>> How do you control multi-lot variability across animal serum...

>> How do you control multi-lot variability across animal serum batches?

SI>> We have quite a strict criteria in relation to thefetal bovine serum and it links to mixing certain tests, we ensure its safe, it's being irradiated etc.| would look at things like capacity of the serum as well to try and ensure the best consistency aspossible each time.

>> How about if we take thelast question before the break, Dr.Garcia?

>> Thank you.| have a clarifying question, | understand the heterogeneity and concerns about the group as to the difference in manufacturing each lot or product at the time.And the concern there may be variation between the products used in clinical trials and protocols against commercial products.

>> My question relates to the testing.The applicant used phenotypes in the 105 and these innovation of receptors.Is acceptable for the FDA?Or is he a state agency asking for additional testing to be done prior to release of the product?

SI>> We don't describe or prescribe what tests the manufacturers have to rely on for these assays.We don't really say we can't use Caesar we can or we need to do something in addition.

We are asking the question in a different way, are those theway the sponsor the applicant has used them sufficiently to say each batch will be thesame?| think our concern as we stated the issue we don't see a correlation of individualpatient outcomes with individual lots.Are they doing this assay, are they using the quality attribute that will associate or predict thatquality attribute with the clinical outcome?Were not sinners are useful or informative assays as a general class but in particular case here, does that answer your question?

>> If | could expand my question, it wasn't clear to methat the morning that | thoroughly understand complex and multifaceted.It's a biological issue but, the company knows through MLA of the agent,?

Geraldine>> I'll ask the doctor to respond to that question.

SI >> Certainly.As we tried to show you, REM stem cell has service receptors able to sense inciting inflammatory cytokines, the receptor is a very important one, the gammareceptor is another.You put the cells into an inflammatory microenvironment, we have high levels and through these receptors, cell senses the information and is activated.The pathway goes through TNF R1, through B which is in master regulator of multiple factors and is well established this cell and secretes the anti-inflammatory mediators downstream resulting from activation.Those factors include CCL to NMC SF act onthe pro-inflammatory macrophage which is made TNF in the first place and is the M1 macrophage and switches it off.It turns it into an M2 macrophage whichis an modular cell that produces interleukin that is an important static and that modulates an inventory microenvironment as occurs in GVHD.

SI >> In addition, through parallel pathways, the stem cell releases actors and Dempsey measurement of multiple factors and some regulatory, some traditional pathways is the measurement of the matrix as witches to measure the ability of the cell T cell activation is important also.We are dealing with living cell able to sense inflammation, response information, and through multiple factors switch off the inflammatory process is at the core of damaging and that causes death.Yes, we understand very well and is a question of how best to measure those in vitro to ensure we have a safe and effective and reproducible product for use inthis very bad disease.

>> No further questions.

>> Will now take a 10 minute break.