|Issuer:||Center for Biologics Evaluation and Research|
|Issued:||Jan. 15, 2010||Closed:||March 22, 2010|
Department of Health and Human Services
Public Health Service
Food and Drug Administration
Center for Biologics Evaluation
1401 Rockville Pike
Rockville, MD 20852-1448
JAN 15 2010
RETURN RECEIPT REQUESTED
Robert L. Parkinson
Chairman, President and CEO
Baxter Healthcare Corporation
One Baxter Parkway
Deerfield, IL 60015, USA
Dear Mr. Parkinson:
The Food and Drug Administration (FDA) conducted an inspection of Baxter S.A., located on Boulevard Rene Branquart 80, B-7860, Lessines, Belgium between October 12 and October 19, 2009. During the inspection, the FDA investigators documented significant deviations from current good manufacturing practice (CGMP) in the manufacture of Gammagard Liquid and Gammagard S/D intermediates. These deviations from CGMP include 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 Gammagard Liquid and Gammagard S/D intermediates. Specific areas of concern include, but are not limited to:
1. Your investigation into recurrent clogging of filters is incomplete. For example:
a) Recurrent clogging of (b)(4) filters of the (b)(4) processes in Gammagard Liquid production was determined to be caused by (b)(4) . Since January 2008, approximately 107 Gammagard Liquid product lots had filter clogging events, to include 3 lots with (b)(4) filter clogging and 104 lots with (b)(4) filter clogging. 106 lots were manufactured for United States distribution, and approximately 78 of the impacted lots have been shipped to the US as of October 2, 2009.
b) Gammagard Liquid lots impacted by filter clogging events at the (b)(4) ANX steps were not placed on stability to evaluate the impact of increased (b)(4) and filter clogging events on the product.
c) Actions have not been implemented to correct and prevent the filter clogging (b)(4) , and filter clogging events from recurring. Approximately 42% of Gammagard Liquid lots manufactured in 2009 from (b)(4) had filter clogging events at the (b)(4) step. For example:
i. Lot LE12J049Z, February 15, 2009, Exception Report (ER) 09/129, described five filter clogging events. This lot was shipped to the US on March 31, 2009 and released on April 14, 2009.
ii. Lot LE12Jl39G, May 14, 2009, ER 09/377, described eight filter clogging events. This lot was shipped to the US on June 25, 2009 and released June 24, 2009.
iii. Lot LE12J172Z, 07-Jun'09, ER 09/445, described six filter clogging events. This lot was shipped to the US on July 28, 2009 and released August 3, 2009.
2. You failed to follow written procedure, SOP LE-09-FT03076, for initiating exception reports and investigations. For example:
a) Prior to July 18, 2008, SOP LE-09-FT03076 required an exception report for filter replacement events at the (b)(4) process step. An exception report was not initiated for a filter replacement event at the (b)(4) process step for Gammagard Liquid lot LE12H030Z.
b) The procedure was revised on August 19, 2009, to require an exception report only after (b)(4) filter clogging events for the (b)(4) loading and washing operations combined. After this date, however, exception reports were not initiated for approximately 15 Gammagard Liquid lots with five or more filter clogging events at the (b)(4) step.
c) From July 18, 2008 to September 27, 2009, approximately (b)(4) (49%) Gammagard Liquid lots were processed using 4 or more filter changes. Exception reports were not initiated for any of these (b)(4) lots. Historically these steps required only (b)(4) filter changes and no corrective actions were taken to remedy the problem.
PRODUCTION AND PROCESS CONTROLS
3. You failed to ensure that validation of the Solvent/Detergent (S/D) treatment step for viral inactivation was conducted with (b)(4) present in the product and there are no data to support that S/D treatment of the (b)(4) solution is effective. This (b)(4) caused multiple filter clogging events leading to a lack of assurance that viral inactivation at the S/D step was sufficient for the following three Gammagard Liquid lots:
a) Lot LE12H014 had four filter clogging events at the (b)(4) step and one filter clogging event at the (b)(4) step. This lot was shipped to the US on March 10, 2008 and released March 20, 2008.
b) Lot LE12H196 had one filter clogging event at the (b)(4) step and two filter clogging events at the (b)(4) step. This lot was shipped to the US on September 18, 2009 and released October 16, 2009.
c) Lot LE12H286 had one filter clogging event at the (b)(4) step and one filter clogging event at the (b)(4) step. This lot was shipped to the US on January 6, 2009 and released on January 9, 2009.
4. There are no extractable/leachable studies for the (b)(4) and (b)(4) Filters. Studies performed by the filter manufacturer used material that was not representative of the actual process.
CHANGES TO AN APPROVED APPLICATION
5. You failed to inform FDA about each change in the production process established in your approved license application(s) [21 CFR 601.12]. Specifically, SOP LE-09-FT03076 was revised on August 19, 2009 to routinely allow (b)(4) filter changes for the (b)(4) operations. This change (b)(4) Filter (for the (b)(4) process). This change in filter (b)(4) was not reported to FDA.
The deficiencies described in the Form FDA 483 and 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 Baxter S.A.’s Lessines, Belgium facility will attain CGMP compliance with regard to the above observations. Please include in that description how you will use all relevant information to implement effective corrective and preventive actions.
We acknowledge receipt of your written responses dated November 6, 2009 and December 3, 2009, which address the inspectional observations on the Form FDA 483 issued at the close of the inspection, and we have reviewed their contents. Corrective actions addressed in your letters may be referenced in your response; however, we believe that your responses did not provide sufficient detail to fully assess the adequacy of your corrective actions. Our comments and requests for further information regarding these corrective actions are detailed below. The items correspond to the observations listed on the Form FDA 483:
483 Observation #4
We acknowledge your commitment to open a CAPA to address critical process control parameters, (b)(4) . Please contact the Office of Blood Research and Review’s Regulatory Project Manager, Mr. Kelly Lewis, at 301-827-9427 to further discuss the issues pertaining to component (b)(4) levels in upstream processing.
483 Observation #5
In your response to Observation #5 you commit to a retrospective review of procedural changes back to January 2009 with submission to FDA of any changes requiring reporting under 21 CFR 601.12. Please note that your change in the allowable number of filters used as per SOP LE-09-FT03076 appears to fall into this category and should be reported.
Neither this letter nor the observations noted on the form FDA 483, which were discussed with you at the conclusion of the inspection, are intended 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 Federal Food, Drug and Cosmetic Act, Public Health Service Act, all applicable federal laws and regulations, and the standards in your license. Federal agencies are advised of the issuance of all Warning Letters about biological products so that they may 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 regulatory action without further notice. Such actions may include license suspension and/or revocation.
Please notify this office 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 response should be sent to the U.S. Food and Drug Administration, Center for Biologics Evaluation and Research, HFM-600, 1401 Rockville Pike, Rockville, Maryland 20852-1448. If you have any questions regarding this letter, please contact Robert A. Sausville, Director, Division of Case Management, CBER at 301-827-6201.
Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
cc Valerie De Schutter
Director, Quality/FQMR, Bioscience
Boulevard Rene Branquart 80
B-7860 Lessines, Belgium