Review Memo for the Pre-License Inspection

To: Damaris Lopez-Rosario, CSO, OCBQ/ DIS/ PSB, HFM-654
       File STN 125259/0

From: Gang Wang, Ph.D., Biologist, OCBQ/DMPQ/MRB II, HFM-676
 

Cc:  Robin Levis, Ph.D., Biologist, Committee Chair, OVRR/DVP, HFM-451
       Rebecca Olin, Director Regulatory Officer, OCBQ/DMPQ/MRB II, HFM-676

Through:  Chiang Syin, Ph.D., Chief, OCBQ/DMPQ/MRB II, HFM-676

Subject: Review Memo for the Pre-License Inspection (PLI) on GlaxoSmithKline Biologicals’ manufacturing facility for the Cervarix ® vaccine located in Brussels, Belgium. 


A Pre-License Inspection (PLI) on GlaxoSmithKline Biologicals ( GSK), US License # 1617, Brussels, Belgium, was performed on September 12 to September 21, 2007 by the Center for Biologics Evaluation and Research (CBER). The scope of the PLI was to perform an inspection for GSK’s Cervarix ® (Human Papillomavirus Vaccine, AS04 Adjuvant-Adsorbed) for Intramuscular Injection under the BLA 125259/0. The CBER inspection team consisted of Gang Wang, Rebecca Olin and Robin Levis.

Cervarix ® is a prophylactic HPV vaccine (HPV 16/18 L1 VLP AS04) to protect females from 10 years of age onwards for the prevention of cervical cancer by protecting against incident and persistent infections, cytological abnormalities including ASC-US, cervical intraepithelial neoplasia ( CIN) and pre-cancerous lesions ( CIN2+) caused by the most common oncogenic genotypes, human HPV-16 and HPV-18 major capsid proteins (L1). The vaccine is assembled into virus-like particles (VLPs) and adjuvanted with AS04. The AS04 adjuvant is a combination of an aluminium salt and 3-O-desacyl-4’-monophosphoryl lipid A (MPL).

GSK’s Cervarix ® --------(b)(4)-------- is located in a -----(b)(4)----- facility (Building -(b)(4)-) on the Wavre-Nord site which is located approximately -(b)(4)- from the Rixensart site. Building -(b)(4)- is a new facility specifically designed to manufacture HPV ----(b)(4)----- and has not been inspected by FDA previously.

The formulation operations for Cervarix ® take place in the licensed facilities Buildings -(b)(4)- and -(b)(4)- which manufacture multi-products including Engerix-B ®, Havrix ®, Infanrix ®, Twinrix ®, Pediarix® and Boostrix®.

The filling operations for Cervarix ® take place in the licensed facilities Buildings -(b)(4)- and -(b)(4)- which manufacture multi-products including Engerix-B ®, Havrix ®, Infanrix ®, Twinrix ®, Pediarix ®, Boostrix ® and Fluarix™

The labeling and packaging operations for Cervarix ® take place in the licensed Building -(b)(4)- which is a multi-product facility.

Production of MPL takes place in Building -(b)(4)- at GSK’s newly acquired facility, Corixa Corporation, located in Hamilton, Montana. This facility was not inspected during the current PLI.

The current inspection focused on the systems that are used to manufacture and provide quality controls for Cervarix ®. The inspection team reviewed the documents related to facility and equipment validation, process validation, aseptic process validation, environmental monitoring, quality systems, computer systems, QC laboratory controls, and production process, etc. In addition, the inspection team also observed the aseptic filling and packaging processes of a vaccine product during the PLI. Detailed descriptions of the PLI can be found in the Establishment Inspection Report (EIR).

A Form FDA 483 was issued to the firm at the final close out meeting on September 21, 2007. A total of three inspectional observations were made (see following).

On October 16, 2007, GSK submitted their written responses to the 483, which were subsequently reviewed by the inspection team. The 483 observations (in Italics), GSK’s responses (in plain) and my comments (in bold) are summarized below.

1.The clean hold times --------(b)(4)--------- for the ---(b)(4)--- tanks used in Buildings -(b)(4)- and -(b)(4)-, the -(b)(4)- tanks used in Buildings -(b)(4)- and -(b)(4)-, and the ----(b)(4)--- for ---------(b)(4)----------- production used in Building -(b)(4)- have not been validated. 

  GSK Responses: Previously, GSK conducted two validation studies in 1997 and 2004, respectively, to validate and authorize a ---(b)(4)--- hold time for -----(b)(4)----- tanks ---(b)(4)-. The validation study was repeated in 2007 using a bracketing approach to reconfirm the ---(b)(4)--- clean hold time ----------(b)(4)-----------. Validation study was presented during the inspection. This study includes two worst case approaches:

?Storage conditions in a ---------(b)(4)--------- during validation versus storage in -------(b)(4)----- during production.
?Storage period of -(b)(4)- during validation versus -(b)(4)- in production.



In their response, GSK commits to qualify the holding time for ------------(b)(4)-----------------------------------------------------------------------------------------------------------------. The rational for the vessel choices will include both worst case and representative conditions. The study will be done on -(b)(4)- for each of the -(b)(4)- tanks and will be completed by April 2008.

Per my further request, GSK confirmed in an email dated September 21, 2009 that they have ever since qualified the holding time for -----------------------(b)(4)-----------------------------------------------------------------------------------------------. Qualification of the holding time has been performed under Validation protocols:

•VA20071063: Validation of the maintenance of pyrogenic-free status of cleaned and -(b)(4)- vessels and --(b)(4)-- after storage
•VA20080014: Validation of the maintenance of pyrogenic-free status of cleaned and -(b)(4)- vessels after storage

Validations results met the acceptance criteria and conclusions were approved by the validation department on May 05, 2008 and April 11, 2008 respectively.

Comment: Based on the information submitted, GSK has fulfilled their commitment to validate the cleaning hold time of the equipment. The responses are acceptable.
2.Information submitted in the BLA is not always correct and does not represent actual characterization results or process conditions. Examples include but are not limited to: 

a.Release data for the ------------(b)(4)-------------- test by the --(b)(4)-- assay for -(b)(4)- adsorbed monovalent bulk lots ------------------------(b)(4)----------------------------------------------------------------- was incorrect. Data included in the BLA were from the -----------(b)(4)-------------- test performed using the -(b)(4)- assay. 
b.Quality control release specifications provided during the inspection state that the release test for general safety will only be performed on consistency lots. The BLA states that the release test for general safety will be conducted as a final container release test for the -(b)(4)- commercial lots

GSK Responses: GSK states that although they had taken great care to produce accurate, articulate and detailed documentation for the BLA, errors were still not caught during file preparation. They accept the recommendation of the review team and are performing a further QC of the CMC section of the BLA. Thus far, they have not identified discrepancies in the CMC section, with the exception of two typographical or copy/paste inaccuracies which have no impact on any conclusion regarding the quality, safety, purity or potency of Cervarix. GSK further states that they will also attempt to ascertain how the discrepancies in the file escaped detection initially, with the aim to improve the quality of future applications.

GSK states that the data for -------------------(b)(4)--------------------- for HPV-18 L1 VLP adsorbed monovalent bulks showed in Table 4 of m3.2.P.3.4 and Table 4 of m2.3 in the initial BLA will be corrected and the corrected Table 4 will be included in the response to the agency’s “Information Request” dated October 1, 2007.

As requested, the specification for the QC test for General Safety of Cervarix final containers has been revised to remove the statement regarding the number of times the test will be conducted post-licensure. The revised specification will be included in the response to the agency’s “Information Request” dated October 1, 2007.

This request was addressed by removing the asterisk notation from beneath Table 2 entitled: “HPV final container vaccine specification” in m3.2.P.5.1. The asterisk has been removed and the revised Table 2 will be included in the response to the agency’s “Information Request” dated October 1, 2007.

The asterisk, which read, “*Performed on -(b)(4)- additional commercial lots” was reflective of an internal target set by GSK to trigger a request for the removal of the abnormal toxicity test (i.e. regions other than the U.S) or a request for exemption from the general safety test (i.e. in the U.S., pursuant to 21 CFR 610.11(g)(2)) for the Cervarix vaccine. At such time as -(b)(4)- commercial lots had been tested (and provided the lots had passed), and in addition to the data package already available for general safety testing on the clinical trial lots, GSK intended to request of FDA an exemption from the general safety test(s) per the CFR provision. GSK has not submitted information as part of the initial biologics license application for Cervarix to justify that the test of general safety is unnecessary to assure the safety, purity and potency of the product.

GSK commits to submit their responses to Agency’s “Information Request” dated October 1, 2007 by October 31, 2007.

On November 21, 2007, GSK submitted an amendment to the pending BLA to address two comprehensive tables summarizing the inaccuracies or typographical errors identified in the CMC sections (Table 1 for HPV-16/18 L1 VLP and Table 2 for MPL). GSK listed the inaccuracies or errors in the original BLA and also the corrections in these two tables. GSK proposed not to revise the BLA sections at this time, but rather to incorporate the minor revisions when the relevant BLA sections are updated due to post-approval changes.

CBER Comment: I discussed the firm’s responses to this observation with Dr. Robin Levis, the product reviewer and the inspector. She acknowledged that she has reviewed the amendment and indicated that the firm’s responses were acceptable.
3. SOP # GSOPBIO_QA_1203_20002, Request for Process Change (RPC), was not strictly followed to assure that requests are appropriately evaluated and approved before change activities are implemented. 


RPC # 1300001405 requesting New Cleaning Method for -(b)(4)- at the Hamilton, Montana site was approved by QA GMP in Production in Building -(b)(4)-, Room -(b)(4)-, Hamilton, Montana Site, was already completed on July 18, 2006. Additionally, there was no documentation to show that the Hamilton site was retrained regarding the proper use of the Change Control System.

GSK Responses: GSK commits that the staff in Hamilton will be re-trained regarding the proper use of the change control system. In addition, in order to maintain robustness of the process, there will be weekly follow-up of all RPC generated from the Hamilton site performed by the Global QA department in Belgium. The target date is December 2007.

CBER Comment: The responses appear adequate.

In summary, the inspectional issues related to the observations made during the PLI have been adequately addressed, and the responses appear acceptable.
