ID Biomedical Corp., a subsidary of GSK Biologicals 6/12/14
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Department of Health and Human Services
|Public Health Service|
Food and Drug Administration
| ||Center for Biologics Evaluation and|
1401 Rockville Pike
Rockville, MD 20852-1448
June 12, 2014
UPS EXPRESS MAIL
Site Director, Quebec Operations
GSK Biologicals, North America
2323 du Parc Technologique Blvd
Quebec City, Quebec, Canada G1P 4R8
Dear Mr. Glavas:
The Food and Drug Administration (FDA) conducted an inspection of ID Biomedical Corporation of Quebec d/b/a GlaxoSmithKline Biologicals (GSK), located at 2323 du Parc Technologique Blvd, Quebec, Canada G1P4R8, from March 31, to April 9, 2014. During the inspection, FDA investigators documented deviations from current good manufacturing practice (CGMP) requirements in the manufacture of your licensed biological drug product Flulaval and its intermediates. Deviations from CGMP include non-compliance with the applicable requirements of Section 501(a)(2)(B) of the Federal Food, Drug and Cosmetic Act (FD&C Act), the requirements of your biologics license application (BLA) approved under Section 351(a) of the Public Health Service Act (PHS Act), and Title 21, Code of Federal Regulations (21 CFR) Parts 210 and 211. At the close of the inspection, FDA issued a Form FDA 483, Inspectional Observations, which described a number of significant objectionable conditions relating to your facility’s compliance with CGMP. Significant deviations observed during the inspections include, but were not limited to, the following:
1) You failed to assure that appropriate written procedures designed to prevent microbiological contamination of drug products purporting to be sterile, are established and followed. Such procedures include validation of all aseptic and sterilization processes [21 CFR 211.113(b)]. Specifically, deviation #200217121 was initiated March 5, 2012, to investigate out of trend (OOT) results for endotoxin. The average endotoxin in the first 20 seasonal (b)(4) monovalent lots for 2012 was higher than the first 20 in 2010, and 2011. The investigation concluded that the endotoxin results have been atypical since May 2011.
Additionally, significant deviations in the manufacture of your intermediates were observed during the inspection. These deviations violate Section 501(a)(2)(B) of the FD&C Act and the requirements of your BLA approved under Section 351(a) of the PHS Act. Specific areas of concern include, but are not limited to:
2) Controls for the purified water system at your facility are inadequate to prevent bioburden and endotoxin excursions. For example:
a. The 2012 Annual Product Quality Review report for water indicates that there were many bioburden excursions in purified water system (b)(4)(Loop (b)(4)). Water from Loop (b)(4) is used in part to humidify air in (b)(4). Different types of bacteria were found, but in the majority of cases, the microorganisms found were Ralstonia pickettii and Achromobacter spp.
b. Deviation #200217554, initiated on March 7, 2012, indicates that a water-borne organism, Achromobacter xylosoxidans, found in water from one of the farms, and in water from one of the hatcheries, was also isolated from the purified water system in your facility.
c. The 2013 Annual Product Quality Review report for water concludes that four alert limits and one action limit were reached for water system (b)(4) (Loop (b)(4)). Water from Loop (b)(4) is used in part for equipment washing. Organisms isolated from these five excursions included Ralstonia pickettii and Achromobacter xylosoxidans. Achromobacter xylosoxidans and other water borne gram negative bacteria have been implicated in product contamination issues at your facility as far back as 2011.
d. There is no set schedule for disinfection of your water system. The system is only disinfected on (b)(4). The system was disinfected twice in 2011, five times in 2012, four times in 2013, and once in 2014 to date. In addition, the water system is circulated at (b)(4) temperature and is cleaned with (b)(4). No (b)(4) is used in the system.
3) Manufacturing controls in place for both the (b)(4) containing and the (b)(4) manufacturing processes are inadequate to control bioburden and endotoxin. Throughout 2013-2014 the process continued to generate Out of Specification (OOS) results for bioburden and endotoxin even after several corrective and preventive actions (CAPAs) were implemented. For example:
a. In 2011, 24 (b)(4) monovalent lots were rejected due to OOS endotoxin results.
b. Deviation #200217554 was initiated March 7, 2012, when eight (b)(4) monovalent lots were OOS for bioburden and endotoxin. These lots were rejected.
c. Deviation #200244479 was initiated on July 18, 2012, for eight (b)(4) monovalent lots that were OOS for endotoxin. These lots were rejected.
d. In 2013, (b)(4) monovalent lots used for process validation, had bioburden or endotoxin excursions. These lots were manufactured on the same equipment as commercial lots for release to the US. In most cases, the contaminating organisms were identified as Pseudomonas spp. and Stenotrophomonas maltophilia, both water-borne, gram negative rods.
e. In 2014, 20 of the (b)(4) lots manufactured (21%) showed bacterial growth and endotoxin excursions (b)(4). These lots were rejected.
4) From 2012 to 2014, viral inactivation of several monovalent lots could not be confirmed. Your explanation was that the observed microbial contamination caused high mortality of the test eggs before the (b)(4) test could be completed. These lots were rejected. For example:
a. In June 2012, Lot (b)(4) was found contaminated with Stenotrophomonas maltophilia, interfering with the (b)(4) test.
b. In May 2013, Lot (b)(4) was found contaminated with Pseudomonas aeruginosa, interfering with the (b)(4) test.
c. In March 2014, Lot (b)(4) was found contaminated with both Pseudomonas spp. and Stenotrophomonas maltophilia, interfering with the (b)(4) test.
5) Your investigation into the repeated bioburden excursions associated with (b)(4) is inadequate. You used a (b)(4) approach (testing 3 of the (b)(4)) to investigate the (b)(4), even though (b)(4) was most often implicated. (b)(4) was not always tested. For example:
a. In April 2013, contamination of (b)(4) was identified as the root cause for the 80% mortality rate of (b)(4) eggs. The eggs were found contaminated with Achromobacter xylosoxidans. The investigation in June, 2013, included taking swab samples from the (b)(4). Swabs taken from (b)(4) were tested for bioburden but the swab sample taken of (b)(4) was not tested for bioburden, even though it was the (b)(4) implicated in the contamination event.
b. A new cleaning validation study was approved and implemented in January 2014. The study included (b)(4) steps. The study did not include (b)(4).
c. On March 31, 2014, a new (b)(4) cleaning cycle was validated and implemented for the (b)(4). The study did not include (b)(4).
The deficiencies described in the Form FDA 483 issued at the close of the inspection referenced above and this letter are an indication of your quality control unit not fulfilling its responsibility to assure the identity, strength, quality, and purity of your licensed biological drug product and intermediates. FDA expects ID Biomedical and GSK to undertake a comprehensive and global assessment of all of its manufacturing operations to ensure that all products conform to FDA requirements. Please describe in detail how ID Biomedical and GSK will attain CGMP compliance with regard to the above deviations.
REVIEW OF YOUR INSPECTIONAL RESPONSES
We acknowledge receipt of your written responses dated April 15 and April 29, 2014, as well as additional information received on June 10, 2014, which address the inspectional observations on the Form FDA 483 issued at the close of the inspection of ID Biomedical Corporation, Quebec, Canada. Additionally, we acknowledge your commitments of corrective and preventive actions you have planned to address the above deficiencies. However, you have provided insufficient detail in your response. Further information and discussion with ID Biomedical and GSK will be necessary to adequately review and assess your planned actions.
To facilitate your remediation efforts, we request a meeting with you and other senior management at ID Biomedical and GSK to further discuss the issues cited in this letter and your proposed responses to address them.
Given the potential contributions of Flulaval to the public health, we encourage frequent interaction between your management and technical staff with FDA to help ID Biomedical and GSK move forward with corrective actions as rapidly as possible.
Neither this letter, nor the observations listed on the Form FDA 483 presented at the conclusion of the inspection, is intended to be an all-inclusive list of deviations that may exist at your facilities. We remind you that it is the responsibility of ID Biomedical and GSK to ensure that your establishment is in compliance with the provisions of the Federal Food, Drug, and Cosmetic Act, the 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 corrective action 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 following address: US Food and Drug Administration, Center for Biologics Evaluation and Research, Document Control Center, 10903 New Hampshire Ave. WO71 - G112, Silver Spring, MD 20993-0002. To schedule a meeting at your earliest convenience, please contact Robert McElwain, Consumer Safety Officer, in the Division of Case Management at (240) 402-9015.
Mary A. Malarkey
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
Kimber Poffenberger, Ph.D.
VP, Head of NA Regulatory Affairs
2301 Renaissance Blvd., Mailcode RN0210
King of Prussia, PA 19406
President, North American Pharmaceuticals
2301 Renaissance Blvd.
King of Prussia, PA 19406