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  5. Biotest Pharmaceuticals Corp. - 11/25/2014
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Biotest Pharmaceuticals Corp.

Biotest Pharmaceuticals Corp.

United States

Issuing Office:
Office of Regulatory Affairs

United States


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

Public Health Service
Food and Drug Administration
 Office of Regulatory Affairs
12420 Parklawn Drive
Rockville, MD 20857
Telephone: (301) 796-2720
FAX: (301) 827-4090 



November 25, 2014

Mr. Jordan Siegel
Chief Executive Officer
Biotest Pharmaceuticals Corporation
5800 Park of Commerce Boulevard NW
Boca Raton, Florida 33487

Dear Mr. Siegel:

The Food and Drug Administration (FDA) conducted an inspection of Biotest Pharmaceuticals Corporation, located at 5800 Park of Commerce Boulevard NW, Boca Raton, Florida, between August 5 and August 15, 2014. During the inspection, FDA investigators documented significant deviations from current good manufacturing practice (CGMP) requirements in the manufacture of your Bivigam, (b)(4)-HB and Rabies Immune Globulin 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), 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) Part 601.

At the close ofthe inspection, FDA issued a Form FDA 483, lnspectional Observations, which described a number of significant objectionable conditions relating to your facility's compliance with CGMP. Specific deviations observed during the inspection include, but are not limited, to the following:

Failure Investigations

You failed to document manufacturing investigations conducted for lots associated with confirmed out of specification (OOS) test results. For example, five OOS results for Protein by (b)(4) were identified at three different processing steps during the fractionation of five out of eight lots. All of the OOS intermediate lots were approved and released.

Process Validation

1.    You failed to validate, minimum and maximum process times for the Bivigam process. The process steps were changed due to an increase in production of Bivigam from 2-3 lots to 5-6 lots per week. Specifically, the maximum process time for Bivigam and (b)(4)HB from the (b)(4) centrifugation complete to Fraction II+III centrifugation step was changed from (b)(4) hours to  (b)(4) hours. The maximum process time for the Bivigam ultrafiltration and diafiltration (UF/DF) step was changed from (b)(4) hours to (b)(4) hours.

2.    You failed to validate minimum and maximum mixing times for the Bivigam and (b)(4)HB manufacturing process. There were 17 instances where mixing times were exceeded from April 4 to July 7, 2014. For example:

a)    Per DEV10351 dated July 12, 2014, total stir time at step 4.6.4 of (b)(4) hours was exceeded with the total time of (b)(4) hours, which was 61 hours over the limit.

b)    Per DEV10350 dated July 12, 2014, total stir time at step 5 of (b)(4) hours was exceeded with the total stir time of (b)(4) hours, which was 31 hours above the limit.

c)    Per DEV9162 dated March 27, 2013, the total stir time at step 5.8.3 was (b)(4) hours, which was 23 hours longer than the established range.

Laboratory Controls

You failed to validate Method QC 2100 Revision 16, for the determination of total protein by (b)(4) used in the testing of Fraction II+III for Intermediate Rabies Immune Globulin.


You failed to inform the FDA about each change in the product, production process, quality controls, equipment, facilities, responsible personnel, or labeling established in the approved license application [21 CFR 601.12]. For example:

a) You did not report to the FDA and provide validation data to support the use of multiple filters in the bulk filtration step for Bivigam. Such a change requires approval of a supplement prior to distribution of the product (601.12(b)).

b) You did not report to FDA the change to the maximum process times for Bivigam and (b)(4)HB from the (b)(4) centrifugation complete to Fraction II+ III centrifugation step from (b)(4) to (b)(4) hours.

c) You did not report to the FDA the change to the maximum process time for the Bivigam ultrafiltration and diafiltration (UF/DF) step from (b)(4) hours to (b)(4) hours with no minimum process time.

The deficiencies described in the Form FDA 483 issued at the close of the inspection referenced above and in this letter are an indication of your quality control unit not fulfilling its responsibility to assure the identity, strength, quality, and purity of your biological drug intermediates. FDA expects Biotest to undertake a comprehensive and global assessment of all of its manufacturing operations to ensure conformance to FDA requirements. Please describe in detail how Biotest will attain CGMP compliance with regard to the above deviations.

We acknowledge receipt of Biotest' s written response dated September 4, 2014 which addresses the inspectional observations on the Form FDA 483 issued at the close of the inspection. We have reviewed your response and note that it does not provide sufficient detail to fully assess the adequacy of the corrective actions. For example, your response fails to discuss implementation of adequate quality unit oversight to ensure prompt identification, correction, and follow up to problems associated with the manufacture of your products. Corrective actions addressed in your letter may be referenced in your response to this letter.

Neither this letter nor the list ofinspectional observations (Form FDA 483) is meant to be an allinclusive list of deficiencies that may exist at your facility. We remind you it is your responsibility, as management, to assure that your establishment is in compliance with all provisions of the Federal Food, Drug, and Cosmetic Act, the Public Health Service Act, all applicable federal laws and regulations and the standards of your license. Federal agencies are advised of the issuance of all Warning Letters about biological and pharmaceutical 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 action includes license suspension and/or revocation, seizure and/or injunction.

Please notify this Office in writing, within 15 working days of receipt of this letter, of specific steps you have taken to correct the noted violations and to prevent their recurrence. 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.

Your reply should be sent to the Food and Drug Administration, Office of Medical Products and Tobacco Operations, 12420 Parklawn Drive, Room 2142, Rockville, Maryland 20857. If you have any questions regarding this letter, please contact Fabio Mattiasich, Compliance Officer, at (718) 662-5580.

Alonza Cruse
Acting Director
Office of Medical Products and
Tobacco Operations

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