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Wednesday, September 19, 2007

Genzyme Corporation 19-Sep-07

Department of Health and Human Services' logoDepartment 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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Thursday, September 6, 2007

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

Department of Health and Human Services' logoDepartment 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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