THIS DOCUMENT LISTS OBSERVATIONS MADE BY THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OF YOUR FACILITY. THEY ARE INSPECTIONAL OBSERVATIONS, AND DO NOT REPRESENT A FINAL AGENCY DETERMINATION REGARDING YOUR COMPLIANCE. IF YOU HAVE AN OBJECTION REGARDING AN OBSERVATION, OR HAVE IMPLEMENTED, OR PLAN TO IMPLEMENT, CORRECTIVE ACTION IN RESPONSE TO AN OBSERVATION, YOU MAY DISCUSS THE OBJECTION OR ACTION WITH THE FDA REPRESENTATIVE(S) DURING THE INSPECTION OR SUBMIT THIS INFORMATION TO FDA AT THE ADDRESS ABOVE. IF YOU HAVE ANY QUESTIONS, PLEASE CONTACT FDA AT THE PHONE NUMBER AND ADDRESS ABOVE.

DURING AN INSPECTION OF YOUR FIRM (WE) OBSERVED:

1. The following monovalent lots with high levels of bioburden at the [ Redacted ] step were re-processed/re-filtered, processed into trivalent lots, and released into US market for distribution during 2001/2002 Fluvirin campaign without CBE30 and/or CBER notifications:
   1. A/Panama lot #760351 with total bioburden volume of 6.48x10⁹ cfu was re-filtered into lot #760591 and used in the formulation of trivalent lot #s: 760688, 760641 & 760640 and in at least final Fluvirin released lot #E10821LA.
   2. A/New Caledonia lot 759931 with total bioburden volume of 3.29x10⁹ cfu was re-filtered into lot #760137 and used in the formulation of trivalent lot #760843 & 760092 and in at least final Fluvirin released lot #E11941LA.
   3. A/Panama lot #759864 with total bioburden volume of 4.45 ×10¹⁰ cfu was re-filtered into lot 760136 and used in the formulation of two trivalent lots 761025 & 761095 and in at least final Fluvirin release lot #E12821MA.
   4. There is no procedure that requires stability assessment of re-filtered batches, including SOP BLE024 Fluvirin Reprocessing at Monovalent and Trivalent Blend Stage. The only stability study that included re-filtered batches, R/0184/07/00 dated August 1, 2000, was not designed as refiltration protocol and assessed only previous monovalent strains, rather than those currently processed. The study also only assessed one syringe and one vial lot in one monovalent strain. The Stability Report does not include volume refiltered or pre-filtration bioburden. There is no protocol for assessment of stability of re-filtered Fluvirin when the monovalent strains change from season to season.
2. Control and failure investigations into bulk Fluvirin monovalent blends/lots at [ Redacted ] step with high levels of bioburden is deficient, in that lots were noted with total volume of high bioburden levels of e.g., 9.66×10 ⁶ cfu, 7.07×10⁷ cfu & 1.26 x 10⁷ cfu in year 2000/2001 and 2001/2002 campaigns and no formal investigations has been opened to find the root cause of the high levels of bioburden in these lots.
3. There is no documentation that the decisions to continue with the manufacturing of the Fluvirin monovalent lots with high levels of bioburden levels were based on the pathogenicity of the organisms that were isolated from the sampled lots, e.g., gram negative: Serratia marcesens, Enterobacter cloacea, and Pseudomonas putida.
4. Sterility failure investigations do not fully include all potential roots of contamination and corrective actions are incomplete. For example,
   1. The NCR investigations of Monovalent Blend Pool Batch #762492 refiltered into Batch #762835 dated July 2002 and batch # 761650 dated May 2002 implicated aseptic connections as potential root causes but failed

EMPLOYEE(S) NAME AND TITLE (Print or Type)
Omotunde O Osunsanmi, CSO
Robert W. Jennings, CSO
Robin Levis, Ph.D. Regulatory Coordinator
Jonathan McInnis, Biologist

The observations of objectional conditions and practices listed on the front of this form are reported:

1. Pursuant to Section 704(b) of the Federal Food, Drug and Cosmetic Act, or
2. To assist firms inspected in complying with the Acts and regulations enforced by the Food and Drug Administration.

"Upon completion of any such inspection of a factory, warehouse, consulting laboratory, or other establishment, and prior to leaving the premises, the officer or employee making the inspection shall give to the owner, operator, or agent in charge a report in writing setting forth any conditions or practices observed by him which, in his judgement, indicate that any food, drug, device, cosmetic in such establishment (1) consists in whole or in part of any filthy, putrid, or decomposed substance or (2) has been prepared, packed, or held under insanitary conditions whereby it may have become contaminated with filth, or whereby it may have been rendered injurious to health. A copy of such report shall be sent promptly to the Secretary."