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Vaccines

Review of Vero Cell Banks used for Vaccine Production and Adventitious Agent Testing of Virus Seeds and Vaccine Human Rotavirus Vaccine (HRV) - Rotarix

MEMORANDUM

 

DATE: April 1, 2008
FROM: Laraine S. Henchal, Microbiologist Reviewer, DVRPA, OVRR, Chair BLA Committee
THROUGH: Loris McVittie, Ph.D., Branch Chief, Viral Vaccines Branch, DVRPA, OVRR
TO: File of STN # 125265/0, BLA from GlaxoSmithKline, Inc. for Human Rotavirus Vaccine, Live, Oral (Rotarix®)
SUBJECT: Review of Vero cell banks used for vaccine production and adventitious agent testing of virus seeds and vaccine Human Rotavirus Vaccine (HRV) as presented in STN#125265/0.

VIRUS SEED LOTS (m3.2.S.2.3.1.1 and .3.1.2 Control of Materials)

History

The Serotype G1 HRV strain (genotype P[8]) which GSK used to make vaccine product is designated RIX4414. It was derived from strain 89-12, initially developed by Avant Therapeutics, Inc. ---------------. The virus was isolated in ------------- from a child in Cincinnati with a natural case of rotavirus with mild diarrhea. This original isolate was passaged 26 times in primary African Green monkey kidney cells (AGMK) by Avant for use as seed material. The P26 virus was ------- passaged by -- --------------- AVANT, -------, which passaged the seed virus an additional 7 passages to P33. This was the material that was clinically tested ---------------. The additional 7 passages were performed in an AGMK cell line that ------- characterized in --------.

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NOTE: Rotavirus potency (and identity) assays covered by other reviewers for CMC and statistics.

COMMENTS: Testing conducted on the Master Seed Bank is adequate and covers the basic tests which woul dbe conducted on these materials. GSK has elected to do a ---- -------------------------- on the ------------ in order to -------- the Master materials for ----------.

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------------------------. All assays were negative for the presence of the target virus sequences, indicating no contaminants of the listed viruses in the seed virus bank.

COMMENTS: The battery of testing performed on the ------- ----- Seed was extensive and included the full gamut of -------------------------------- which may have ------------------------------------------------------ ---------------------------------- treatment, and cloning steps that GSK has performed. Additionally, since -------- -------- cloning was undertaken on this seed and ----- used for initial production was from ------------------- sources, I consider there to be no TSE issues with this virus seed. The seed was -------------------------- because of the use of ----------- which were partially derived from bovine materials. The processes used to manufacture ----------- include ----------- and ---- ---------- and are generally considered to be capable of inactivating TSE agents.

VERO CELL BANKS (m3.2.S.2.3.2)

Master and Working Cell Bank History

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COMMENTS: The level of testing conducted on the Master Cell Bank is consistent with guidance at the time of its establishment. All tests were negative for the presence of any adventitious agents, and the tests were carried out in accordance with the 1993 Points-to-Consider document for vaccine made in mammlian cell substrates (an earlier document from CBER was issued in 1987, which was a compilation of generally accepted testing). The number of animals studied in the in vivo testing, and periods of observation were all appropriate. Bovine and ------- virus testing is adequate, although the testing -------------- ----------------- in the currently recommended 9 CFR testing. I believe it is not necessary in this case, as ------------- with bovine and ------------- is how the 9 CFR tests are carried out, with --- as the output in most cases. There was ------ evident in any of the testing. In addition, specific analysis was carried out for the major contaminants of concern, the --------------- virus and the ------------------. These two tests are the ones that are required as a minimum for bovine and ------- testing. The bank has also been developed to be ----------, so no further exposure to bovine agents would occur during vaccine production.

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COMMENTS: The results of all tests performed on the ---------- Working Cell Bank for Vero cells (VERO--/RIX4415/WCB) as established by GSK were satisfactory with no indication of the presence of any adventitious agent for which tests were performed. The introduction of -------------------- ------------ for the establishment of the ---------- bank, though, did raise issues of exposure to possible bovine adventitious agents. GSK did not conduct additional bovine virus testing on the WCB or the --- cells. However, after inquiry on March 9, 2008, GSK submitted the CoA of the ---------------- used for this ----- passage on 10 Mar 2008. The proper testing as per 9 CFR for bovine viruses had been conducted by the vendor; the lot was negative for the presence of those bovine viruses.


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COMMENTS: Results of all testing conducted on the --- bank were negative for presence of any adventitious agents, and there is no indication that the Vero cells as established by GSK at this level of production ------------------------ are ------------ In addition, retrovirus testing including the PERT assay as requested in CBER's letter to manufacturers of vaccines made in mammalian cells of Dec 18, 1998, was conducted on the ---, where one would expect any endogenous retroviruses present to be induced and detected. In addition, GSK also had this bank tested extensively for known ------ viruses ------ as undertaken ----------- with which CBER is familiar as a ----------------

Viral Harvest Testing from Vaccine Lots

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COMMENTS: The lots stated above all had satisfactory results on the tests performed. Of note: The company has requested in their cover letter for the original BLA submission to be allowed to discontinue the testing for absence of --------------------------. In Module 3.2.S.4.4, GSK presents the data from ------------------ with ------------- testing and all were negative. CBER usually has recommended that ------------- testing only be done if necessary based on the passage history of the virus seeds. Since this is derived from a human strain it makes sense that the testing has been conducted up to the current point. However, because the strain was ----------------- cloned from almost the beginning of its existence in GSK's hands, it was probably not necessary at all. Si I agree with the discontinuation of this test for the --------- ----------

Conclusions

The adventitious agent testing as described by GSK for Rotavirus Vaccine, Oral (Rotarix®) is adequate for U.S. licensure.

Modern live viral vaccine production is well controlled. With assurance that the starting materials have been well-characterized, the testing plan for the virus vaccine can be kept to a basic set of general tests which will detect any unforeseen adventitious agents which may find their way into the production stream. I concur with the request for discontinuation of the ------------- test and the General Safety test (see CMC review for more detail on this).

With regard to the virus seeds as established for Rotarix®, I believe that the virus seeds are extremely well-characterized. Firstly, the ----- treatment was carried out to avert any possible contamination with a ------------- contaminant that had been seen in the ---- ---- by the ------------------------------------------- -------------- original ------------- by the vaccine's developer. Next, in addition to the ----- treatment, GSK undertook to clone the virus in order to make the virus strain more homogeneous, but by so doing thereby also eliminated any possible carryover of a viral contaminating agent to which the vaccine virus may have been exposed to during development in the process. I had some concern regarding use of bovine derived materials in the ----- ---------------------------------------------------- ---------------------------------------------- to eliminate any exposure to additional bovine materials during manufacture. However, the ------ of the ---------- used for this initial passage for the ---------------- conducted the appropriate testing for bovine viruses. The testing conducted on both the master and working virus seeds is extensive and covers the testing as recommeded by CBER and the EMEA. This ---------- virus seed will be sufficient to supply the needs for rotavirus vaccine for the next ----- -------.

The Vero cells were originally obtained from the ----- by GSK at level ---- in ----. ------------------------ ------- in the TSE story. Any material obtained 1980 and before are considered not at risk for TSE contamination. --------------------------------------------------------- ----------------- used at that time was ------------------ -------- The U.S. had its first case of BSE only a few years ago. However, due to concerns arising from the use of bovine derived ----------------------------------------- ------------------------------------------------------ ----------- used for manufacture of this -------------------------------- was obtained from ---------- which remains a TSE-free country. The --------------------- was tested in ---- using tests considered to be necessary at that time. The --- cell bank was tested in ---- with a slightly more extensive battery of tests, including many for --------------------------------------------------- -------------- testing on passage --- (reflects passage level of cells at ---------------- process) -------------- ---, ------------------------------------------------. I consider the Vero Cell Banks to be adequately characterized for a live viral vaccine administered orally.

The above review encompasses a review of the original submission as submitted on June 1, 2007 (received in CBER on June 4, 2007). In addition, subsequent to an information request sent by me to the company on November 6, 2007, I reviewed the company response in amendment #11, received December 7, 2007. This consisted of pinpointing the location in the BLA of the numerous GSK Bio mongraphs and the detailed product reports in section 3.2.R. Additional information requests were sent to GSK on March 9, 2008 in regard to ------ testing for ------ and ------- viruses on ---------------- and ------- used in the production of the ---------- seeds and cell banks and virus production materials. The response received on March 12, 2008 (Amendment #25) was satisfactory. In regard to the cell substrate and adventitious agent testing conducted by GSK for Rotarix®, I recommend the approval of this application.

 

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