Shocker: FDA views treatment with ethylene oxide, a highly toxic carcinogen, & irradiation as minimal manipulation

ethylene oxideWhat does the FDA define as “minimally manipulated” when it comes to biologics such as stem cells?

You will be shocked to find out, but they include irradiation and treatment with the super toxin/carcinogen, ethylene oxide.

In a recent post I discussed the issue of an apparent “minimal manipulation” exception (some might even call it a loophole) in federal regulations whereby clinics offering stem cell therapies could avoid having their therapies be explicitly approved by the FDA using its conventional vetting process.

The idea is that if cells have not been substantially altered prior to transplantation (hence “minimally manipulated”) then they can be used for transplant without going through the standard, far more thorough FDA approval process.

The rub comes from vagueness about what “minimal manipulation” means and how clinics inevitably interpret it much more loosely and broadly than the FDA does.

The overall term used to describe these kind of cellular or tissue products is HCT/P, which is an acronym for “human cells, tissues, and cellular or tissue-based products”.

HCT/Ps that are defined as minimally manipulated are regulated simply by a federal code called 21 CFR Part 1271 that you can read in your ample spare time here.

However, HCT/Ps that are not minimally manipulated are regulated both by 1271 AND by the standard FDA regulatory process for biologics.

Not surprisingly,  for-profit companies selling stem cell therapies do not want to have to deal with that extra regulation so they very much want their products to be classified as minimally manipulated. Strictly from the stand point of making money, this is logical because meeting higher regulatory standards is very expensive. From the standpoint of patient safety, things become more murky. So what does “minimal manipulation” really mean?

With a huge hat tip to Lee Buckler, pasted at the bottom are more details on minimal manipulation.

You of course may read it all, but here’s a concise summary.

What does NOT constitute minimal manipulation is not entirely clear but definitely any growth in culture or use of growth factors is not allowed.

As best as I can tell, what DOES constitute minimal manipulation?

1) antibiotic treatment

2) cell separation  (it is unclear to me if FACS is allowed for this purpose or only sedimentary separation)

3) centrifugation

4) cryopreservation

5) sterilization by ethylene oxide treatment or irradiation.

I buy the first four things, but that last one is really a tremendous surprise for me. I’m frankly shocked that the FDA defines treatment with a highly toxic chemical and/or irradiation, which can introduce random DNA mutations in cells, to be minimal manipulation.

Call me a purist, but those seem like huge manipulations to me.

Irradiation of cells profoundly and permanently changes them, often in ways that promote cancerous behavior.

Ethylene oxide is an incredibly dangerous, flammable, explosive, and toxic, but very useful industrial chemical. You can read its MSDS (safety sheet) here. Scary stuff.

It is 100% clear that this chemical, which is also a key ingredient in particularly lethal bombs, has both cancer and reproductive hazards, but almost certainly other dangers as well. It is a known human carcinogen.

I remain stunned that radiation and ethylene oxide treatment are considered “minimal”. There is an organization funded by ethylene oxide producers that promotes its use for sterilization.

I have no problem with its use for sterilizing things such as surgical instruments, which can then be rinsed, but using it on cells to then be given to patients?

Yikes.

More broadly, in the end, for any given company, they must consult with the FDA to determine on a case-by-case basis what is and what is not minimal manipulation as specifically relates to their product in question.

The detailed regulations themselves:

http://www.gpo.gov/fdsys/pkg/FR-1998-05-14/html/98-12751.htm  Page 26748

2. Minimal Manipulation

One of the criteria for regulation of a human cellular or tissue-

based product under section 361 of the PHS Act and part 1271 is that it

be minimally manipulated. Minimal manipulation is defined in

Sec. 1271.3(g). For structural tissue, minimal manipulation is defined

as processing that does not alter the original relevant characteristics

of the tissue that relate to the tissue’s utility for reconstruction,

repair, or replacement. For example, separation of structural tissue

into components whose relevant characteristics relating to

reconstruction or repair are not altered would be considered minimal

manipulation, as would extraction or separation of cells from

structural tissue in which the remaining structural tissue’s relevant

characteristics relating to reconstruction and repair remain unchanged.

Other examples of procedures that would be considered minimal

manipulation include: Cutting, grinding, and shaping; soaking in

antibiotic solution; sterilization by ethylene oxide treatment or

irradiation; cell separation; lyophilization; cryopreservation; and

freezing.

For cells (structural and nonstructural) and nonstructural tissues,

minimal manipulation is defined as processing that does not alter the

relevant biological characteristics and, thus potentially, the function

or integrity of the cells or tissues. For example, FDA considers cell

selection (e.g., selection of stem cells from amongst lymphocytes and

mature cells of other lineages) to be minimal manipulation.

FDA considers the processing of cells and tissue to be “more than

minimal” if information does not exist to show that the process meets

the definition of minimal manipulation. Examples of manipulation not

considered minimal, based on current scientific knowledge, include cell

expansion, encapsulation, activation, and genetic modification. FDA

recognizes that the subsequent accumulation of clinical data and

experience about a particular process may demonstrate that it does not

alter the original relevant characteristics of the cells or tissue, and

the agency will consider this information in determining whether a

procedure should be considered minimal as opposed to more-than-minimal

 

[[Page 26749]]

manipulation. For example , FDA previously considered demineralized

bone products (DMB) to be more than minimally manipulated. However, at

the March 17, 1997, public meeting, and during a July 11, 1997, meeting

between the American Association of Tissue Banks and FDA, the agency

was urged to reconsider its position regarding the regulatory status of

DMB. After reviewing information provided, the agency believes that the

relevant characteristics that relate to DMB’s utility for replacement,

reconstruction and repair are not altered by processing bone specimens

into DMB. Therefore, FDA proposes to regulate DMB under section 361 of

the PHS Act provided it is used for homologous function and is not

combined with a noncellular or nontissue component that is a drug or

device because FDA believes DMB falls within the minimal manipulation

definition.

 

http://www.fda.gov/ohrms/dockets/98fr/011901a.htm   Page 5457

We agree that the TRG will continue to play a role in providing

recommendations for certain decisions made by the Center director

interpreting the term “minimal manipulation.” At this time, examples

of HCT/P’s that we consider to be minimally manipulated include those

that have been subjected to the following procedures: Density gradient

separation; selective removal of B-cells, T-cells, malignant cells, red

blood cells, or platelets; centrifugation; cutting, grinding, or

shaping; soaking in antibiotic solution; sterilization by ethylene

oxide treatment or irradiation; cell separation; lyophilization;

cryopreservation; or freezing. We do not agree that the expansion of

mesenchymal cells in culture or the use of growth factors to expand

umbilical cord blood stem cells are minimal manipulation.

 

 

 

3 Comments


  1. Hi Paul – Thanks for the interesting and troubling commentary on some potential problems with the current definition of “minimal manipulation.” You might compare the FDA wording with the EMA definition of “substantial manipulation” of ATMPs (the category that includes many cellular medicinal products. The EMA clearly excludes irradiation from “substantial manipulation,” but does not go into detail about what antibiotic/antimicrobial agents are excluded. (You can find a list of the ATMP criteria in the presentation here: http://www.ich.org/fileadmin/Public_Web_Site/Training/ASEAN_Q5C_workshop_May_2011/SESSION_IVb_ATMPs.pdf)

    Given your concerns, you might consider contacting the FDA regarding their thinking behind these criteria. The regulations need to evolve with the science in order to maximize patient safety and trust.

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