Human Cells, Tissues, and Cellular and
Tissue-Based Products (HCT/Ps) from
Adipose Tissue: Regulatory
Considerations
Draft Guidance for Industry
This guidance document is for comment purposes only.
Submit one set of either electronic or written comments on this draft guidance by the date provided
in the Federal Register notice announcing the availability of the draft guidance. Submit electronic
comments to http://www.regulations.gov. Submit written comments to the Division of Dockets
Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, Rm. 1061, Rockville,
MD 20852. You should identify all comments with the docket number listed in the notice of
availability that publishes in the Federal Register.
For questions on the content of this guidance, contact CBER, Office of Communication, Outreach,
and Development (OCOD) at 240-402-7800 or 800-835-4709. For questions about this document
concerning products regulated by CDRH, contact the Office of the Center Director at 301-796-5900.
If you need additional assistance with regulation of combination products, contact the Office of
Combination Products at 301-796-8930.
U.S. Department of Health and Human Services
Food and Drug Administration
Center for Biologics Evaluation and Research (CBER)
Center for Devices and Radiological Health (CDRH)
Office of Combination Products in the Office of the Commissioner (OCP)
December 2014
Human Cells, Tissues, and Cellular and
Tissue-Based Products (HCT/Ps) from
Adipose Tissue: Regulatory
Considerations
Draft Guidance for Industry
Additional copies are available from:
Office of Communication, Outreach, and Development,
WO71, Room 3128
Center for Biologics Evaluation and Research
Food and Drug Administration
10903 New Hampshire Ave.
Silver Spring, MD 20993
Phone: 800-835-4709 or 240-402-7800
[email protected]hs.gov
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/Guidances/default.htm
or
Office of the Center Director
Guidance and Policy Development
Center for Devices and Radiological Health
Food and Drug Administration
10903 New Hampshire Ave., WO66, Room 5431
Silver Spring, MD 20993
Phone: 301-796-5900
http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/GuidanceDocuments/default.htm
or
Office of Combination Products
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Office of the Commissioner
Food and Drug Administration
10903 New Hampshire Ave., WO-32 Hub 5129
Silver Spring, MD 20993
(Tel) 301-796-8930
(Fax) 301-796-8619
combination@fda.gov
http://www.fda.gov/CombinationProducts/default.htm
Contains Nonbinding Recommendations
Draft – Not for Implementation
i
Table of Contents
I. INTRODUCTION.................................................................................................................1
II. BACKGROUND ...................................................................................................................2
III. IS MY HCT/P FROM ADIPOSE TISSUE REGULATED AS A DRUG, DEVICE,
AND/OR BIOLOGICAL PRODUCT? ...............................................................................3
A. Is My HCT/P from Adipose Tissue More Than Minimally Manipulated? .........3
21 CFR 1271.10(a)(1) ............................................................................................................3
B. What is Homologous Use of My HCT/P from Adipose Tissue? ...........................4
21 CFR 1271.10(a)(2) ............................................................................................................4
C. What if I Combine My HCT/P from Adipose Tissue with Another Product? ....5
21 CFR 1271.10(a)(3) ............................................................................................................5
D. What if My HCT/P from Adipose Tissue has a Systemic Effect or is Dependent
on the Metabolic Activity of a Living Cell for its Primary Function? 21 CFR
1271.10(a)(4) ..............................................................................................................5
E. What Regulations Apply if My HCT/P from Adipose Tissue is Regulated as a
Biological Product? ...................................................................................................6
F. What Must I do if My HCT/P from Adipose Tissue Meets the Criteria for
Regulation Solely Under Section 361 of the PHS Act and Part 1271? .................7
IV. EXCEPTIONS TO FDA REGULATION 21 CFR 1271.15 ..............................................7
A. Is My HCT/P from Adipose Tissue that is Implanted into the Same Individual
During the Same Surgical Procedure Subject to FDA Regulation?.....................7
21 CFR 1271.15(b) ................................................................................................................7
B. Are There Other Exceptions that Would Result in Me or My HCT/P from
Adipose Tissue Being Excepted from FDA Regulation? .......................................9
C. What Must I Do if I Do Not Meet One of the Exceptions Listed in .....................9
21 CFR 1271.15? ...................................................................................................................9
V. ADDITIONAL INFORMATION ........................................................................................9
A. How Can I Get More Information About the Appropriate Regulatory
Considerations for My HCT/P from Adipose Tissue? ..........................................9
B. How Can I Get More Information About the IND Process for My HCT/P from
Adipose Tissue that Requires Premarket Approval? ..........................................10
C. How Do I Register as an HCT/P Manufacturer? .................................................10
Contains Nonbinding Recommendations
Draft – Not for Implementation
1
Human Cells, Tissues, and Cellular and Tissue-Based Products 1
(HCT/Ps) from Adipose Tissue: 2
Regulatory Considerations 3
4
5
Draft Guidance for Industry 6
7
8
This draft guidance, when finalized, will represent the Food and Drug Administration’s (FDA or 9
Agency’s) current thinking on this topic. It does not create or confer any rights for or on any 10
person and does not operate to bind FDA or the public. You can use an alternative approach if the 11
approach satisfies the requirements of the applicable statutes and regulations. If you want to 12
discuss an alternative approach, contact the appropriate FDA staff responsible for implementing 13
this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed 14
on the title page of this guidance. 15
16
17
I. INTRODUCTION 18
19
FDA defines articles containing or consisting of human cells or tissues that are intended for 20
implantation, transplantation, infusion or transfer into a human recipient as “human cells, tissues, or 21
cellular or tissue-based products” (HCT/Ps) in Title 21 of the Code of the Federal Regulations 22
(CFR) Part 1271, specifically 21 CFR 1271.3(d). The Agency regulates HCT/Ps with a tiered, risk-23
based approach designed to provide the appropriate level of oversight to protect the public health. 24
We, FDA, are issuing this guidance to provide you, sponsors, clinicians, and other establishments 25
that manufacture
1
and use HCT/Ps from adipose tissue, with recommendations for complying with 26
the regulatory requirements for HCT/Ps, as set forth in 21 CFR Part 1271, as established under the 27
authority of section 361 of the Public Health Service (PHS) Act as well as recommendations for 28
complying with section 351 of the PHS Act and the Federal Food, Drug, and Cosmetic (FD&C) 29
Act, and the applicable regulations. 30
31
HCT/Ps include adipose tissue and cells obtained from adipose tissue. Adipose tissue is typically 32
defined as a connective tissue that stores energy in the form of lipids, insulates the body, and 33
provides cushioning and support for subcutaneous tissues and internal organs. It is composed of 34
clusters of cells (adipocytes) surrounded by a reticular fiber network and interspersed small blood 35
vessels, divided into lobes and lobules by connective tissue septa.
2
Additionally, adipose tissue 36
37
1
The term “manufacture” means, but is not limited to, any or all steps in the recovery, processing, storage, labeling,
packaging, or distribution of any human cell or tissue, and the screening or testing of the cell or tissue donor
(21 CFR 1271.3(e)).
2
Chapter 6. Adipose Tissue. In: Mescher AL. eds. Junqueira's Basic Histology: Text & Atlas, 13e. New York:
McGraw-Hill; 2013. http://accessmedicine.mhmedical.com/content.aspx?bookid=574&Sectionid=42524592.
Contains Nonbinding Recommendations
Draft – Not for Implementation
2
contains other cells, including preadipocytes, fibroblasts, vascular endothelial cells, and a variety of 38
immune cells.
3
Because connective tissue provides structure and support to the body, FDA 39
considers connective tissue, including adipose tissue, to be a structural tissue. 40
41
FDA has recently received numerous inquiries regarding HCT/Ps manufactured from adipose 42
tissues. This guidance, when finalized, will provide the Agency’s current thinking with respect to 43
regulatory considerations for adipose tissue. 44
45
FDA’s guidance documents, including this guidance, do not establish legally enforceable 46
responsibilities. Instead, guidances describe the FDA’s current thinking on a topic and should be 47
viewed only as recommendations, unless specific regulatory or statutory requirements are cited. 48
The use of the word should in FDA’s guidances means that something is suggested or 49
recommended, but not required. 50
51
52
II. BACKGROUND 53
54
Under FDA’s risk-based HCT/P regulatory framework, which is set forth in 21 CFR Part 1271, 55
certain HCT/Ps are regulated solely under section 361 of the PHS Act and the regulations under 56
21 CFR Part 1271; no premarket review is required for these HCT/Ps. In 21 CFR 1271.10, the 57
regulations identify the criteria for regulation solely under section 361 of the PHS Act and 58
21 CFR Part 1271. An HCT/P is regulated solely under section 361 of the PHS Act and 59
21 CFR Part 1271 if it meets all of the following criteria (21 CFR 1271.10(a)): 60
1) The HCT/P is minimally manipulated; 61
2) The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, 62
or other indications of the manufacturer's objective intent; 63
3) The manufacture of the HCT/P does not involve the combination of the cells or tissues 64
with another article, except for water, crystalloids, or a sterilizing, preserving, or storage 65
agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or 66
storage agent does not raise new clinical safety concerns with respect to the HCT/P; and 67
4) Either: 68
i) The HCT/P does not have a systemic effect and is not dependent upon the 69
metabolic activity of living cells for its primary function; or 70
ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of 71
living cells for its primary function, and: 72
a) Is for autologous use; 73
b) Is for allogeneic use in a first-degree or second-degree blood relative; or 74
c) Is for reproductive use. 75
76
77
78
3
Brown SA, Levi, B, Lequeux, C, et al. Basic Science Review on Adipose Tissue for Clinicians. Plast. Reconstr. Surg.
126:1936, 2010
Contains Nonbinding Recommendations
Draft – Not for Implementation
3
III. IS MY HCT/P FROM ADIPOSE TISSUE REGULATED AS A DRUG, DEVICE, 79
AND/OR BIOLOGICAL PRODUCT? 80
81
An HCT/P that does not meet all of the criteria set out in 21 CFR 1271.10(a), and the establishment 82
that manufactures the HCT/P does not qualify for any of the exceptions in 21 CFR 1271.15, will be 83
regulated as a drug, device, and/or biological product under the FD&C Act and/or section 351 of 84
the PHS Act, and the applicable regulations. This section of the guidance describes FDA’s current 85
thinking as to how the four criteria in 21 CFR 1271.10(a) apply to HCT/Ps from adipose tissue and 86
provides relevant examples of HCT/Ps from adipose tissue as well as the appropriate regulatory 87
pathway with respect to each example. In some of the examples, the HCT/Ps from adipose tissue 88
may fail to meet more than one of the four criteria in 21 CFR 1271.10(a). In addition, this section 89
identifies certain regulations that apply if an HCT/P from adipose tissue is regulated as a drug, 90
device, and/or biological product. This section also describes the requirements applicable to you as 91
a manufacturer of an HCT/P from adipose tissue that meets the criteria for regulation solely under 92
section 361 of the PHS Act and 21 CFR Part 1271. 93
94
A. Is My HCT/P from Adipose Tissue More Than Minimally Manipulated? 95
21 CFR 1271.10(a)(1) 96
97
Under the 21 CFR Part 1271 regulatory framework, a structural tissue is more than 98
minimally manipulated if the processing alters the original relevant characteristics of the 99
tissue relating to the tissue's utility for reconstruction, repair, or replacement 100
(21 CFR 1271.3(f)(1)). As described above, adipose tissue is typically defined as a 101
connective tissue composed of clusters of adipocytes and other cells surrounded by a 102
reticular fiber network and interspersed with small blood vessels, divided into lobes and 103
lobules by connective tissue septa. 104
105
For purposes of applying the regulatory framework, we generally consider adipose tissue to 106
be a structural tissue, with characteristics for reconstruction, repair, or replacement that 107
relate to its utility to cushion and support the other tissues in the subcutaneous layer 108
(subcutaneum) and skin. 109
110
Adipose tissue is sometimes processed by various means (e.g., enzymatic digestion, 111
mechanical disruption, etc.) to isolate the non-adipocyte or non-structural components of 112
adipose tissue. In some instances, these non-adipocyte or non-structural components are 113
cultured and expanded. Processing to isolate non-adipocyte or non-structural components 114
from adipose tissue (with or without subsequent cell culture or expansion) is generally 115
considered more than minimal manipulation. This is because the connective tissue and 116
structural components of the adipose tissue are entirely removed from the non-adipocyte or 117
non-structural isolates, thereby altering the original relevant characteristics relating to the 118
tissue’s utility for reconstruction, repair, or replacement. 119
120
121
Contains Nonbinding Recommendations
Draft – Not for Implementation
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Adipose tissue may also be processed to remove cellular components to obtain the 122
decellularized extracellular matrix portion of adipose tissue. Adipose tissue processed this 123
way generally is considered more than minimally manipulated because removal of the cells 124
leaves very little bulk and alters the ability of the adipose tissue to provide cushioning and 125
support. 126
127
In contrast, processing that does not affect the adipose tissue’s utility as a structural tissue 128
for reconstruction, replacement, or repair may be considered minimal manipulation. 129
Examples include aliquoting, rinsing, removal of macroscopic debris, and freezing. 130
131
Example A-1: Adipose tissue is recovered by tumescent liposuction. The adipose tissue 132
undergoes processing or manipulation (e.g., enzymatic digestion, mechanical disruption, 133
etc.) to isolate cellular components, commonly referred to as stromal vascular fraction, 134
which is considered a potential source of adipose-derived stromal/stem cells for clinical 135
therapeutic uses. This processing breaks down and eliminates the structural components 136
that function to provide cushioning and support, thereby altering the original relevant 137
characteristics of the HCT/P relating to its utility for reconstruction, repair, or replacement. 138
Therefore, based on the definition of minimal manipulation for structural tissue, this 139
processing would generally be considered more than minimal manipulation. 140
141
Example A-2: Adipose tissue is recovered from a deceased donor and is treated with acid 142
and/or detergent, washed, de-cellularized, and ground to obtain a homogenous fibrous tissue 143
suspension. This processing to remove adipocytes and manufacture an acellular adipose 144
tissue matrix or scaffold alters the original relevant characteristics of the adipose tissue 145
relating to its ability to cushion and support the subcutaneum. Therefore, this processing 146
would generally be considered more than minimal manipulation. 147
148
B. What is Homologous Use of My HCT/P from Adipose Tissue? 149
21 CFR 1271.10(a)(2) 150
151
The use of the HCT/P from adipose tissue is determined from the labeling, advertising, or 152
other indications of the manufacturer’s objective intent. To evaluate whether the use of an 153
adipose derived HCT/P would meet the regulatory definition of homologous use, you 154
should consider whether the adipose tissue used for the repair, reconstruction, replacement, 155
or supplementation of a recipient’s cells or tissues performs the same basic function or 156
functions
4
in the recipient as in the donor (21 CFR 1271.3(c)). 157
158
159
4
When the Agency initially proposed this exception, FDA explained that basic function of a structural tissue is what
the tissue does from a biological/physiological point of view, or is capable of doing when in its original state. See
“Establishment Registration and Listing for Manufacturers of Human Cellular and Tissue Based Products, 63 Federal
Register 26744 at 26749 (May 14, 1998).
Contains Nonbinding Recommendations
Draft – Not for Implementation
5
For example, the use of an HCT/P from adipose tissue for the repair, reconstruction, 160
replacement, or supplementation of a subcutaneous adipose tissue defect would be 161
considered a homologous use (21 CFR 1271.10(a)(2)). In these situations, FDA would 162
consider the HCT/P from adipose tissue to be performing the same basic function in the 163
recipient as in the donor (21 CFR 1271.3(c)). 164
165
Example B-1: Adipose tissue is recovered and processed for use, as reflected by the 166
labeling, advertising, or other indications of the manufacturer’s objective intent, to 167
cosmetically fill voids in the subcutaneous space in the face or hands. Because this use is a 168
basic function of adipose tissue, to support the subcutaneum, using HCT/Ps from adipose 169
tissues in this manner would generally be considered a homologous use. 170
171
Example B-2: Adipose tissue is recovered and processed for use, as reflected by the 172
labeling, advertising, or other indications of the manufacturer’s objective intent, to treat 173
bone and joint disease. Because adipose tissue does not perform this function in the donor, 174
using HCT/Ps from adipose tissue to treat bone and joint disease is generally considered a 175
non-homologous use. 176
177
Example B-3: Adipose tissue is recovered and processed for injection into the breast, as 178
reflected by the labeling, advertising, or other indications of the manufacturer’s objective 179
intent, for non-implant breast augmentation. The breast is composed of lobes of glandular 180
tissue and branching ducts, interspersed with fat and ligaments that support the breast and 181
give it shape; and nerves, blood vessels, and lymphatic tissues. The basic function of breast 182
tissue is to produce milk (lactation) after childbirth. Because this is not a basic function of 183
adipose tissue, using HCT/Ps from adipose tissues for breast augmentation would generally 184
be considered a non-homologous use. 185
186
C. What if I Combine My HCT/P from Adipose Tissue with Another Product? 187
21 CFR 1271.10(a)(3) 188
189
If you combine your HCT/P from adipose tissue with an article except for water, 190
crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water 191
crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety 192
concerns with respect the HCT/P, your HCT/P from adipose tissue would be regulated as a 193
drug, device, and/or biological product under the FD&C Act and/or section 351 of the PHS 194
Act, and the applicable regulations. 195
196
D. What if My HCT/P from Adipose Tissue has a Systemic Effect or is Dependent 197
on the Metabolic Activity of a Living Cell for its Primary Function? 21 CFR 198
1271.10(a)(4) 199
200
If the HCT/P from adipose tissue has a systemic effect or is dependent upon the metabolic 201
activity of living cells for its primary function, and is not intended for autologous use or use 202
by a first- or second-degree blood relative, then it does not meet the criteria in 203
Contains Nonbinding Recommendations
Draft – Not for Implementation
6
21 CFR 1271.10(a) for regulation solely under section 361 of the PHS Act and the 204
regulations in Part 1271. Autologous use is the implantation, transplantation, infusion, or 205
transfer of human cells or tissue back into the individual from whom the cells or tissue were 206
recovered (21 CFR 1271.3(a)). 207
208
Example D-1: Adipose tissue is recovered from an unrelated allogeneic donor. Stem cells 209
are isolated from that adipose tissue and seeded onto a bone scaffold for repair of 210
pathologically or surgically created bony voids. The manufacturer advertises the stem cells 211
as contributing to the primary function of filling, augmenting, or repairing the bone void by 212
giving rise to osteoblasts, which mineralize the allograft and increase its durability; this 213
function depends on the metabolic activity of the cells. The HCT/P from adipose tissue is 214
dependent upon the metabolic activity of living cells for its described primary function of 215
repairing the bone void and it is not intended for autologous use or allogeneic use in a first- 216
or second-degree blood relative. Therefore, the HCT/P would generally be considered not 217
to meet the criteria in 21 CFR 1271.10(a) for regulation solely under section 361 of the PHS 218
Act and the regulations in Part 1271. 219
220
E. What Regulations Apply if My HCT/P from Adipose Tissue is Regulated as a 221
Biological Product?
5
222
223
HCT/Ps that are regulated as biological products, are subject to section 351 of the PHS Act 224
and the FD&C Act, and require pre-market approval. Such HCT/Ps are subject to the 225
applicable drug regulations, including the requirements in Parts 210 and 211, and the 226
applicable requirements in Parts 600 through 680. Such products are also regulated under 227
section 361 of the PHS Act and are subject to requirements in Part 1271 designed to prevent 228
the introduction, transmission, and spread of communicable diseases. As part of these 229
regulations, you are required to register as an establishment, and list your HCT/Ps 230
(21 CFR 1271.1(b)(2)) (see section V.C. of this document). 231
232
In order to lawfully market a biological product, a biologics license must be in effect 233
(42 USC 262(a)). Such licenses are issued only after a determination by FDA that the 234
establishment(s) and the biological products meet the applicable requirements to ensure the 235
continued safety, purity, and potency of such products (21 CFR 601.2(d)). For clinical 236
studies of investigational drug products, the sponsor must have an investigational new drug 237
(IND) application in effect in accordance with the FD&C Act (21 USC 355(i)) and FDA 238
regulations (21 CFR Part 312 and 21 CFR 601.21). See section V.B. of this document 239
about obtaining more information regarding the IND process. 240
241
242
5
Some HCT/Ps from adipose tissue may be regulated as devices. For more information about device regulation, see
CDRH’s webpage Device Advice – Overview of Medical Device Regulation
(http://www.fda.gov/MedicalDevices/DeviceRegulationandGuidance/Overview/default.htm). Refer to section V.A
below regarding obtaining more information about the regulatory considerations of your HCT/P from adipose tissue.
Contains Nonbinding Recommendations
Draft – Not for Implementation
7
F. What Must I do if My HCT/P from Adipose Tissue Meets the Criteria for 243
Regulation Solely Under Section 361 of the PHS Act and Part 1271? 244
245
If you are a domestic or foreign establishment that manufactures an HCT/P that is regulated 246
solely under section 361 of the PHS Act and 21 CFR Part 1271, you must, in accordance 247
with 21 CFR 1271.1(b)(1): 248
249
1) Register with FDA (See section V.C. of this document); 250
2) Submit to FDA a list of each HCT/P manufactured; and 251
3) Comply with all applicable requirements contained in 21 CFR Part 1271. 252
253
Establishment means a place of business under one management, at one general physical 254
location that engages in the manufacture of HCT/Ps, including: 255
256
1) Any individual, partnership, corporation, association, or other legal entity 257
engaged in the manufacture of HCT/Ps; and 258
2) Facilities that engage in contract manufacturing services for a manufacturer of 259
HCT/Ps. 260
(21 CFR 1271.3(b)). 261
262
Manufacture means, but is not limited to, any or all steps in the recovery, processing, 263
storage, labeling, packaging, or distribution of any human cell or tissue, and the screening 264
and testing of the cell or tissue donor (21 CFR 1271.3(e)). 265
266
Example F-1: Adipose tissue is recovered by tumescent liposuction. The lipoaspirate is 267
processed to eliminate macroscopic debris to produce a smooth and uniform suspension for 268
subcutaneous injection to cosmetically fill voids in the subcutaneous space in the face or 269
hand. Provided the adipose tissue meets all of the criteria in § 1271.10(a), this HCT/P from 270
adipose tissue, processed and used in this manner, would be regulated solely under section 271
361 of the PHS Act and 21 CFR Part 1271. The facility that is processing the adipose tissue 272
is manufacturing an HCT/P from adipose tissue, and is required to register with FDA and 273
comply with all requirements in 21 CFR Part 1271 applicable to the manufacturing steps 274
that it performs. 275
276
277
IV. EXCEPTIONS TO FDA REGULATION 21 CFR 1271.15 278
279
A. Is My HCT/P from Adipose Tissue that is Implanted into the Same Individual 280
During the Same Surgical Procedure Subject to FDA Regulation? 281
21 CFR 1271.15(b) 282
283
Part 1271 recognizes exceptions from the requirements of 21 CFR Part 1271. Typically this 284
would mean that products and establishments that meet one of these exceptions are not 285
subject to FDA regulation. Under 21 CFR 1271.15(b), an establishment is not required to 286
comply with the requirements of 21 CFR Part 1271 if it removes HCT/Ps from an 287
288
Contains Nonbinding Recommendations
Draft – Not for Implementation
8
individual and implants such HCT/Ps into the same individual during the same surgical 289
procedure. If your establishment meets this exception, you are not required to comply with 290
the HCT/P requirements in 21 CFR Part 1271.
6
291
292
In regard to HCT/Ps from adipose tissue, we generally consider the exception in 293
21 CFR 1271.15(b) to apply only if the HCT/P from adipose tissue is for autologous use, is 294
removed and implanted within a single operation or in a limited number of predetermined 295
operations in order to achieve the intended effect, and does not undergo processing steps 296
beyond rinsing, cleansing, or sizing. Limited handling such as rinsing and cleansing to 297
remove debris would allow the HCT/P from adipose tissue to retain the structural function, 298
while other processing steps such as cell isolation, cell expansion, or enzymatic digestion 299
generally would not. Thus, if such other processing steps are performed that prevent the 300
HCT/P from adipose tissue from remaining “such HCT/P,” the establishment manufacturing 301
the HCT/P from adipose tissue would generally not be considered to meet the exception 302
under 21 CFR 1271.15(b). 303
304
Example A-1: Adipose tissue is recovered by tumescent liposuction. The lipoaspirate is 305
centrifuged at a low speed before blood and extracellular fluid are decanted. The remaining 306
adipose tissue is resuspended in sterile saline. Because nothing else is added to the adipose 307
tissue, and only minor handling is performed (e.g., no steps were taken to isolate stem cells 308
from the lipoaspirate, commonly referred to as stromal vascular fraction), the adipose tissue 309
would remain a connective tissue composed of clusters of adipocytes and other cells 310
surrounded by a reticular fiber network and interspersed small blood vessels. It is then re-311
injected into the subcutaneous space of the same patient from whom it was removed, in a 312
single operation or in a limited number of predetermined operations in order to achieve the 313
intended effect. We generally would consider the establishment manufacturing this HCT/P 314
from adipose tissue to meet the exception under 21 CFR 1271.15(b), and the establishment 315
would not be required to comply with the requirements in 21 CFR Part 1271. 316
317
Example A-2: Adipose tissue is recovered by tumescent liposuction. Stem cells from the 318
lipoaspirate are then isolated. Cell isolation would typically cause the adipose tissue to no 319
longer be “such HCT/P.” Thus, even if this processed HCT/P from adipose tissue is 320
injected into the same patient from whom it was removed during the same surgical 321
procedure, the establishment would generally not be considered to qualify for the exception 322
under 21 CFR 1271.15(b). 323
. 324
325
326
6
For more information on this topic, you may wish to consult the draft guidance entitled, “Same Surgical Procedure
Exception under 21 CFR 1271.15(b): Questions and Answers Regarding the Scope of the Exception; Draft Guidance
for Industry” dated October 2014. When finalized, this guidance will represent FDA’s current thinking on this topic.
Contains Nonbinding Recommendations
Draft – Not for Implementation
9
B. Are There Other Exceptions that Would Result in Me or My HCT/P from 327
Adipose Tissue Being Excepted from FDA Regulation? 328
329
Yes, there are additional exceptions described in 21 CFR 1271.15. If you meet any one of 330
the following exceptions, you are not required to comply with the regulations in 331
21 CFR Part 1271: 332
333
1) You are an establishment that uses HCT/Ps solely for nonclinical scientific or 334
educational purposes (21 CFR 1271.15(a)). 335
336
2) You are a carrier who accepts, receives, carries, or delivers HCT/Ps in the usual 337
course of business as a carrier (21 CFR 1271.15(c)). 338
339
3) You are an establishment that does not recover, screen, test, process, label, 340
package, or distribute, but only receives or stores HCT/Ps solely for implantation, 341
transplantation, infusion, or transfer within your facility (21 CFR 1271.15(d)). 342
343
4) You are not required to register or list your HCT/Ps independently, but you must 344
comply with all other applicable requirements in Part 1271, if you are an 345
individual under contract, agreement, or other arrangement with a registered 346
establishment and engaged solely in recovering cells or tissues and sending the 347
recovered cells or tissues to the registered establishment (21 CFR 1271.15(f)). 348
349
C. What Must I Do if I Do Not Meet One of the Exceptions Listed in 350
21 CFR 1271.15? 351
352
If you are an establishment that manufactures an HCT/P and you do not qualify for any of 353
the exceptions under 21 CFR 1271.15, your HCT/P from adipose tissue will be regulated as 354
a drug, device, and/or biological product unless, as previously described, it meets all of the 355
criteria in 21 CFR 1271.10. If your HCT/P is regulated as a drug, device, and/or biological 356
product it will be subject to the FD&C Act and/or section 351 of the PHS Act, and the 357
applicable regulations in 21 CFR Part 1271 as well as 21 CFR Parts 210, 211, 600 through 358
680, and 820 through 821. If your HCT/P is regulated solely under section 361 of the PHS 359
Act and 21 CFR Part 1271, you must comply with all requirements in 21 CFR Part 1271 360
applicable to the manufacturing steps you perform. 361
362
363
V. ADDITIONAL INFORMATION 364
365
A. How Can I Get More Information About the Appropriate Regulatory 366
Considerations for My HCT/P from Adipose Tissue? 367
368
The Agency provides two mechanisms through which a manufacturer may obtain a 369
recommendation or decision regarding the classification of an HCT/P: 370
371
Contains Nonbinding Recommendations
Draft – Not for Implementation
10
1) The Tissue Reference Group, a group comprised of representatives from CBER 372
and the Center for Devices and Radiological Health (CDRH), provides product 373
sponsors with an informal process through which they may obtain an Agency 374
recommendation regarding the application of the criteria in 21 CFR 1271.10(a) to 375
their HCT/Ps for a given indication. Information about this process as well as what 376
you may want to include to facilitate review of your request can be found at: 377
http://www.fda.gov/BiologicsBloodVaccines/TissueTissueProducts/RegulationofTis378
sues/ucm152857.htm 379
380
2) A Request for Designation (RFD) may be submitted to the Office of Combination 381
Products (OCP) to obtain a formal Agency decision regarding the regulatory identity 382
or classification of an HCT/P (21 CFR Part 3). A description of that process and 383
information on how to submit an RFD can be found at: 384
http://www.fda.gov/CombinationProducts/RFDProcess/default.htm. Additional 385
information may be found at 386
http://www.fda.gov/Regulatoryinformation/Guidances/ucm126053.htm. You may 387
also contact OCP to obtain an informal classification for your HCT/P. 388
389
You may use either one of these mechanisms to obtain a response to a question as to 390
whether your adipose tissue-derived HCT/P is regulated solely under section 361 of the 391
PHS Act and 21 CFR Part 1271, or if it meets one of the exceptions in 21 CFR 1271.15. 392
393
B. How Can I Get More Information About the IND Process for My HCT/P from 394
Adipose Tissue that Requires Premarket Approval? 395
396
Further information about IND requirements for biological products may be obtained 397
through the Regulatory Management Staff, Office of Cellular, Tissue, and Gene Therapies, 398
at 240-402-8190 or CBER[email protected]. 399
400
C. How Do I Register as an HCT/P Manufacturer? 401
402
FDA regulations require establishments that perform one or more steps in the manufacture 403
of HCT/Ps to register and submit a list the products with the Agency. If you are a 404
manufacturer that is required to register, you must do so within 5 days after beginning 405
operations (21 CFR 1271.21(a)). Registrations must be updated annually in December, 406
except if the ownership or location of the establishment changes, you must submit an 407
amendment to the registration within five days of the change (21 CFR 1271.21(b)). 408
409
FDA has created Form FDA-3356, Establishment Registration and Listing for HCT/Ps, for 410
establishments to submit HCT/P establishment registration and listing information to FDA. 411
The form can be submitted electronically, (Electronic Human Cell and Tissue Establishment 412
Registration (eHCTERs). Instructions for completing the electronic registration form are 413
located on our website, 414
http://www.fda.gov/BiologicsBloodVaccines/GuidanceComplianceRegulatoryInformation/415
EstablishmentRegistration/TissueEstablishmentRegistration/ucm148775.htm. 416
