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Vaccines, Blood & Biologics

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Vaccines

Cell Substrate Review

BLA STN#: 125280
Sponsor:Intercell
Product: IXIARO (Japanese encephalitis vaccine, purified, inactivated)

To:  The File – 125280/0
       Robin Levis, DVP
      Lewis Markoff, DVP
      Richard Daemer, DVRPA
      Daryll Miller, DVRPA
      Norman Baylor, OVRR

From:  Barry Falgout, DVP

Subject:  Cell substrate review and approval recommendation.

Memo Date:   03/02/2009

 

Cell substrates/adventitious agents overview.

IXIARO is JE virus strain SA 14-14-2 grown in Vero cells, -(b)(4)--purified, formalin inactivated, then adjuvanted with alum. Adventitious agent contamination of the product could theoretically come from three sources: the virus seed, the Vero cell bank used to grow the virus, or accidental introduction during the manufacturing process itself. The first two potential concerns are the subject of this review, the manufacturing process and its controls are reviewed elsewhere by Dr. Li Yu.

In summary, the information in the BLA documents that the JE SA 14-14-2 working virus seed bank and the Vero cell banks are well made, well-characterized, and are free of adventitious agent concerns. Based on this, I recommend approval of this BLA.

 Passage history of the JE SA 14-14-2 virus.

The parental JE virus was originally isolated from mosquitoes and then passaged a large number of times, in China. This is summarized in Figure 3.2.S.2.3.1-2, shown below.

Figure 3.2.S.2.3.1-2: Development History of SA (14 ) 14-2 Virus

In 1986, the SA 14-14-2 virus was adapted to grow in primary dog kidney cells by researchers at WRAIR, -------------------------------(b)(4)-------------------------------------- ------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------ --------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------- -----------------------.

[ --(b)(4)-- ]

 

The risks of adventitious agent contamination will be considered separately for the JE SA 14-14-2 virus prepared in China, the dog kidney cell adaptation at WRAIR; the Vero cell bank, Vero cell adaptation, and master virus seed process at -(b)(4)-, and finally the working virus seed preparation at Intercell.

Isolation of JE SA 14-14-2 in China

There is no information in the BLA about the preparation or testing of the JE SA 14-14-2 virus from China. Given that the virus was passaged in numerous cell types and animals over the course of many years - see Figure 3.2.S.2.3.1-2 above – there were plenty of opportunities to pick up viral (or microbial) contaminants. Still, these concerns are alleviated by the fact that the eventual virus seeds are well-tested for adventitious agents. Also, the product is formalin-inactivated, and section 3.2.A.2 presents data validating that the inactivation process kills between -(b)(4)- and -(b)(4)- logs of three different test viruses. Therefore, there are no concerns regarding adventitious viral agents.

With regard to the possibility of TSE contamination, the work leading up to the penultimate SA 14 clone 5-3 was completed and published in the literature by 1973, and thus is not a concern. The work describing the last passages in mice and primary hamster kidney cells leading to JE SA 14-14-2 was published in 1981. Given that the passaging likely occurred in China in 1980 or before, there are no concerns regarding TSE agents in preparations sourced from China.

Adaptation of JE SA 14-14-2 to growth in primary dog kidney (PDK) cells.

There is a very brief description of the process used to make the PDK cells, and the passaging of the JE SA 14-14-2 virus, in a 1988 paper from the literature reproduced as Annex II of 3.2.A.2.2.1 Appendix 9. The PDK cells were prepared by the Salk Institute from healthy 9-week old male Beagles, and were frozen on liquid nitrogen until use. Animals were necropsied to confirm the absence of any obvious diseases or neoplasms. Cells were tested by broth and agar inoculation for microbial sterility and absence of mycoplasma. Cells were also shown not to react with a polyvalent antiserum specific to four canine adventitious viral agents. Despite the absence of details, the testing done provides some assurance that the cells were not contaminated with microbes or viruses.

---------(b)(4)-------------------------------------------------------------------------- 

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---------(b)(4)------------------------------------------------------------------------- 

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[ --(b)(4)-- ]

 

---------------(b)(4)---------------------------------------------------------------------------------- -------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------------

------------(b)(4)----------------------------------------------------------------------------- -----------------------------------------------------. After the IND pre-phase III meeting, CBER had sent a letter to Intercell, dated October 28, 2004, which addressed this issue as our answer to question 2, reproduced below.

  • “Question 2: Is the TSE compliance safety evaluation of the Vero Master Cell Bank and the Japanese Encephalitis Virus SA 14-14-2 Master Virus Seed Bank as presented in the detailed summary (Attachment 3) acceptable to the FDA and therefore the risk of TSE transmission in considered minimal? Although the risk of TSE transmission might be minimal, there are a number of passages of the virus seed for which there was no documentation as to the source of animal materials used in its preparation. Therefore, the vaccine as currently manufactured would be placed on the "unknown" list on the CBER website in regard to use of animal materials from unknown sources. If the Master Virus Seed were to be rederived by -(b)(4)- rounds of plaque purification, with documentation of source materials from BSE-free countries as determined by the USDA, then the vaccine would be removed from the "unknown" list. Alternatively, the Master Virus Seed could be rederived using recombinant DNA technology, again with documentation of source materials. This could be done prior to the Phase 3 studies or done post-licensure via supplement to the BLA.”

Since Intercell did not re-derive the virus seeds, this would seem to indicate that IXIARO should go on the “unknown” list. However, the CBER public web site (http://www.fda.gov/cber/bse/bse.htm) offers specific advice about re-deriving virus seeds.

“Working bacterial and viral seed banks and working cell banks that were established using bovine-derived materials sourced from countries on the USDA list should be re-derived with bovine-derived materials from countries not on the USDA list. However, master bacterial and viral seed banks established in a similar manner do not need to be re-derived; the potential risk presented by the master seed banks is even more remote than that presented by the working seed banks and is outweighed by the risk of altering the bacterial or viral vaccine through re-derivation.”

Thus, since the undocumented serum was used at -(b)(4)- while deriving a ---(b)(4)------ seed, this advice indicates it is not a concern, and IXIARO does not have to be put on the “unknown” list, and furthermore suggests that the virus seed should not be re-derived.

In my opinion, given the facts that the serum was perhaps from the US and that the ---------------(b)(4)------------------- seed, the risk of TSE contamination in the final product is vanishingly small. Thus, I agree that IXIARO does not need to be listed. However, given the simple nature of the product, I also do not think there is any risk of altering the properties of the vaccine by re-deriving the master virus seed. Should Intercell choose to do this, in my opinion all Intercell would need to do is demonstrate that the -------(b)(4)-------- seed still induces neutralizing antibodies in the -(b)(4)- potency assay similar to the original virus seed.

19 pages determined to be not releasable: (b)(4)


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