NorthWest Biotherapeutics Inc (NWBO)

[Rkmatters]

It honestly took me no time to find it. But, I did imagine that you thought you gave me something impossible to find.

I once did a really dumb thing when I was tipsy teenager. I had this crazy idea I was going to make breakfast for my dorm mates around midnight and I decided I needed access to the second floor kitchen cafeteria. I first tried to gain entry ways by the first floor, as they used to keep the buildings open, but of course those stairwell doors to the cafeteria were all locked. The kitchen was in the "U" of the cafeteria, and so I reasoned that there would need to be a fire escape that would lead to the food delivery area, so off I went to explore. And as it turns out I was correct; a ladder from the basement led to two floors up to the kitchen and I climbed up and gained entry. I never did make the breakfast that I planned, as immediately after I got into the kitchen, I ended up getting spooked by noises which echoed up; and I miscalculated where they were coming from. I probably scared the heck out of the delivery man who would have called campus police on me, if I didn't make some excuse as to why I was inside, before I dashed away and escaped. Anyway, I'm telling you this as I tend to think of about how to best to get the results before I do the search, if the first attempt doesn't work. Same way as the 17 year old in me thought about getting into the campus cafeteria kitchen. :D

As for NWBO, the point is we don't know what is going on, and your mind always goes dark when it comes to them. I'm glad I've shown you there is some room for doubt, even though you probably still think it's a safety. JK. :)

Here's one that involves a BLA. Manufacturing needed improvement before they could approve the product. It took a year before they replied to the FDA:


Regulatory history

Isolagen Technologies, Inc (renamed Fibrocell Technologies, Inc in 2009) marketed an autologous fibroblast product, referred to as Isolagen TherapyTM (IT), as a cosmetic treatment in the United States from December 1995 to February 1999 without FDA premarket approval. IT was also marketed in the United Kingdom between 2002 and 2007. In compliance with FDA’s regulation of somatic cell therapies and the requirement to file Investigational New Drug Applications (IND) and follow a formal Biologics License Application (BLA) approval process, IT was removed from the US marketplace in 1999, and clinical trials of azficel-T were initiated in 2003 under IND --(b)(4)--.

Fibrocell Technologies, Inc submitted BLA STN#125348 on March 6, 2009 to request marketing approval of azficel-T. A Cellular, Tissue, and Gene Therapies Advisory Committee (AC) meeting was held in October 2009 to discuss the safety and efficacy of azficel-T (see section 8 Advisory Committee Meeting below). The majority of AC members stated that azficel-T was shown in clinical trials to be effective for the treatment of nasolabial fold wrinkles. However, the majority also expressed concern regarding the safety of the product. Some AC members suggested that gaining knowledge of the biological activity of the product at the histological level was necessary to increase understanding of the risks associated with the product.
SBRA STN# 125348 4

On December 18, 2009, FDA issued a Complete Response (CR) letter to Fibrocell Technologies, Inc, to request additional information on the manufacturing quality and controls and on the clinical safety of azficel-T. On December 22, 2010, the applicant resubmitted the BLA with complete responses to all FDA information requests in the CR letter. The December 22, 2010 amendment and subsequent amendments addressed adequately all of the outstanding issues from the FDA CR letter.



The review of the BLA original submission identified CMC deficiencies that were included in the CR letter issued December 19, 2009. Those deficiencies included:
* Specific deficiencies cited in the form 483 Pre-License Inspection report had not been resolved. ?
* Studies conducted to validate the stability of the cells during shipping over a proposed 48 hour time limit were not sufficiently robust to assure product quality. ?
* The validation study performed for the collagen assay was not adequate. ?
* Qualification and comparability of the ----(b)(4)---- had not yet been performed. ?
* Photographic documentation of morphology was needed. ?
* Tighter controls were needed to prevent over-confluence of the cells in tissue culture. ?
*  Specifications for hold times and passage rules during the manufacturing process ?were not adequate to assure the quality of the final product. ?
* Validation of the container closure system was inadequate. ?
* Addition of the potency assay to the stability protocol was needed. ?
* The characterization of cell types other than fibroblasts (-------(b)(4)----------------- ?------------) present was needed. ?
* One of the assays used for culture media qualification was still under ?development and needed to be completed. ?Fibrocell submitted amendments to the BLA to address each of these deficiencies. After review of all amendments the review team concludes that the responses are adequate and there are no outstanding CMC issues. ?b) CBER Lot Release ?An exemption is being granted from CBER Lot Release testing, including no requirement for submission of product samples to CBER. Instead, Fibrocell has agreed to a post- marketing commitment (-------(b)(4)---------------------------------------------------------------- ---------------------------------------------. The rationale for this decision is based on the autologous nature of the product and the short dating period of the final product. (--------- ---------(b)(4)--------------------------and therefore a single lot failure has minimal impact on the public health. The cellular product is administered fresh and has only a 24-hour shelf life. This does not allow enough time to provide samples to CBER to test the product prior to expiry. ?
SBRA STN# 125348 7

c) Facilities Review/Inspection

A pre-license inspection (PLI) was conducted August 31 – September 4, 2009 to support the review and licensure of azficel-T and the manufacturing facility. The inspection was conducted at Fibrocell’s manufacturing site in Exton, Pennsylvania which is to be the sole manufacturing site for the commercial product for the current BLA. The facility information for this site is:

Fibrocell Technologies, Inc 405 Eagleview Boulevard Exton, PA 19341
?FEI: 3005836954

The Exton facility is an ---(b)(4)---- square-foot, U-shaped building dedicated to the manufacture of azficel-T that was commissioned from October 2005 to February 2006. The facility consists of Manufacturing Area (approximately ----(b)(4)----.), Cleanroom Production Space, Quality Testing Laboratories, Warehouse, Shipping/Receiving, and Cryogenic Storage. The facility has a -------------------------(b)(4)------------------------------ -------------------------------------------------------. All in-process and final product manufacturing is conducted at this facility. All in-process and final product testing is also performed at this facility with the exception of mycoplasma testing which is performed by a contract testing facility.
During the PLI, the inspection team observed manufacturing processes specially designed and conducted for the PLI. The observations included biopsy receipt, tissue digestion, cell culture, cell harvest, cell cryopreservation, Quality Control (QC) testing, cell thaw, and aseptic filling of cryovials. The PLI resulted in issuance of a Form FDA 483 containing nine observations. The major deficiencies included an inadequate system for documentation of deviations and their subsequent investigation, inadequate Environmental Monitoring (EM), an inadequate media fill study, and the lack of cleaning validations for the BSCs and Cleanrooms.
The subsequent response to the Form FDA 483 issues provided by the applicant (detailed in an amendment to the BLA submitted 8/27/2010) fully addressed all the issues which are now considered resolved. As the PLI was conducted less than two years prior to the approval date, CBER determined a re-inspection was not necessary. Based on the 2009 inspection and responses to Form FDA 483, the overall compliance status of Fibrocell’s Exton Pennsylvania manufacturing facility is deemed acceptable for product approval.

d) Environmental Assessment

A request for a categorical exclusion from an Environmental Assessment under 21 CFR §25.31(c) was submitted to the BLA in the original submission. The applicant believes this application meets the categorical exclusion criteria and to their knowledge no extraordinary circumstances exist. The Agency agrees with this conclusion and the requirement of an environmental assessment is not warranted.

http://www.fda.gov/downloads/BiologicsBloodVaccines/CellularGeneTherapyProducts/ApprovedProducts/UCM262780.pdf