FREQUENTLY ASKED QUESTIONS

HCT/Ps are defined in 21 CFR 1271.3(d) as articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient.(1)

The Food and Drug Administration regulates a cellular therapy product solely as an HCT/P (i.e. "361 product") if it meets all the criteria in 21 CFR 1271.10(a)

HCT/Ps that meet all of the criteria in 21 CFR 1271.10(a) are subject only to regulation under section 361 of the Public Health Service Act (PHS Act) and the regulations in 21 CFR part 1271. An HCT/P that falls into this category is sometimes referred to as a “361 HCT/P” and no premarket authorization is required. (2)

21 CFR 1271.10(a) Criteria:

1. The HCT/P is minimally manipulated;
2. The HCT/P is intended for homologous use only, as reflected by the labeling, advertising, or other indications of the manufacturer’s objective intent;
3. The manufacture of the HCT/P does not involve the combination of the cells or tissues with another article, except for water, crystalloids, or a sterilizing, preserving, or storage agent, provided that the addition of water, crystalloids, or the sterilizing, preserving, or storage agent does not raise new clinical safety concerns with respect to the HCT/P; and
4. Either:

• (i) The HCT/P does not have a systemic effect and is not dependent upon the metabolic activity of living cells for its primary function; or
• (ii) The HCT/P has a systemic effect or is dependent upon the metabolic activity of living cells for its primary function, and:
  a) Is for autologous use;
  b) Is for allogeneic use in a first-degree or second-degree blood relative; or
  c) Is for reproductive use. (1)

If a Product/Tissue Allograft meets all these requires it is allowed for transplantaion. All HCTP Tissue Allografts supplied by One Biologics are classified under Section 361 of the Public Health Service Act (PHS Act) and the regulations in 21 CFR part 1271.

If an HCT/P does not meet the criteria set out in 21 CFR1271.10(a), and the establishment that manufactures the HCT/P does not qualify for any of the exceptions in 21 CFR 1271.156, the HCT/P will be regulated as a drug, device, and/or biological product under the FD&C Act, and/or section 351 of the PHS Act (42 U.S.C. 262), and applicable regulations, including 21 CFR Part 1271, and premarket review will be required.(2)

None of One Biologics HCTP Tissue Allogafts are classified under Section 351.

Section 351 of the PHS Act governs biological products that do not meet the criteria to be regulated solely under Section 361 of the PHS Act. Products regulated under Section 351 are regulated similarly to drugs or devices which must have an IND in effect or acquire pre-market approval to be commercially marketed. In contrast, Section 361 governs HCT/Ps that meet all four criteria listed in 21CFR 1271.10(a). Products that fall under section 361 do not need an IND or premarket approval to be sold because if they retain their primary functions and are used in homologous fashion, they are considered a known quantity and thus would not warrant further investigation.

Because of the unique nature of HCT/Ps, FDA proposed and in 2005 implemented a tiered, risk-based approach to the regulation of HCT/Ps. Although FDA is authorized to apply the requirements in the Federal Food, Drug, and Cosmetic Act (FD&C Act) and the Public Health Service Act (PHS Act) to those products that meet the definition of drug, biologic, or device, under this tiered, risk-based approach, those HCT/Ps that meet specific criteria or fall within detailed exceptions do not require premarket review and approval.(2)

The FDA's Request for Designation (RFD) process allows sponsors to obtain the agency's official determination of the primary mechanism of action (PMOA) of a product. The PMOA guides the selection of the lead FDA center responsible for regulating the product.

It is not necessary to submit an RFD for every product. It is recommended submitting an RFD when the classification of a product or the Agency Center to which it should be assigned is UNCLEAR OR IN DISPUTE.

None of One Biologics HCTP Tissue Aloografts require an RFD at this moment.

1. For structural tissue, processing that does not alter the original relevant characteristics of the tissue relating to the tissue’s utility for reconstruction, repair, or replacement;
2. For cells or nonstructural tissues, processing that does not alter the relevant biological characteristics of cells or tissues.(1)

All of One Biologics HCTP Tissue Allografts are minimally manipulated and qualify for this definition.

As defined in 21 CFR 1271.3(c), homologous use means the repair, reconstruction, replacement, or supplementation of a recipient’s cells or tissues with an HCT/P that performs the same basic function or functions in the recipient as in the donor. This criterion reflects the Agency’s conclusion that there would be increased safety and effectiveness concerns for HCT/Ps that are intended for a nonhomologous use, because there is less basis on which to predict the product’s behavior, whereas HCT/Ps for homologous use can reasonably be expected to function appropriately (assuming all of the other criteria are also
met).(1)

Yes, if a product does not have objective evidence of minimal manipulation (that the tissue maintains its ability to perform the same basic function(s) as it did in the donor), the FDA assumes that the product does not meet this criteria.

Please note that if information
does not exist to show that the processing meets the definition of
minimal manipulation, FDA considers the processing of an HCT/P to be “more than minimal manipulation” that cannot qualify for regulation solely under section 361 of the PHS Act and 21 CFR Part 12718.

The FDA gives individual examples of both homologous and non-homologous use as well as minimal manipulation and more than minimal manipulation.

Minimal Manipulation Examples

Structural tissues may be processed by various machining and other mechanical methods to change the size or shape of the HCT/P. Such processing can be either minimal manipulation or more than minimal manipulation depending on whether the processing alters the original relevant characteristics of the structural tissue relating to its utility for reconstruction, repair, or replacement.

• A manufacturer performs threading and other mechanical machining procedures to shape bone into dowels, screws, and pins. The HCT/Ps are generally considered minimally manipulated because the processing does not alter the bone’s original relevant characteristics relating to its utility to support the body and protect internal structures.
• A manufacturer grinds bone to form bone chips and particles. The HCT/Ps would generally be considered minimally manipulated because the processing does not alter the bone’s original relevant characteristics relating to its utility to support bodily structures.
• A manufacturer exposes bone to acid at elevated temperature to demineralize bone and dissolve collagen in order to form a gel. The HCT/P is generally considered more than minimally manipulated because the processing alters the bone’s original relevant characteristics relating to its utility to support the body and protect internal structures.

Example 10-2: Original relevant characteristics of amniotic membrane relating to its utility to serve as a barrier generally include the tissue’s physical integrity, tensile strength, and elasticity.

• A manufacturer processes amniotic membrane to preserve it and package it in sheets. The HCT/P generally is considered minimally manipulated because the processing does not alter the original relevant characteristics of the HCT/P relating to its utility to serve as a barrier.
• A manufacturer grinds and lyophilizes amniotic membrane and packages it as particles. The HCT/P generally is considered more than minimally manipulated because the processing alters the original relevant characteristics of the HCT/P relating to its utility to serve as a barrier.

Example 10-3: Original relevant characteristics of fascia lata, relating to its utility to cover muscle and aid in movement, generally include its strength, flexibility, and its fibrous, sheet-like configuration. A manufacturer grinds sheets of fascia lata into particles. The HCT/P generally is considered more than minimally manipulated because the processing alters the original relevant characteristics of the HCT/P relating to its utility to cover muscle and aid in movement.

Example 10-4: The original relevant characteristics of skin relating to its utility to serve as a protective covering generally include its large surface area, keratinized, water-resistant epithelial layer (epidermis), and dense, strong, and flexible connective tissue layer (dermis).

• A manufacturer processes skin by mechanical meshing and cryopreservation and packages it in sheets as meshed skin. The HCT/P generally is considered minimally manipulated because the processing does not alter the original relevant characteristics of the skin relating to its utility as a protective covering.
• A manufacturer processes skin by removing the epidermis and then grinding the dermis into particles. The HCT/P generally is considered more than minimally manipulated because the processing alters the original relevant characteristics of skin related to its utility as a protective covering

Yes. Homologous use for any given tissue type depends on the function(s) of that tissue in the donor. Below are two FDA examples of structural tissue and a description of their original relevant characteristics. For homologous application, the end product (after processing) must maintain its original relevant characteristics in order to perform the same basic function(s) as it did in the donor.

Example 10-1: Original relevant characteristics of bone relating to its utility to support the body and protect internal structures include strength, and resistance to compression. Milling, grinding, and other methods for shaping and sizing bone may generally be considered minimal manipulation when they do not alter bone’s original relevant characteristics relating to its utility to support the body and protect internal structures.

Example 10-2: Original relevant characteristics of amniotic membrane relating to its utility to serve as a barrier generally include the tissue’s physical integrity, tensile strength, and elasticity.(1)

The FDA gives individual examples of both homologous and non-homologous use as well as minimal manipulation and more than minimal manipulation.

Homologous Use Examples

Example 19-1: Sources of hematopoietic stem/progenitor cells (HPCs) include cord blood, peripheral blood, and bone marrow. The basic functions of HPCs include forming and replenishing the lymphohematopoietic system.

• HPCs from mobilized peripheral blood are intended for transplantation into an individual with a disorder affecting the hematopoietic system that is inherited, acquired, or the result of myeloablative treatment. This is homologous use because the peripheral blood product performs the same basic function of reconstituting the hematopoietic system in the recipient.
• HPCs from bone marrow are in tended for infusion into an artery with a balloon catheter for the purpose of limiting ventricular remodeling following acute myocardial infarction. This is not homologous use because limiting ventricular remodeling is not a basic function of bone marrow.
• HPCs from cord blood are intended for intravenous infusion to treat cerebral palsy purportedly through the repair of damaged tissue in the brain through paracrine signaling or differentiation into neuronal cells. This is not homologous use because there is insufficient evidence to support that repair of neurologic tissue through paracrine signaling or differentiation into neuronal cells is a basic function of these cells in the donor.

Example 19-2: The basic functions of the cornea include protecting the eye and serving as its outermost lens. A corneal graft is transplanted to a patient with corneal blindness. This is homologous use because a corneal graft performs the same basic functions in the donor as in the recipient.

Example 19-3: The basic functions of a vein or artery include serving as a conduit for blood flow throughout the body. A cryopreserved vein or artery is used for arteriovenous access during hemodialysis. This is homologous use because the vein or artery is supplementing the vessel as a conduit for blood flow.

Example 19-4: The basic functions of amniotic membrane include serving as a selective barrier for the movement of nutrients between the external and in utero environment, protecting the fetus from the surrounding maternal environment, and serving as a covering to enclose the fetus and retain fluid in utero.

• Amniotic membrane is used for bone tissue replacement to support bone regeneration following surgery to repair or replace bone defects. This is not a homologous use because bone regeneration is not a basic function of amniotic membrane.
• An amniotic membrane product is used for wound healing and/or to reduce scarring and inflammation. This is not homologous use because wound healing and reduction of scarring and inflammation are not basic functions of amniotic membrane.
• An amniotic membrane product is applied to the surface of the eye to cover or offer protection from the surrounding environment in ocular repair and reconstruction procedures. This is homologous use because serving as a covering and offering protection from the surrounding environment are basic functions of amniotic membrane.

Example 19-5: The basic functions of pericardium include covering, protecting against infection, fixing the heart to the mediastinum, and providing lubrication to allow normal heart movement within chest. Autologous pericardium is used to replace a dysfunctional heart valve in the same patient. This is not homologous use because facilitating unidirectional blood flow is not a basic function of pericardium. The use of an HCT/P from adipose tissue for the repair, reconstruction, replacement, or supplementation of adipose tissue would be considered a homologous use. In these situations, FDA would consider the HCT/P from adipose tissue to be performing the same basic function in the recipient as in the donor. In contrast, the use of an HCT/P from adipose tissue for the treatment of a degenerative, inflammatory, or demyelinating disorder would generally be considered a non-homologous use.

Example 19-6: The basic functions of adipose tissue include providing cushioning and support for other tissues, including the skin and internal organs, storing energy in the form of lipids, and insulating the body.

• Adipose tissue is used to fill voids in the face or hands (e.g., for cosmetic reasons). This is homologous use because providing cushioning and support, is a basic function of adipose tissue.
• An HCT/P from adipose tissue is used to treat musculoskeletal conditions such as arthritis or tendonitis by regenerating or promoting the regeneration of articular cartilage or tendon. This is generally not considered a homologous use because regenerating or promoting the regeneration of cartilage or tendon is not a basic function of adipose tissue.
• An HCT/P from adipose tissue is used to treat neurological disorders such as multiple sclerosis by limiting the autoimmune reaction and promoting remyelinization. This is generally not considered a homologous use because limiting the autoimmune reaction and promoting remyelinization are not basic functions of adipose tissue.
• Adipose tissue is used for transplantation into the subcutaneous areas of breast for reconstruction or augmentation procedures. This is homologous use because providing cushioning and support is a basic function of adipose tissue.(1)

HCT/Ps may perform multiple functions and FDA acknowledges that structural tissues contain cells. FDA also acknowledges that some manufacturers assert that an HCT/P has both a structural and cellular/nonstructural function. However, under the regulations, HCT/Ps are considered either structural tissues or cells/nonstructural tissues. HCT/Ps that physically support or serve as a barrier or conduit, or connect, cover, or cushion are generally considered structural tissues for the purpose of applying the HCT/P regulatory framework.(1)

An HCT/P may perform the same basic function or functions even when it is not used in the same anatomic location where it existed in the donor. A transplanted HCT/P could replace missing tissue, or repair, reconstruct, or supplement tissue that is missing or damaged, either when placed in the same or different anatomic location, as long as it performs the same basic function(s) in the recipient as in the donor.(1)

Yes! One Biologics is responsible for all steps in our OnePure Process that take place after recovery, including the processing, storage, labeling, packaging, and distribution of any human cell or tissue products marketed by One Biologics.

Donors undergo thorough screening for potential risk factors and clinical evidence of communicable diseases. A detailed medical and social history is collected in advance to ensure the donor meets all eligibility requirements. These tissues undergo extensive medical, social, and blood testing before processing. Only tissue cleared after this stringent screening regimen is processed and re-tested under standards established by the American Association of Tissue Banks (AATB) and FDA requirements. Every precaution is taken to eliminate the potential risk of infectious diseases through comprehensive testing following the Clinical Laboratory Improvement Amendments of 1988 (CLIA) and 42 CFR Part 493 and the FDA. One Biologics verifies each step of the manufacturing process to ensure the most stringent safety standards are met and maintained, from start to finish.

One Biologics produces HCTP products regulated under Section 361 of the PHS Act, intended to be used in homologous fashion as a covering, barrier, cushioning and/or structural support to the site of a defect.

Our 361 HCTP Tissue Aloografts have a shelf life of 2 years when the product is appropriately stored between -40 and -80 degrees Celsius. One Biologics’ facility houses multiple PHCbi Ultra-Low freezers for product storage, including an entire section where each new batch is quarantined until sterility results are received and the product is cleared for distribution. For physicians wishing to purchase and store products locally, we offer -30 degree Celcius medical freezers nearly any quantity of vial for up to 90 days from receiving date.

One Biologics processes the perinatal tissue to maintain its original, relevant characteristics relating to its ability to repair, replace, or supplement missing or damaged tissue.

Unfortunately no. We provide compliant 361 HCTP Tissue Allografts as a FDA registered tissue bank. We do not have the authority, nor does the FDA give us the right or themselves have the authority to tell physicians and eligible providers how to practice medicine. We provide educational materials on what the tissue allograft is and it is on the physician or provider to use the tissue allograft in an homologous use intention.

The FDA keeps an online database of all registered tissue establishments and products in Human Cell and Tissue Establishment Registration (HCTERS). This online database allows you to search for FDA registration by company or tissue allograft name.

We have compiled all relevant regulatory information concerning our tissue allografts BELOW for your convenience.

FDA Tissue Guidances

Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment Registration and Listing

CFR - Code of Federal Regulations Title 21 PART 1271 HUMAN CELLS, TISSUES, AND CELLULAR AND TISSUE-BASED PRODUCTS

AATB Guidance Documents