ZaCh System S.A., 10/23/09

Department of Health and Human Services	Public Health Service Food and Drug Administration
	CENTER FOR DRUG EVALUATION AND RESEARCH Division of Manufacturing and Product Quality International Compliance Branch White Oak, Building 51 10903 New Hampshire Avenue Silver Spring, MD 20993

 

 

Warning Letter

WL: 320-09-012

VIA FEDERAL EXPRESS MAIL

October 23, 2009

Mr. Bruno Michel, Deputy General Manager
ZaCh System S.A.
Zone Industrille La Croix Cadeau
B.P.10079
Avrille Cedex 49240
France

Dear Mr. Michel:

This is regarding a June 8 - 11, 2009 inspection of your active pharmaceutical ingredient (API) manufacturing facility, ZaCh System S.A., located at Avrille Cedex, France, conducted by Investigator Rebecca Parrilla. The inspection identified significant deviations from the Current Good Manufacturing Practice (CGMP) requirements for the manufacture of APIs. These 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)] in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, or holding do not conform to or are not operated or administered in conformity with CGMP requirements.

We have received your firm's response of July 24, 2009, and note that it lacks sufficient corrective actions.

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

1. Failure to have appropriate procedures (or practices) in place to prevent cross contamination.

In March 2008, your firm received a complaint regarding metallic foreign material found in Pioglitazone HCl (Lots (b)(4)). It was not until you initiated an investigation to identify the source of the metallic particles that you became aware of a cross-contamination problem involving three different APIs and one intermediate product. Approximately 0.40 g of Pioglitazone HCl, 0.07 g of (b)(4) (b)(4), 0.94 g of Venlafaxine HCl, and 0.01 g of (b)(4) (intermediate) were found present inside a (b)(4) of your (b)(4). Metallic particles and residual solvent were also found inside the threads of a screw located inside the sealed box. You concluded that the possible root cause for the cross-contamination of APIs was the improper re-assembly of the (b)(4) that occurred during the last maintenance intervention of 2007.

We are concerned with your failure to take appropriate action against all potentially affected lots of APIs manufactured and released for distribution during the period of April 2007 (last maintenance date) to March 2008 (date cross-contamination was discovered). According to your response, a total of (b)(4) lots of four different products ((b)(4) Pioglitazone HCl, Venlafaxine HCl and Intermediate) were during this period in the (b)(4).

We are also concerned that as of September 23, 2009, you have only tested a limited number of API batches manufactured between April 2007 and March 2008. We do not object to your decision to use a contract, or more specialized laboratory, to assist in the improvement of your analytical methods and testing of the affected products. However, we remain concerned that while your investigation remains open, your customers may still be manufacturing products with the affected API lots.

In the information you submitted to the agency after the inspection, and in comments made during the September 23,2009 meeting at CDER Office of Compliance, you suggested that because your process validation demonstrated homogeneity, the cross contamination would have been detected in your retain samples. We disagree with your assessment because process validation is not intended to evaluate the uniformity or homogeneity of a cross-contamination.

We note that the extent of the contamination remains unknown. You have been unable to clearly explain the presence of Pioglitazone HCl found in a retain sample of Venlafaxine HCL (Lot #(b)(4)). This is a concern because no Pioglitazone HCl was detected in the retain sample of the first batch of the Venlafaxine HCl campaign (Lot #(b)(4)) which was produced immediately after the product changeover from Pioglitazone HCl. There were several other manufacturing campaigns and cleaning operations conducted between Venlafaxine Lot # (b)(4) and contaminated Lot #(b)(4) 

We are also concerned that you became aware of the cross-contamination problem in March 2008, but did not notify your customers of the problem until after the June 2009 FDA inspection. The corrective actions provided in your response lack assurance that the issue has been fully resolved.

Include in your response to this letter the action you intend to take regarding all API lots with detected cross-contamination that were shipped to the United States. Also include in your written response a copy of your Standard Operating Procedure that requires you to notify your U.S. customers of any quality problems at the time of occurrence.

2. Failure of your quality unit to exercise its responsibility to ensure the APIs manufactured are in compliance with CGMP, and meet established specifications for quality and purity.

During the inspection, Investigator Parrilla discussed several issues with your firm's management that were not addressed in the documentation related to the cross contamination investigation of March 2008. These included:

a. Your investigation failed to include direct evidence to support the indentified root cause of the cross-contamination (improper re-assembly of (b)(4); product found inside the threads of a screw). The suspected source of the cross-contamination is not a product-contact surface.

b. Your investigation failed to recognize information in the impurity profile documentation for Pioglitazone HCl batches manufactured between April 2007 and March 2008. An unknown peak was detected, but reported as "0.00 %" due to the small amount detected and your procedures for rounding results.

c. Your investigation failed to recognize that your rationale for establishing the worst case scenario for the cross-contamination, which dictated the sampling scheme used to detect contamination in retain samples, could not be supported based on the results from the samples tested. Specifically, you assumed that any cross-contamination would be more prevalent in the initial batches of each campaign. However, the results for testing of retain samples from Venlafaxine HCl Batch # (b)(4) included no traces of the previous product (Pioglitazone HCl). In contrast to your assumptions, the results for Venlafazine HCl Batch # (b)(4) (manufactured approximately 30 days later, after an API intermediate production campaign, and after five cleaning operations) were determined to be in the range of 50 ppm of Pioglitazone HCl. This indicates a flaw in your rationale for sample selection, or possible insufficient information from testing of Batch # (b)(4)

d. Your investigation failed to recognize that the cross-contamination is not uniformly distributed throughout a batch or campaign. Therefore, your testing of retain samples from suspect batches would not generate meaningful data to support a decision regarding the safety of the batches in question. Consequently, your proposed corrective actions regarding the development of a more sensitive method to better detect cross-contamination in your retain samples, cannot alone support your position related to the safety of the affected drug products.

Your response lacked any supporting documentation. Please provide additional information regarding your corrective actions for these specific deficiencies.

3. Failure to thoroughly investigate all Out-of-Specification (OOS) results.

Regarding Observation #3 on the Form FDA 483 Inspectional Observations (FDA-483), your firm's evaluation of the OOS results obtained for Related Substances testing of Pioglitazone HCl Lot #(b)(4)  (reprocessed batch) was inadequate. We disagree with your decision to release this batch. Specifically, your firm's practice of injecting and reinjecting new preparations of the sample solution until a passing result is obtained is unacceptable. In addition, your initial conclusion that "a phenomenon causing the degradation of the product in solution" was not supported by the investigation.

Your response indicates that you have initiated "a study on the specific event." However, your response fails to provide supporting documentation related to how the study will be conducted or if the study will include an evaluation of the associated production
operations.

Please provide details of the corrective actions you plan to implement to address this deficiency. We have concerns that other lots may have been released due to poor handling of OOS results.

4. Failure to monitor cleaning procedures, after validation, to ensure effectiveness.

Regarding FDA-483 Observation #2, the April 2007 - March 2008 cross-contamination incident indicates that your firm failed to adequately monitor the effectiveness of your validation for the cleaning procedures. Your response fails to provide specific details for how your firm will monitor the effectiveness of future cleaning operations.

The deviations cited in this letter are not intended to be an all-inclusive list of the deviations that exist at your facility. You are responsible for investigating and determining the causes of the deviations identified above and for preventing their recurrence and the occurrence of other deviations. If you wish to continue to ship APl's to the United States, it is the responsibility of your firm to ensure compliance with all U.S. standards for CGMP and all applicable U.S. laws and regulations.

Until all corrections have been completed and FDA has confirmed corrections of the deviations and your firm's compliance with CGMPs, this office will recommend withholding approval of any new applications or supplements listing your firm as an API manufacturer. In addition, failure to correct these deviations may result in FDA denying entry of articles manufactured at ZaCh System S.A., Avrille Cedex, France into the United States. The articles could be subject to refusal of admission pursuant to Section 801(a)(3) of the Act [21 U.S.C § 381(a)(3)], in that, the methods and controls used in their manufacture do not appear to conform to current good manufacturing practice within the meaning of Section 501(a)(2)(B) of the Act [21 U.S.C. § 351(a)(2)(B)].

We urgently need to discuss with you additional corrective actions related to the lots of APIs found with traces of cross-contamination that were shipped to the United States. Therefore, we recommend you contact Giuseppe Randazzo at Giuseppe.Randazzo@fda.hhs.gov or at (301)796-3277 within five days of receipt of this letter to arrange for a teleconference to further discuss this matter.

Within fifteen working days of receipt of this letter, please notify this office in writing of the specific steps that you have taken to correct these deviations. Include an explanation of each step being taken to prevent the recurrence of deviations and copies of supporting documentation. If you cannot complete corrective action within fifteen working days, state the reason for the delay and the date by which you will have completed the correction. Please identify your response with FEI # 3002808164.

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

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

 

Sincerely,

/s/

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

-

Close Out Letter

• Zach System S.A. - Close Out Letter 4/12/11

-

-

Sumitomo Chemical Co., Ltd.

Department of Health and Human Services	Public Health Service Food and Drug Administration
	CENTER FOR DRUG EVALUATION AND RESEARCH Division of Manufacturing and Product Quality International Compliance Branch While Oak. Building 51 10903 New Hampshire Avenue Silver Spring, MD 20993

Warning Letter

VIA FEDERAL EXPRESS MAIL

WL: 320- 09-11

August 24, 2009


Mr. Shinji Kawamura

General Manager, Gifu Plant

Sumitomo Chemical Company Limited

3750 Juhachicho

Maid, Anpachi-Cho, Anpachi-Gun

Gifu Prefecture, Japan 503-0125
Dear Mr. Kawamura:
This is regarding an April 6-9, 2009, inspection of your active pharmaceutical ingredient

(API) manufacturing facility, Sumitomo Chemical Company Limited, located at 3750

Juhachicho, Maid, Anpachi-Cho, Anpachi-Gun, Gifu Prefecture, Japan, conducted by

Investigator, Jose R. Hernandez and Chemist, Javier O. Vega. The inspection revealed

significant violations from U.S. current good manufacturing practice (CGMP) in the

manufacture of APls. The CGMP violations were listed on an Inspectional Observations

(FDA-483) form issued to you at the close of the inspection.
These violations cause the APls manufactured by your firm to be adulterated within the

meaning of Section 50 I(a)(2)(B) of the Federal Food, Drug, and Cosmetic Act (the Act)

[21 USC § 351(a)(2)(B)]. Section 501 (a)(2)(B) of the Act requires that all drugs, as

defined in the Act, be manufactured, processed, packed, and held according to CGMP.
We have received your firm's responses of May 14 and August 12,2009, and note that

they lack sufficient corrective actions.
Specific violations observed during the inspection include, but are not limited, to:

1. Your firm does not assure that suitable processing (b)(4) is used for the (b)(4) step of the Hydralazine HCI manufacturing process. This API is

intended for use in parenteral drug products. Your firm currently uses (b)(4)

and does not test this (b)(4) for endotoxins and total microbial

count. [FDA-483 Observation 8]

Your written response states that you do not intend to conduct endotoxin testing for

(b)(4) or sanitize your (b)(4) system. It is essential that non-sterile APls intended for use

in parenteral drug products are manufactured using (b)(4) that is suitable for the process

stage and that routine monitoring is performed to ensure ongoing (b)(4) system control.

Our inspection found that your firm uses (b)(4) at the (b)(4) and

(b)(4) stage, and failed to test for total microbial count and endotoxins.

Please refer to ICH Q7A Guidance for Industry for guidance regarding" quality of

active pharmaceutical ingredients intended for use in parenteral drug products.

2. Your firm's (b)(4) system is not designed to minimize the risk of microbial

contamination. [FDA-483 Observation 8]

Your written response states that you are in the process of re lacin the distribution

pipes, connections, and flexible hoses. However, your (b)(4) tank #(b)(4)

cannot be drained and has been in use since 1990. Your (b)(4), approximately 100-

meter, distribution pipe contains numerous threaded connectors, at least two flexible

hoses, and has no mechanism for (b)(4). This design is not conducive for

controlling the (b)(4) system's microbial and endotoxin levels. We continue to have

serious concerns about the impact of your (b)(4) system's design on endotoxin and

microbial load.

Please provide us with a corrective action plan for how you will address these concerns.

3. The new method validation for bicalutamide API did not include sensitivity

(limit of quantitation), linearity, accuracy, or an appropriate precision

determination. [FDA-483 Observation 1]

The establishment inspection report indicates that the new method has not been validated

for the aforementioned validation elements, and the precision was conducted with only

three injections. Your response states that you have revised your method validation

protocol, but does not indicate whether your protocol includes the elements, or if you

have performed the method validation. Please provide us with your revised stability and

method validation protocols, and method validation report.
Please note that an analytical method should be adequate for its intended use. The extent

of the analytical method validation studies will depend on the purpose of the analysis and

the complexity of the manufacturing process. Adequate analytical performance elements

should be considered in the validation to establish that the method meets proper standards

of accuracy and reliability, as well as the requirements for the intended analytical

procedures. For example, the validation of the assay method of a component may include

performance elements such as accuracy, precision, specificity, linearity, and range. For a

method used to determine impurities, additional elements such as quantitation limit and

detection limit will be required.



The violations cited above, or on the FDA-483 issued to your firm, are not an all inclusive

list of the CGMP violations that may exist at your facility. FDA inspections

are audits that are not intended to address all deficiencies from CGMP, or violations

that may exist at a firm. If you wish to continue to ship APIs to the United States, it is

the responsibility of your firm to ensure compliance with all U.S. standards for CGMP

and all applicable U.S. laws and regulations.
Until all corrections have been completed and FDA has confirmed corrections of the

violations, and your firm's compliance with CGMPs, this office may recommend

withholding approval of any new applications or supplements listing your firm as an API

manufacturer. In addition, failure to correct these violations may result in FDA denying

entry of articles manufactured at Sumitomo Chemical Company Limited, Gifu Prefecture,

Japan, into the United States. The articles could be subject to refusal of admission

pursuant to Section 801(a)(3) of the Act [21 U.S.C § 381(a)(3)], in that, the methods and

controls used in their manufacture do not appear to conform to current good

manufacturing practice within the meaning of Section 501 (a)(2)(B) of the Act [21 U.S.C

§ 351 (a)(2)(B)].
Please respond to this letter within thirty days of receipt and identify your response

with FEI #3002808125. If you have questions or concerns regarding this letter, contact

Karen Takahashi, Compliance Officer, at the below address and telephone number.

U.S. Food and Drug Administration

Center for Drug Evaluation and Research

Division of Manufacturing and Product Quality

International Compliance Branch

White Oak, Building 51, RM 4244

10903 New Hampshire Ave

Silver Spring, MD 20993

Tel: (301) 796-3191

Fax: (301) 847-8741

Sincerely,

/S/
Richard L. Friedman

Director

Division of Manufacturing and Product

Quality

Office of Compliance

Center for Drug Evaluation and Research

-

Abbott Molecular 8/12/09

Department of Health and Human Services	Public Health Service Food and Drug Administration
	Chicago District 550 West Jackson Blvd., 15th Floor Chicago. Illinois 60661 Telephone: 312-353-5663

August 12, 2009

WARNING LETTER

CHl-08-09

CERTIFIED MAIL

RETURN RECEIPT REQUESTED

Mr, Miles W. White

President and Chief Executive Officer

Abbott Laboratories

100 Abbott Park Road

Abbott Park, IL 60064-6092

Dear Mr, White:

During an inspection of your firm, Abbott Molecular, located in Des Plaines, Illinois, from June 2 to June 29, 2009, two investigators from the United States Food and Drug Administration (FDA) determined that your firm manufactures in vitro diagnostic products for human use, Under Section 201(h) of the Federal Food, Drug and Cosmetic Act (the Act) [21 U.S.C. § 321(h)], these products are defined as devices because they 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 any function of the body.

The inspection revealed that these devices are adulterated within the meaning of section 501(h) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C. § 351(h)], in that the methods used in, or the facilities or controls used for, their manufacture, processing, packing, storage, or installation are not in conformity 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. We received a written response to the FDA-483 observations from Augustine Smith, Quality Director, dated July 21,2009, Our comments to the response are included after the discussion of each of the violations noted below, which include, but are not limited to:

1. Failure to maintain and implement complete procedures for acceptance or rejection of finished device production runs, lots, or batches as required by 21 CFR § 820,80(d). For example, final kit release testing for Realtime HBV is performed using a sample volume of (b)(4) whereas the product label lists sample volumes of both 0.5 and 0.2 mL. The final kit release testing does not include a sample volume of (b)(4).Furthermore, this violation is directly related to an FDA-483 citation from the previous inspection of 2/5-21/2007.

During the inspection, your employees explained that your firm conducted a correlation study showing that the 0.2 mL and the 0.5 mL protocols produced similar values, so performing final kit release testing utilizing both samples volumes was not necessary. Likewise, your written response states that you intend to continue to use only the (b)(4) sample volume for product release testing.

However, as explained by the investigators during the close-out meeting, the data

provided failed to sufficiently demonstrate that utilization of the (b)(4) sample volume is "worst case." Among other things, your written response will require additional clarification since the supporting documentation in Attachment 1 (95 pages) and Attachment 2 (27 pages) fails to clearly connect the specific supporting documentation with the issue.

2. Failure to adequately control products that do not conform to specifications as required by 21 CFR § 820.90(a). For example,

a. Calibrator A master lot was initially rejected and the material quarantined from further use; however, the rejected material was subsequently used as a test material.

b. Twenty heated covers for the (b)(4) instrument were distributed after the firm became aware of circuit flaws in May 2007. The part was not quarantined until May 2009.

Your response provides updates to ten (10) separate procedures which you state were revised to provide additional information which, if available at the time of the incident(s), would have prevented the objectionable occurrence. While we acknowledge adding details in procedural revisions, this is not a foolproof strategy to achieve compliance, and must be further evaluated after full implementation.

3. Failure to establish and follow procedures for the identification, documentation, and validation or verification of design changes prior to the implementation of the changes as required by 21 CFR § 820.30(i). For example,

a. Design changes to the Abbott Real Time HBV assay eliminated acceptance

criteria and did not consider user needs or other stakeholder needs since the impact assessment of the change PR38 which allowed for contamination of PCR wells erroneously stated that the User Needs document is not affected.

b. Guidelines and criteria for testing of genotypes G and H were not established during design of the Realtime HBV assay, and yet the Design Verification Protocol states that if genotypes G and H are available they will be tested.

Your response is inadequate. Among other things, it fails to address the underlying design issues related to contaminated PCR plates, but instead, attempts to justify the potential for low level contamination. Your response to FDA-483 item 3c. is potentially acceptable. The documentation that was added to the design history file will be reviewed for accuracy and completeness at a follow-up FDA inspection. Your response to FDA 483 item 3d. indicates that the documentation was changed/corrected to reflect the testing that actually occurred, but does not address the fact that the protocol was initially not executed as written.

4. Failure to have completely defined procedures for implementing corrective and preventive actions as required by 21 CFR § 820.100(a). For example, corrective action was taken to "contain" all materials associated with a low value of Calibrator A during laboratory testing. The investigation into the associated error code revealed that the initial instructions for "containment" of specific materials stated "contain QC test material," but failed to clearly list all of the specific materials, and thus the master lot samples associated with the error were not contained. No specific corrective action was taken with respect to the procedures associated with the details of conducting and implementing corrective and preventive actions to assure that subsequent instructions will be clear and complete.

Your response does not promise or define any specific improvements to your corrective and preventive action system, but merely states you are opening an investigation to "identify opportunities" for improvement. 

5. Failure to identify acceptance criteria for design outputs as required by 21 CFR § 820.30(d). For example, the impact assessment of the design change made to PR38 did not address the acceptance criteria with respect to user needs for the issue of potential crossover contamination of PCR sample wells when a highly reactive sample is in a nearby well.

Your response is inadequate in that it failed to provide the basis for utilizing an updated risk profile which redefined the risk levels as "Broadly acceptable risk" and deleted the previously utilized elements which included "probability of occurrence" and "severity" ratings to determine overall risk.

6. Failure to completely define the corrective and preventive action procedures addressing the investigation of the cause of nonconformities relating to product, processes, and the quality system as required by 21 CFR § 820.100(a)(2). For example,

a. There was no follow-up investigation of an effectiveness check failure in response to AM-1-24-INV.

b. The form, obvious error checklist, does not provide sufficient detail for conducting laboratory investigations.

c. Investigation activities for 123-CAPA and 122-CAPA were not documented.

d. Procedure AM14-01 does not include a list of acceptable obvious root causes.

Your response provides updates to certain procedures; however, the proposed corrective action may not completely correct the shortcomings with your corrective and preventive action system.

You should take prompt action to correct the violations addressed in this letter. Failure to promptly correct these violations may result in legal action being initiated by the Food and Drug Administration without further notice. These actions include, but are not limited to, seizure, injunction, and/or civil money penalties. Also, federal agencies are advised of the issuance of all Warning Letters so that they may take this information into account when considering the award of contracts. Additionally, FDA may withhold approval of requests for export Certificates to Foreign Governments, or approval of pending applications listing your facility will not be granted until the violations are 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 those corrections. If corrective action cannot be completed within 15 working days, state the reason for the delay and the time within which the corrections will be completed.

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 Inspectional Observations, Form FDA 483 (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 with all requirements of federal law and FDA regulations.

Your response should be sent to: Lorelei Jarrell, Compliance Officer, Food and Drug Administration, 550 W. Jackson Blvd., 15th floor, Chicago, IL 60661. If you have any questions about the content of this letter, please contact Ms. Jarrell at 312-596-4216.

sincerely,

/s/

Scott MacIntire 

District Director

-