FDA clarifies minimal manipulation of cell/ tissue products

by Alexey Bersenev on December 22, 2014 · 7 comments

in cell product, regulation

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FDA just released a draft of new interesting and highly anticipated document, which defines and clarifies minimal manipulation of human cell and tissue products. This guidance is a good response to misunderstanding of regulatory pathways, applied to some cell/tissue products (HCT/P). The goal is stated clearly: “improve stakeholders’ understanding of the definitions of minimal manipulation”. Defining minimal manipulation of cell/ tissue product is a “million dollar question”, because regulatory pathway differs dramatically. If your product is more than minimally manipulated, you going to take typical “drug pathway” to wide clinical use, means apply for IND, conduct clinical trials, spend 10-15 years and invest a lot lots of money! I’d like to highlight and discuss some important (in my opinion) points from this guidance.

  1. The key feature of the guidance is “Questions and Answers” section, where FDA gives multiple examples and explains potential confusions. This is probably the biggest difference of this document with everything, that was released by FDA earlier.
  2. Guidance clearly defines and emphasizes minimal manipulation for (i) structural and (ii) nonstructural tissues. The difference between these two is frequently missed in understanding of HCT/P regulation pathways.
  3. A big advantage of the guidance is examples of manipulations with adipose tissue – highly controversial and poorly understood type of HCT/P. The big message here is the following: If you isolate cells from adipose tissue (which is structural), you pretty much have no chance to fit in minimal manipulation criteria. Once you digest fat tissue or use other means to isolate cells, you alter “original relevant characteristics”, which is providing “padding and cushioning”, and therefore, perform more than minimal manipulations. The only example of minimal manipulation here is fat tissue fragments transfer for cosmetic purposes (liposculpture). One mention of stromal vascular fraction, I’d like to cite:

    Original relevant characteristics of adipose tissue, a structural tissue, to pad and cushion against shocks generally include its bulk and lipid storage capacity. A manufacturer recovers adipose tissue by tumescent liposuction and processes the adipose tissue to isolate cellular components, commonly referred to as stromal vascular fraction, which is considered a potential source of adipose-derived stromal/stem cells. The HCT/P generally is considered more than minimally manipulated because the processing breaks down and eliminates the structural components that provide cushioning and support, thereby altering the original relevant characteristics of the HCT/P relating to its utility for reconstruction, repair, or replacement.

  4. One of the most important things to understand is how structural tissue becomes a “drug” (more than minimally manipulated). Key words here – powder, homogenization, lyophilization, enzymatic digestion, relevant biological characteristics. One of the best examples you can find in the guidance is amniotic membrane – if you decellularize it and leave it as a whole sheet – you fit in minimal manipulation, but if you make a powder from it after decellularization – you’re manufacturing a drug. It’s all about integrity of the tissue!
  5. Interestingly, grinding and fragmentation of the tissue could be either minimal of more than minimal manipulation. For example, for bone tissue it’s considered as minimal.
  6. Another take home message: If you don’t provide information to support minimal manipulation of your product, FDA sees it as “more than minimally manipulated” by default.
  7. Finally, one thing for discussion: Guidance gives example of manipulations with hematopoietic tissue (a) minimal – stem/ progenitor cell selection (CliniMACS) and (b) more than minimal – expansion in culture or enhancement by drug via incubation. Does it mean that pretty much any CliniMACS procedure (T- or B-cell depletion) is minimal manipulation? No IND required? And for the second part:

    This HCT/P derived from cord blood would generally be considered more than minimally manipulated because the processing affects the production of intracellular or cell-surface proteins and other markers of cell lineage, activation state, and proliferation, thereby altering the cells’ relevant biological characteristics of multipotency and capacity for self-renewal.

    Isn’t repopulation of bone marrow relevant biological characteristic here? And frequently it’s not altered by expansion process! Latest expansion protocols allow to retain multipotency and self-renewal capabilities of hematopoietic stem cells. I guess, they may indicate other reason why “cell culture” case is more than minimal manipulation.

Overall, this guidance provides a good clarification on “minimal manipulation” and defines many terms. It is absolutely “must read” document for every cell product developer! Because it’s in a draft form right now, your comments are welcome! Feel free to contact FDA directly on this matter. Also, please give some examples of tough products in comments and we can go through it here.

{ 6 comments… read them below or add one }

Mike August 6, 2015 at 5:03 pm

with adipose in mind, if no enzymatic process is used, wouldn’t that pass the test?


Doug August 14, 2015 at 10:38 am

Is the speed at which a biological product (Blood, Bone Marrow, Adipose Tissue) for the extraction of stem cells considered to be an issue involving the notion of “beyond minimal manipulation”? For instance, the faster or longer a biological product is centrifuged. Is there evidence to suggest that this changes the morphological or genetic/cellular makeup of the stem cell being extracted?


Nassim Abi Chahine December 19, 2015 at 10:59 pm

To minimze the volume of a bone marrow aspirate and prevent anemia, as a mononuclear cell (MNC) product user, I give an injection of Filgrastim to easily aspirate the needed quantity of MNC 24 h later.
After collecting the MNC buffy coat by centrifugation 2g/10min I inject it back to the damaged organ by arterial catheterization, having in mind the best organ repopulation via the highest injected MNC concentration.
Kindly clarify if this is considered by FDA a minimal cell manipulation and if not what should I modify/delete in my procedure to fit in? Is it the growth factor?
Thank you very much for your answer, if will be highly appreciated.


Alexey Bersenev December 20, 2015 at 2:11 pm

If you are infusing BM MNC for the the purpose of reparation damaged/ diseased organ X, different from bone marrow, this is non-homologous use. Therefore, as per FDA your product should be regulated as 351 drug/ biologic.


Nassim Abi Chahine December 20, 2015 at 3:35 pm

Thank you for this clarification


greg April 5, 2016 at 11:12 am

Pericytes are found in all tissues of the body where there is vascular tissue. They perform the same function in each tissue, angiogenesis and tissue renewal. So depending on what tissue you get them from will determine where you can use them? Pericytes from fat tissue can only be used in adipose tissue conversely pericytes from adipose tissue cannot be used in any other tissue because they came from adipose even though they are found in all other tissue? And with the current guidelines they cannot be used even in fat because it was difficult to extract them? Seems like the sun is the center of the universe with these people, eventually they will be shown to be ignorant in their understanding and proclamations. Typical government bureaucracy. Maybe I’m not getting the reasoning in their arguments. Does their function dictates their use, or does their neighborhood dictate their use? The difficulty of extraction and isolation has nothing to do with either. Does anybody wonder why there is confusion when trying to understand their guide lines? Logic and reason seems absent with these guidelines.


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