| Public Health Service Food and Drug Administration |
Center for Biologics Evaluation and |
Department of Health and Human ServicesWARNING LETTER
APR 15 2011
CBER-11-01
EXPRESS MAIL
Mr. Tobias Marguerre
General Manager/Member of the Board
Octapharma AB
Elersvagen 40
Stockholm, Sweden SE-112 75
Dear Mr. Marguerre:
The Food and Drug Administration (FDA) conducted an inspection of Octapharma AB, located at SE-112 75, Elersvagen 40, Stockholm, Sweden, between January 10 and January 20, 2011. During the inspection, the FDA investigators documented significant deviations from current good manufacturing practice (CGMP) in the manufacture of Octagam® and Octagam intermediates. Theses 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) Parts 210, 211, and 600-680.
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 Octagam® and Octagam intermediates. These include, but are not limited to, the following:
1. You failed to establish and follow written production and process control procedures designed to assure that the drug products have the identity, strength, quality, and purity they purport or are represented to possess [21 CFR 211.100]. Specifically, the validation of your (b)(4) process for Octagam® is inadequate. There were numerous deviations concerning clarity and IgA in final containers during your validation studies that were not addressed and that continued during manufacture of distributed final container lots. In addition, you made further modifications to your process to address deficiencies which have not been validated.
2. You failed to thoroughly investigate any unexplained discrepancy or the failure of a batch or any of its components to meet any of its specifications and failed to extend the investigation to other batches of the same drug product and other drug products that may have been associated with the specific failure or discrepancy [21 CFR 211.192]. Specifically:
a. You failed to perform an investigation for Octagam® Lots (b)(4) and (b)(4) manufactured with intermediate pastes from your facilities other than Stockholm which were identified as having manufacturing deviations.
b. You failed to investigate Octagam® Lot C937A843/U which had been released to the U. S. market and tested out of specification for measles and for clarity at the 3 month stability timepoint.
c. Your investigations for the out of specification results for clarity are inadequate. For example:
i. You released for distribution to the U. S. market Octagam® Lots C005A845/U and C005B845/U, which both tested out of specification for clarity of final product containers with approved test method Q617, entitled, “Clarity, limit tests.” Test results obtained for both the lots were III, when the specification is (b)(4). Your investigation report dated February 15, 2010, indicated that “ (b)(4) parameters that give (b)(4) batches the (b)(4). These lots were retested with unapproved assay Q750, entitled, “Determination of Clarity by (b)(4) with passing results.
ii. You released for distribution to the U. S. market Octagam® Lot C008A845/U, which tested out of specification for clarity with a result of III. You later reanalyzed the lot and invalidated the initial test results.
3. You failed to reject drug products failing to meet established standards or specifications [21 CFR 211.165(f)]. For example, you released for distribution to the U. S. market Octagam® Lots C005A845/U, C005B845/U, and C008A845/U, which tested out of specification for clarity with your approved test method Q167, entitled, “Clarity, limit tests.”
4. You failed to establish and maintain laboratory controls that include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures [21 CFR 211.160(b)]. Specifically, you used an unvalidated assay Q750, entitled, “Determination of Clarity by (b)(4)” to retest for clarity of Octagam® and based release decisions on the results.
5. You failed to establish and follow written procedures describing the handling and review of all written and oral complaints regarding Octagam® manufactured at your Stockholm facility, and you failed to maintain a written record of each complaint at the establishment where the drug product was manufactured, as such, investigations of complaints were not conducted and written records of investigations were not maintained at your Stockholm facility [21 CFR 211.198 (a) and 211.198(b)(2)]. Specifically, complaints are received at the U. S. Octapharma office and sent to the Vienna facility for investigations. Complaints involving product manufactured at the Stockholm facility are not received or investigated by the Stockholm Quality Control Unit.
6. You failed to inform FDA about each change in the production process established in your approved license application(s) [21 CFR 601.12]. For example:
a. You made changes and modifications to your approved (b)(4) procedure to address out of specification results for clarity in your process. These changes were not reported to the FDA.
b. You used an unapproved assay, Q750, entitled, “Determination of Clarity by (b)(4)” to retest for clarity of Octagam® and based release decisions on the results. This change was not reported to the FDA.
7. You failed to report any event and relevant information associated with the manufacturing or distribution of a licensed biological product that represents a deviation from CGMP, applicable regulations, applicable standards, or established specifications that may affect the safety, purity, and potency of that product [21 CFR 600.14]. For example:
a. You failed to report out of specification results for measles antibody and for clarity at the 3 month stability timepoint for Octagam® batch (b)(4).
b. You failed to report that an AQL inspection was not performed after 100% visual inspection for the following Octagam® batches: (b)(4)
8. You failed to ensure that Octagam® is free from turbidity as determined by visual inspection of final containers [21 CFR 640.101(c)]. For example:
a. You released for distribution to the U. S. market Octagam® Lots C005A845/U and C005B845/U, which both tested out of specification for clarity of final product containers with approved test method Q617, entitled, “Clarity, limit tests.” Test results obtained for both the lots were III, when specification is (b)(4). These lots were retested with unapproved assay Q750, entitled, “Determination of Clarity by (b)(4)” with passing results.
b. You released for distribution to the U. S. market Octagam® Lot C008A845/U, which tested out of specification for clarity with a result of III. You later reanalyzed the lot and invalidated the initial test results.
Additionally, significant deviations in the manufacture of your Octagam® intermediates were observed during the inspection. These deviations violate Section 501(a)(2)(B) of the FD&C Act and Section 351(a) of the PHS Act. Specific areas of concern include, but are not limited to:
PRODUCTION AND PROCESS CONTROLS
9. You failed to follow written production and process control procedures in the execution of the various production and process control functions. For example:
a. You failed to follow your SOP 1002-SI, “Change Control, Responsibility and Work Flow,” in that you made changes to your manufacturing process without following your change control procedures and without Quality Control Unit review and approval.
b. Regarding clarity issues in your Octagam® product, you continue to make modifications to your manufacturing process without Quality Control Unit approval, adequate documentation, and notification to the Agency.
BATCH PRODUCTION AND CONTROL RECORDS
10. You failed to define limits in your Batch Production Records throughout your manufacturing process. For example, Fraction II Batch Record (b)(4), Octagam® Bulk Solution Batch Record (b)(4), and Fraction I+II+III Batch Record (b)(4) do not include complete information relating to the production and control of each batch. This is a repeat violation from the January 2009 inspection. In addition, your batch records have insufficient detail which has caused inconsistency in manufacturing.
CONTROL OF COMPONENTS
11. You failed to establish and maintain written procedures to assure components conform to the appropriate standards of identity, strength, quality, and purity. Specifically, there are no procedures for notification of deviations which occurred during the manufacture of intermediates received from other Octapharma sites, which are used in the manufacture of Octagam® at the Stockholm facility.
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 intermediates and final drug products. Please describe in detail how Octapharma AB’s Stockholm, Sweden 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 February 10, 2011, and April 1, 2011, 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 letter may be referenced in your response; however, we believe that your response did not provide sufficient detail to fully assess the adequacy of your corrective actions. In addition we request further information regarding the corrective actions detailed below. The items correspond to the observations listed on the Form FDA 483.
483 Item #2B
The full report of the (b)(4) sensitivity, including data, is needed to assess the adequacy of your response regarding clarity and thrombotic potential.
483 Item #5A
We acknowledge your commitment to making changes in your SOP 1012-(b)(4), entitled “Handling of Deviations” and SOP 005(b)(4)018/00, entitled “Corporate Guidance for Batch Release Procedure (Regulatory Compliance).” Please be advised that harmonization in your deviation reporting system at all of your manufacturing sites may be necessary to address this issue. Please explain how this will be addressed.
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.
To facilitate your remediation effort we request a meeting with you and other senior management at Octapharma AB to further discuss the issues cited in this letter and your proposed responses to address them.
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. To schedule a meeting at your earliest convenience, please contact Mrs. Maria Anderson at (301) 827-6201.
Sincerely,
/s/
Mary A. Malarkey
Director
Office of Compliance and Biologics Quality
Center for Biologics Evaluation and Research
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