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U.S. Department of Health and Human Services

Inspections, Compliance, Enforcement, and Criminal Investigations

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Baxter Healthcare Corp. 9/10/09


Department of Health and Human Services' logoDepartment of Health and Human Services

Public Health Service
Food and Drug Administration
 Chicago District
550 West Jackson Blvd.
15th Floor
Chicago, Illinois 60661
Telephone: 312-353-5863

September 10, 2009





Mr. Robert L. Parkinson, Jr.
Chairman of the Board, Chief Executive Officer and President
Baxter Healthcare Corporation
One Baxter Parkway
Deerfield, IL 60015

Dear Mr. Parkinson:

The Food and Drug Administration (FDA) conducted an inspection of Baxter Healthcare Corporation, One Baxter Parkway, Deerfield, Illinois, between April 2 and April 22, 2009 and determined that your firm is a specification developer for the (b)(4). Under Section 201(h) of the Federal Food, Drug, and Cosmetic Act (the Act) [21 U.S.C.321(h)], this product is defined as a medical device because it is intended for use in the diagnosis of disease or other conditions or in the cure, mitigation, treatment, or prevention of disease, or is intended to affect the structure or function of the body. The FDA also conducted inspections of Baxter Healthcare Corporation, Los Angeles, California, Baxter Healthcare Corporation, Van Nuys, California, and Baxter Healthcare Corporation, Westlake Village, California, Additionally, followup inspections were conducted at Baxter Oncology GmbH, Kantstrasse 2, Halle/Westfalen German; (b)(4) and (b)(4) between June 8 and June 18, 2009.

These inspections revealed that your device is adulterated within the meaning of Section 501(f)(I)(B) of the Act [21 U.S.C. 351(f)(I)(B)], in that it is a class III device under section 513(f), 21 U.S.C. 360c(f), and does not have an approved application for premarket approval in effect pursuant to section 515(a), 21 U.S.C. 360e(a) or an approved application for an investigational device exemption under section 520(g), 21 U.S.C. 360j(g).

These inspections revealed that your (b)(4) is misbranded within the meaning of Section 502(a) of the Act [21 U.S.C. 352(a)], in that its labeling is false and misleading. Your package insert labeling for this device which was approved under PMA (b)(4), states that (b)(4) are suspended in phosphate buffered saline with (b)(4) United States Pharmacopeia (USP). However, the (b)(4) has been manufactured with (b)(4) since 1999.

These inspections further revealed that this device is adulterated within the meaning of Section 501 (c) of the Act [21 U.S.C. 351 (c)], in that its strength differs from, or its purity or quality falls below, that which it purports or is represented to possess.

The FDA has reviewed your firm's written responses from Gary Ogryzek, dated, May 8, 2009, May 19, 2009, July 13, 2009, and August 10, 2009 and responses from Peter Boddeker of Baxter Oncology GmbH, dated July 10,2009, and (b)(4) dated July 10, 2009. Comments to these responses are to be found below, in relation to each of the noted violations.

Additionally, the (b)(4) is 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, its manufacture, 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 as follows:

1. You failed to have your management with executive responsibility establish its policy and objectives for, and commitment to quality. Management with executive responsibility failed to ensure that the quality policy is understood, implemented, and maintained at all levels of the organization [21 CFR 820.20], in that Quality related activities are conducted as projects outside the Quality System. Examples of projects that are not tracked/monitored within the Quality System include:

a) Proposed Initiatives maintained by the Product Support Team in the (b)(4) database (i.e., investigations into (b)(4) and (b)(4) as potential causes of low yield and/or low purity for the (b)(4) product).

b) (b)(4) Gap Analysis Project to identify changes to the instrument and disposable that were not reported to FDA.

c) Special project regarding Requirements for Language Labeling, which resulted from the "closed-cancelled" CTQ-CAPA-0005.

2. You failed to establish and maintain procedures that ensure that the design requirements relating to your (b)(4) are documented [21 CFR 820.30(c)], in that not all requirements specified in the PMA, such as the use of (b)(4) were documented as Design Inputs in the November 26,2007, "Retrospective Review of the Development of the (b)(4)". This review was conducted to document design inputs, design outputs, and design verifications for the (b)(4)"

3. You failed to establish and maintain procedures for the identification and approval of design changes before their implementation [21 CFR 820.300)] in that, the part numbers for the (b)(4) were consolidated into a single part number via change notice, "Change of label
to be used on the (b)(4) product" dated October 25, 2005. Your use of a single part number for the (b)(4) does not enable distinction between the US licensed Albumin manufactured by your Los Angeles facility, which meets USP requirements, and Albumin manufactured by your Vienna facility, which meets EP requirements.

4. You failed to establish a complete design history file [21 CFR 820.300)] in that, the current Design History File Remediation Program for the (b)(4) does not include an analysis of the (b)(4) design.

Your response is inadequate, in that it fails to include details on how your design process will ensure complete and inclusive design history files for each marketed product.

5. You failed to establish and maintain device master records (DMRs). Your DMR does not include or refer to the location of device specifications such as component specifications [21 CFR 820.181(a).] For example:

a) The device master record for the (b)(4) does not include specifications for the source and characteristics of the (b)(4) used in the production of (b)(4) that complies with the PMA for this approved biological device.

b) The device master record for the (b)(4) does not include specifications for the source and characteristics of the (b)(4) used in the production of (b)(4) that complies with the PMA supplement that has been submitted to FDA.

c) The Bill of Materials for the (b)(4) and the Bill of Materials for (b)(4) lists the same Baxter part number, (b)(4) for (b)(4). The Bills of Material do not have different part numbers to distinguish between (b)(4) manufactured using (b)(4) from Baxter's Los Angeles facility and
(b)(4) manufactured using (b)(4) from Baxter's Vienna facility (b)(4) is required per the PMA.

Your response is inadequate in that it fails to include details on how your process will ensure component requirements are correctly established and maintained.

6. You failed to establish and maintain data that clearly describe or reference the specified requirements, including quality requirements, for purchased or otherwise received product and services [21 CFR 820.50(b)], in that the receiving inspection instruction provided to the supplier as the specification for (b)(4) lists a single Baxter part number, (b)(4) for the (b)(4) and neither specifies the source of the Albumin nor establishes that the (b)(4) used to manufacture beads for the US market must meet USP and license requirements. The beads are received by the Baxter facility in Van Nuys, CA and released by the Baxter facility in Los Angeles CA. The Los Angeles facility labels and packages the (b)(4) Part Number (b)(4) and the (b)(4) Part Number (b)(4) using the same (b)(4).

7. You failed to evaluate and select potential suppliers on the basis of their ability to meet specified requirements [21 CFR 820.50(a)(I)], in that Baxter Supplier Audit of the (b)(4) supplier, dated March 20-23, 2007, did not include findings that (b)(4) was being used in the production of (b)(4) although the agenda of the audit states that Batch Record Review and Control of Incoming Materials were covered. Quality Agreement Document 1126390-2.0, dated December 15, 2006, states that the (b)(4) supplier and Baxter will jointly agree on raw material specifications and confirm by audit.

8. You failed to identify the actions needed to correct and prevent the recurrence of nonconforming product and other quality problems, [CFR 820.100(a)(3)], in that no investigation or other follow up has been conducted on the below-mentioned potential causes of low yield and/or low purity performance issues for the (b)(4) product. Further investigations into these potential causes were identified as proposed initiatives in March 2008:

a) (b)(4)

b) (b)(4)

c) (b)(4)

Your response is inadequate, in that it fails to address the reason that these investigations were placed on hold. Your response does not address the quality system issues that led to the initial failure to follow-through on the investigations. Although you have included a "High Level Investigation Plan" in your response, you have not provided procedures that further define the criteria for determining when to open a high level investigation.

9. You failed to establish and maintain corrective and preventive action procedures and investigate the cause of nonconformities relating to product, processes, and the quality system [21 CFR 820.100(a)(2)], in that your corrective and preventive action (CAPA) procedures do not describe how Product Support Team (PST) investigations and proposed initiatives will be documented, tracked and monitored within the CAPA system.

Additionally, please address the following issues that were noted during the above-mentioned follow-up inspections:

1. It was noted that eluates (b)(4) were placed on hold due to bioburden in the (b)(4) rinse of the (b)(4) system at levels too numerous to count. Your July 24, 2009 communication with FDA via electronic mail states that these eluates have passed all routine (b)(4) QA/QC release tests and additionally extended microbiological tests. You further state that all eluates have been used for manufacturing of the (b)(4) (b)(4) and this bulk was put into a stability study according to the known protocol (b)(4). Please elaborate as to what exactly was done with the eluates and the (b)(4). Please clarify as to whether lots were distributed, and if so, please provide your justification.

2. Please explain how Baxter could direct (b)(4) to use "(b)(4)" a Baxter product, which is not at the concentration used in the (b)(4)manufacturing process. Please address how you handle your component supply chain when there is difficulty specifying and procuring a product made by an affiliated Baxter company. 

3. Please provide insight on whether the fact that your recent batch of (b)(4) is exhibiting (b)(4) and (b)(4) responses, could factor into performance issues of the (b)(4) kit.

You should take prompt action to correct the violation(s) addressed in this letter. Failure to promptly correct these violation(s) may result in regulatory 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 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 Quality System regulation deviations are reasonably related will not be 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 violation(s), or similar violation(s), 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 violation(s) at your facility. It is your responsibility to ensure compliance with applicable laws and regulations administered by FDA. The specific violation(s) 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 violation(s), and take prompt actions to correct the violation(s) and to bring your products into compliance.

Your response should be sent to: Lorelei S. Jarrell, Compliance Officer at the above address. If you have any questions about the content of this letter please contact: Ms. Jarrell at (312) 596-4216 or Fax (312) 596-4195.



Scott J. MacIntire
District Director


cc: Dr. Burckhard Wichert
Plant Manager and Director of Manufacturing Oncology
Kantstrasse 2


Mr. Nick Ecos
General Manager
Ullernchausseen 52
P.O. Box 114 Smestad
Oslo, Norway