1. Samuel B. Barone, MD Division of Human Tissues
“361” Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps)
Samuel B. Barone, MD
Division of Human Tissues

2. Overview What are HCT/Ps? History of Tissue Regulation “361” HCT/Ps
Tissue Rules/21 CFR 1271
Registration
Donor Eligibility
Current Good Tissue Practice

3. What are HCT/Ps?
Regulatory definition: Articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient
Encompass a wide variety of products
21 CFR (d)

4. Examples of HCT/Ps From deceased (cadaveric) donors:
Musculoskeletal tissues
Skin
Dura mater
Cardiovascular tissues
Ocular tissues
Tissue/device and other combined products
From living donors:
Hematopoietic stem/progenitor cells from peripheral and cord blood
Other cell therapy products (e.g. pancreatic islets, mesenchymal stem/stromal cells, fibroblasts)
Reproductive cells and tissues
21 CFR (d)

5. Not HCT/Ps Vascularized organs Minimally manipulated bone marrow
Tissues intended for educational or non-clinical research use (not intended for transplantation)
Xenografts
Blood products
Secreted or extracted products; e.g., human milk, collagen, cell factors
Ancillary products used in manufacture
In vitro diagnostic products
Blood vessels recovered with an organ
21 CFR (d)

6. HISTORY OF TISSUE REGULATION

7. History of HCT/P Regulation
1993: interim final rule for immediate implementation in response to infectious disease concerns with imported tissues
1997: final rule
Musculoskeletal, skin and ocular only (deceased donors)
Legal authority: Section 361 of the Public Health Service (PHS) Act – prevent the introduction, transmission, or spread of communicable diseases

8. Proposed Approach
1997: FDA announced a proposed approach to all human cells, tissues, or cellular or tissue-based products (HCT/Ps)
Tiered, risk-based approach
Broader scope, included previously unregulated cells and tissues
Issued through rulemaking in 3 parts
Entire 21 CFR Part 1271 became effective on May 25, 2005

9. Goals
HCT/Ps carry a potential risk of communicable disease transmission from the donor to the recipient
Prevent the introduction, transmission, and spread of communicable diseases by HCT/Ps

10. 21 CFR Part 1271 Applicability
For some HCT/Ps (“361” HCT/Ps) it is the sole regulatory requirement
Authority from section 361 of the PHS Act
Prevent the introduction, transmission, or spread of communicable disease
No pre-market review

11. “361” HCT/Ps Minimal manipulation
Advertised/labeled for homologous use only
Not combined with another article
Does not have a systemic effect (except for autologous, family-related or reproductive use)
21 CFR (a)

12. Other Cells and Tissues
If the cells or tissues do not meet the requirements to be regulated solely under 361 of the PHS act, are also regulated as drugs, devices, and/or biological products
pre-market approval required
demonstrate safety and efficacy
For these HCT/Ps, Part 1271 applies, but supplements other existing requirements

13. Tissue Reference Group
Provides a single reference point for product specific questions concerning jurisdiction and applicable regulation of HCT/Ps

14. 21 Code of Federal Regulations Part 1271

15. 21 CFR Part 1271 Regulation Issues Addressed
Establishment Registration and Listing
Applicability: types and uses of products that will be regulated by these rules, requirements for registering and listing products
Donor Eligibility
Requirements for donor screening and testing for “relevant communicable disease agents and diseases”
Current Good Tissue Practice (CGTP)
Manufacturing to ensure that HCT/Ps do not contain communicable disease agents, are not contaminated, and do not become contaminated

16. Registration and Listing

17. General Provisions Purpose; Scope Definitions
Criteria for regulation solely under section 361 of PHS Act
Exceptions from the requirements

18. Definition: Manufacture
Manufacture means any or all steps in the recovery, processing, storage, labeling, or distribution of any human cell or tissue, and the screening or testing of the cell or tissue donor
21 CFR (e)

19. Registration and Listing
Any establishment that manufactures HCT/Ps must
Register and submit a list of every HCT/P it manufactures within 5 days after beginning operation
Re-register annually
Update if change in location or ownership
All foreign establishments importing HCT/Ps to the US must register and list each HCT/P
21 CFR , (b)

20. Registration and Listing cont.
Establishment registration is not a pre-market review program
An establishment may begin to market its product once it registers (361 HCT/Ps)
There are periodic inspections, but distribution may begin before the establishment is inspected
21 CFR ,

21. DONOR ELIGIBILITY

22. Donor Eligibility
A donor-eligibility determination, based on donor screening and testing for relevant communicable disease agents and diseases (RCDADs), is required for all donors of HCT/Ps, with some exceptions
HCT/P must not be administered until the donor has been determined to be eligible, with some exceptions
21 CFR (b,c)

23. Donor Screening and Testing
Screening for risk factors and clinical evidence of disease
Current donor medical history interview
Current physical assessment/examination
Medical records; coroner and autopsy reports, if available
Testing
FDA-licensed, cleared, or approved tests
CLIA-certified laboratory (very few outside the US)
21 CFR /.80

24. Viable, Leukocyte-Rich
Requirements
Agent
Required for
Screening
Testing
HIV-1 and -2
All X
Hepatitis B
Hepatitis C
Syphilis
TSE
WNV
Sepsis
Vaccinia
(recent smallpox vaccination)
HTLV-I and –II
Viable, Leukocyte-Rich
CMV
Chlamydia trachomatis
Reproductive
Neisseria gonorrhoeae
Click to add notes
21 CFR (r)/.75/.85

25. Donor Screening and Testing
FDA Guidance for Industry: Eligibility Determination for Donors (8/27/07)
Provides FDA’s current thinking
Assists manufacturers in complying with the requirements

26. CURRENT GOOD TISSUE PRACTICE

27. Subpart D – Current Good Tissue Practice
Methods, facilities, and controls for manufacturing to prevent communicable disease transmission
Broad goals applicable to the wide range of HCT/Ps
Establishments have the flexibility to determine how to meet goals through SOPs
Narrower in scope than GMP
Requires a quality program to prevent, detect, and correct deficiencies that could increase communicable disease risk
21 CFR

28. Requirements Donor eligibility determinations
Exemptions and Alternatives
Quality Program
Personnel
Procedures
Facilities
Environmental Control and Monitoring
Equipment
Supplies and Reagents
Recovery
Processing and Process Controls
Process Changes
Process Validation
Labeling Controls
Storage
Receipt, Pre-distribution Shipment, and Distribution
Records
Tracking
Complaint File
21 CFR

29. Procedures
Establish and maintain procedures for all steps that are performed during manufacture of the HCT/P
Designed to prevent circumstances that increase the risk of introduction, transmission, or spread of communicable disease
Reviewed, approved and followed
Available to personnel
Can adopt standard procedures from another organization
21 CFR

30. Adverse Reaction Reporting
Adverse reaction: A noxious and unintended response to any HCT/P for which there is a reasonable possibility that the HCT/P caused the response
Investigate any adverse reaction involving a communicable disease from an HCT/P that the establishment made available for distribution
Report those that are fatal, life-threatening, result in permanent impairment or permanent damage, or necessitate medical or surgical intervention
21 CFR (a)

31. HCT/P Deviation Reporting
HCT/P deviation: A deviation from applicable regulations, standards, or established specifications, or an unexpected event that relates/may relate to communicable disease transmission or HCT/P contamination
Investigate all deviations related to a distributed HCT/P
That occurred in your facility or
A facility under contract, agreement, or other arrangement to you
Report certain deviations
21 CFR (b)

32. Inspection and Enforcement
Inspections
Usually unannounced
Frequency is at the Agency’s discretion
Inspections include foreign establishments
Donor confidentiality observed
Orders of retention, recall, destruction, and cessation of manufacturing
Address actions FDA can take if manufacture of HCT/Ps is in violation of the regulations
21 CFR

33. Summary What are HCT/Ps? History of Tissue Regulation “361” HCT/Ps
Tissue Rules/21 CFR 1271
Registration
Donor Eligibility
Current Good Tissue Practice

34. Additional Information
21 CFR 1271
Establishment Registration

35. Additional Information
Adverse Reactions Reporting
Biological Product Deviations

36. Information and Contacts
Contact CBER:
Consumer questions:
Manufacturer questions:
Phone: or
CBER Tissue Web-page for
Copies of regulations, guidance and other documents
Registration and listing information