel
Dallas District Director

MAC:txt

cc:
Mr. Jeff Binder, Division President
Abbott Laboratories, Inc.
Abbott Diagnostics Division (ADD)
100 Abbott Park Road
Abbott Park, Illinois 60064

 

Mr. Ken M. Partyka, Site Director
Abbott Laboratories, Inc,
Abbott Diagnostics Division (ADD)
P.O. Box 152020
1921 Hurd Drive
Irving, Texas75038

 

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Niagara Pharmaceuticals Inc. 23-Feb-07

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Rockville, MD 20852

WARNING LETTER

Via FedEx

WL: 320-07-01

FEB 23 2007

Mr. Steve C. Leistner
CEO
Niagara Pharmaceuticals Inc:
60 Innovation Drive
Flamborough, Ontario
L9H7P3
Canada

Dear Mr. Leistner:

We have completed our review of the inspection of your pharmaceutical manufacturing facility in Flamborough, Ontario, Canada, by Investigators Caria Lundi and Susan Jackson, during the period of September 11-13, 2006. The inspection revealed significant deviations from U.S. Current Good Manufacturing Practice (CGMP) Regulations (Title 21 U.S. Code of Federal Regulations (CFR), Parts 210 and 211) in the manufacture of sterile drug products. These deviations were listed on an Inspectional Observations form (FDA-483) issued to you at the close of the inspection.

These CGMP deviations cause your drug products to be adulterated within the meaning of section 5O1(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (Act) [21 U.S.C. 351(a)(2)(B)). This section of the Act requires that all drugs be manufactured, processed, packed, and held according to CGMP. Failure to comply with CGMP constitutes a failure to comply with the requirements of the Act. Also, your firm sterilizes its eyewash preparations using [redacted] irradiation. Under 21 CFR 310.502(a)(11), drug products that are sterilized by irradiation. Under 21 CFR 310.502(a)(11), drug products that are sterilized by irradiation are new drugs that require an approved application as a condition of marketing. The products are, in violation of section 505 of the,Act [21 U.S.C. 355} when they are,shipped into the U.S.

We have received and reviewed your response Letters dated October 6, October 26, November 15, and December 21, 2006. We note that some corrections have been completed, or will soon be implemented. However; your responses continue to be inadequate to address the deficiencies, as explained further below. Based on the review of the establishment inspection report (EIR), specific areas of concern include, but are not limited to:

Unapproved New Drugs

Your firm manufactures an eyewash solution that contains purified water as the declared active ingredient. The product is labeled under various own label distributor trade names. All of the distributors' products bear claims that they are intended to be used to flush loose foreign material from the eyes. In addition, some of these own label distributors' products bear claims that the solution may be used to flush the skin to treat minor acid or alkali burns. Based on the intended use as eyewash and skin flush solutions, these products are drugs as defined in section 201(g) of the Act (Act) [21 U.S.C. § 321(g)]. As eyewash solutions, man of these preparations are also subject to final regulations covering OTC ophthalmic drugs found at 21 CFR Part 349. Others are specifically designed for emergency use and will be subject to the developing regulations for emergency eyewash products within the OTC Drug Review.

You also manufacture an antimicrobial solution that contains, according to the label, chlorhexidine gluconate and propylene glycol as preservative ingredients that are intended to be added to self-contained eyewash stations in order to preserve the emergency eyewash solution in the eyewash station. The preservative solution products are also labeled under various own label distributor trade names. Because these products are intended to be a component of a drug, i.e., eyewash and/or emergency eyewash, they are drugs as defined in section 201(g) of the Act [21 U.S.C. § 321(g)]

Both the eyewash solutions and the antimicrobial preservative solutions cited above are sterilized by [redacted] irradiation. The agency has determined by rulemaking procedures that certain drugs are new drugs within the meaning of section 201(p) of the Act [21 U.S.C. § 321(p)]. Drugs that are sterilized by irradiation are included in this rulemaking (see 21 CFR § 310.502(a)(11)). Therefore, the eyewash solutions and the antimicrobial preservative solutions for emergency eyewash stations that your firm manufactures are new drugs that may not be legally marketed in the United States unless they are the subject of an application that has been approved, under section 505 of the Act [21 U.S.C. § 355]. Please inform us of your intention with respect to filing applications for these products.

Current Good Manufacturing Practices

1) Testing of each batch of drug product for distribution does not include appropriate laboratory determination of satisfactory conformance to the final specifications prior to release. 21 CFR 211.165(a)

We acknowledge your question regarding the appropriate form of [redacted] sterilization of your product and the designation of your product as a drug instead of a medical device. [redacted] is similar to [redacted] but not equivalent. We have determined that your product is a drug, as explained above. Thus, under 21 CFR 211.165(a), appropriate release testing must be performed prior to release of product. This includes [redacted]. We acknowledge that your firm is now quarantining product while these tests are performed and prior to shipment. Testing should continue to be completed prior to release unless alternate release methods are provided for in an approved application. When a new drug application is submitted to the agency, the method of [redacted] sterilization will be evaluated for acceptability.

2) Procedures designed to prevent microbiological contamination of drug products purporting to be sterile do not include adequate validation of the sterilization process. 21 CFR 211.113(b)

We acknowledge that your firm has undertaken validation of the sterilization process using [redacted] however, your firm's response remains inadequate. We understand that your firm perceived a language barrier between the Investigators and the QA Manager; however, everything that was requested of the QA Manager was also requested of the General Manager. The protocol for [redacted] was not submitted for review as part of your response. Please provide us with a copy of the executed validation data for protocol [redacted]. Also, you reference a correction letter from [redacted]. Please provide us with a copy of this letter as well.

3) Written production and process control procedures are not followed in the execution of production and process control functions and are not documented at the time of performance. 21 CFR 211.100(b)

We acknowledge that your firm has updated the batch production records; however, the revised records do not adequately correct the lack of documentation of certain steps. There remains a lack of documentation for several key steps that include, but are not limited to, the documentation of [redacted] and [redacted] necessary for your product.

4) Records are not maintained so that data therein can be reviewed at least annually to evaluate the quality standards of each drug product to determine the need for changes in specifications or manufacturing or control procedures. 21 CFR 211.180(e)

We acknowledge that your firm has created a SOP for annual product reviews and produced a detailed annual product review since the inspection; however, the detailed annual product review submitted to us was only for one of your products, Eyewash 1.9% Boric Acid. Your Water Additive product was not covered and no separate annual product review was submitted. Also, the annual product review that was submitted to the investigator was the first annual product review your firm has ever performed, and did not contain all the necessary requirements for an annual product review as detailed in 21 CFR 211.180(e). Your firm has been shipping both products to the U.S. market for over two years without an annual product review. It is your firm's responsibility to determine the quality standards of both drug products in order to better understand the operating parameters for these products.

5) Batch production and control records do not include in-process results for each batch of drug products produced. 21 CFR 211.188(b)(5)

We acknowledge that your firm has revised the SOP [redacted] however, the documentation of the visual and olfactory characteristics of product by the QA Manager is not included or referenced in the batch production record. The sample logbook would not be adequate to document in-process testing if it is not referenced in the batch record for review during release.

These visual and olfectory results may be overlooked during the review of the batch record since they are not included or referenced in the batch record. In addition, there are no specifications for the visual and olfactory in-process testing.

The issues and violations cited in this letter are not intended to be an all-inclusive statement of violations that may exist at your facility or in connection with your products. You are responsible for investigating and determining the causes of the violations identified above and preventing a recurrence of similar violations. It is your responsibility to assure that your firm complies with the requirements of U.S. 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 action. Failure to correct these issues may result in FDA denying entry of articles manufactured by your firm into the United States, pursuant to Section 801(a)(3) of the Act.

Within 30 working days of receipt of this letter, you should notify this office in writing of the specific steps that you have taken to correct the violations. Include an explanation of each step being taken to prevent the recurrence of similar violations, as well as copies of related documentation.

Please direct your response to Carole Jones, Compliance Officer, at the address and telephone numbers shown below, if you have any questions, written response or concerns regarding these decisions.

U.S. Food & Drug Administration
CDER HFD-325
11919 Rockville Pike
Rockville, MD 20852
Tel: (301) 827-9054; FAX (301) 827-8909

Sincerely,

/S/

Richard Friedman
Director
Division of Manufacturing and Product Quality
Center for Drug and Evaluation and Research

 

 

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