Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Gene Arcy, M.S., CSO

1. Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) Gene Arcy, M.S., CSO AOAC 05/09/2014

2. HCT/Ps • Human cells, tissues and cellular and tissue-based products • Regulatory definition: Articles containing or consisting of human cells or tissues that are intended for implantation, transplantation, infusion, or transfer into a human recipient • Encompasses a wide variety of products

3. 21 CFR Part 1271 Good Tissue Practices (GTPs) prevent the introduction, transmission, or spread of communicable diseases by HCT/Ps.

4. HCT/Ps 21 CFR Part 1271: Applicability For some 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

5. HCT/Ps—Basics If the cells or tissues do not meet the requirements to be regulated solely under 361 of the PHS act, may be regulated as drugs, devices, and/or biological products • Pre-market approval required • Demonstrate safety and efficacy

6. HCT/Ps—Basics Cells or tissues that do not meet the requirements to be regulated solely under 361 of the PHS act, are regulated under Section 351 of the PHS Act and/or the Federal Food, Drug and Cosmetic Act.

7. HCT/Ps—Basics 21 CFR Part 1270 (recovered before 5/25/05) and 21 CFR Part 1271 (recovered on/after 5/25/05) • Subpart A-General Provisions; definitions • Subpart B-Registration and Listing • Subpart C-Donor Eligibility • Subpart D-Current Good Tissue Practice (not applicable to reproductive tissues, except for 21 CFR 1271.150(c) and 1271.155) • Subpart E-Additional Requirements: Reporting, Labeling (not applicable to reproductive tissues) • Subpart F-Inspection and Enforcement

8. HCT/Ps—Basics Core CGTP requirements (§ 1271.150(b)) directly relate to preventing the introduction, transmission, or spread of communicable disease by HCT/Ps, and include requirements for: • Facilities (1271.190(a) and (b)) • Environmental control (1271.195(a)) • Equipment (1271.200(a)) • Supplies and reagents (1271.210(a) and (b)) • Recovery (1271.215) • Processing and process controls (1271.220) • Labeling controls (1271.250(a) and (b)) • Storage (1271.260(a) through (d))

9. HCT/Ps—Basics Core CGTP (Continued) • Receipt, predistribution shipment, and distribution of an HCT/P (1271.265(a) through (d) • Donor eligibility determinations, donor screening, and donor testing (1271.50, 1271.75, 1271.80, and 1271.85) Other CGTP requirements support the core CGTP requirements

10. HCT/Ps—Basics GTP regulations that Apply to 351 biological products, or devices 21 CFR part 1271 • Subpart A – General Provisions • Subpart B – Registration • Subpart C – Donor Eligibility • Subpart D–cGTPs. Most cGTPsapply except that certain ones are covered by cGMPsin 211s and 820s.

11. HCT/Ps—Basics cGTPs***not*** covered by cGMPs • All donor eligibility requirements • Prevention of the introduction, transmission, or spread of communicable diseases • Certain parts of manufacturing arrangements • Procedures for sharing with other establishment information pertaining to possible contamination or potential for transmission of communicable disease

12. HCT/Ps—Basics cGTPs***not*** covered by cGMPs (Continued) • Audits (drugs) • Prohibition on pooling • Predistribution shipment • HCT/P availability for distribution only after donor eligibility established • Packaging and shipping requirements • Record keeping for 10 years ( facility cleaning and sanitation records for 3 years) • Certain records for contracts and agreements • Tracking

13. HCT/Ps—Examples From deceased (cadaveric) donors: • Musculoskeletal tissues (Ex. Bone / Tendon) • Skin • Dura mater • Cardiovascular tissues • Ocular tissues

14. HCT/Ps—Examples From living donors: • Hematopoietic stem/progenitor cells from peripheral and cord blood • Other cell therapy products • pancreatic islets • mesenchymal stem/ stromal cells • fibroblasts • Cells transduced with gene therapy vectors • Reproductive cells and tissues

15. NotHCTPs • Vascularized human organs for transplantation (HRSA oversight) • Whole blood or blood components; blood derivative products • Secreted or extracted human products, e.g. • Milk • Collagen • Cell Factors • Minimally manipulated bone marrow for homologous use and not combined with another article • Ancillary products used in the manufacture of HCT/Ps • Cells, tissues, and organs derived from animals other than humans • In vitro diagnostic products

16. FDA’s approach to cells and tissues developed in the 1990s Key document issued in 1997: • “A Proposed Approach to Regulation of Cellular and Tissue-Based Products”

17. Regulatory Considerations Are my HCT/Ps regulated solely under section 361 of the PHS Act and applicable GTPs (1271s) ? • (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

18. Regulatory Considerations Are my HCT/Ps regulated solely under section 361 of the PHS Act and applicable GTPs (1271s) ? • (4) Either: 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.

19. Regulatory Considerations HCT/Ps Registration and Listing (Form 3356) • Did you list your tissue(s) in the correct column ?

20. Registration / Listing; Form 3356 361 Tissue vs. Devices vs. Drug

21. Registration/Listing 361 Tissue vs. Devices vs. Drug

22. Registration/Listing 361 Tissue vs. Devices vs. Drug

23. Registration/Listing 361 Tissue vs. Devices vs. Drug

24. CBER’s Tissue Reference Group • Provides a single reference point for product-specific questions about HCT/Ps • Considers questions and makes recommendations about jurisdiction related to HCT/Ps. Jurisdiction means whether the HCT/P will be regulated as a 361 tissue, a biological product or a device, and which Center will review the application.

25. Tissue Reference Group Does the product meet the definition of an HCT/P, as defined in section 1271.3(d)? Is the HCT/P regulated solely under section 361 of PHS Act, as described in 1271.10? • Minimally manipulated • Intended for homologous use only • Not combined with another article, with some exceptions • Do not have a systemic effect and not dependent upon metabolic activity of living cells for its primary function; OR • Have systemic effect and are for either Autologous use Allogeneic use in first or second-degree blood relatives Reproductive use

26. Cadaveric Tissues (Not Organs) Bone Ligaments Fascia Cartilage Veins & Arteries Tendons Pericardium Ligaments Skin Corneas & Sclera Dura mater Heart Valves

27. Cadaveric Tissues—General American Association of Tissue Banks (AATB) • Accreditation • Certification • Standards for Tissue Banking—addressing various tissues, recovery through processing through distribution. • Guidance

28. Cadaveric—Tissue Recovery Tissue Recovery Organizations • Coroners • Morgues • Hospitals • Funeral Homes May perform Donor Screening

29. Cadaveric—Tissue Recovery • Sec. 1271.215 Recovery “If you are an establishment that recovers HCT/Ps, you must recover each HCT/P in a way that does not cause contamination or cross-contamination during recovery, or otherwise increase the risk of the introduction, transmission, or spread of communicable disease through the use of the HCT/P.”

30. Cadaveric—Tissue Recovery • May also be recovering tissues for tissue-based medical devices. • Recovery processes do not need to be validated. • Procedures must be in place to prevent contamination/cross contamination

31. Cadaveric—Tissue Recovery Body is already contaminated to one degree or another. The type of microorganisms and the number of microorganism present on the recovered tissue are dependent on many factors. • Whether the donor was septic at the time of death; • The recovery technique; • Environment and personnel who perform the recovery; • Length of time between death and refrigeration and the length of time between death and recovery. • The industry standard recommends to recover tissue within 24 hours if the donor was refrigerated and 12 hours if not refrigerated.

32. Cadaveric Donor Screening Screening • Interview (“Next of Kin”) • Physical exam • Medical history • Review of medical records for risk factors and clinical evidence of relevant communicable disease agents and diseases Donor Testing for Communicable Diseases • Blood sample collected for HIV, type 1 and 2; HBV; HCV; and Treponema pallidum (syphilis)

33. Cadaveric Tissues Tissue Recovery Other factors assessed. “Aseptic” technique • One donor at a time using recovery “packs,” instruments and supplies • Personnel scrub, gown, and glove; similar to hospital Operating rooms • AATB Zone Recovery Technique

34. Cadaveric Tissues Tissue Recovery AATB standards for body storage/holding. Preparation of the room in which recovery takes place. Microbial swabbing of tissues (if required by processor)

35. Cadaveric BONE Bone – Largest percentage of cadaveric tissue in use. • Demineralized Bone Matrix • Cancellous bone – e.g. block, crushed or cubes • Cortical Bone – e.g. femural head, tibia whole or section, femur, cortical bone powder • Machined Bone – e.g. bone dowels, screws, and pins

36. Cadaveric BONE Indications for Use • General orthopedics • Fracture management • Total joint procedures • Spine surgeries (Allograft replaces disc; spine fusion very common in conjunction with metal implant)

37. Cadaveric BONE Example: Demineralized Bone Matrix (DBM) • Prepared by acid extraction (i.e. HCL) of allograft bone • Extraction of mineralized components • Retaining collagen and collagenous proteins and growth factors • Bone Morphogenetic Proteins (BMPs) • Complete DBM about 0.01% but AATB requires <8%

38. Cadaveric BONE Demineralized Bone Matrix (DBM) (Continued) • Powder • Crushed granules • Sponges • Putty • Chips • Gel injected through a syringe

39. Cadaveric BONE Demineralized Bone Matrix (DBM) (Continued) Quality (Devices) • In vitro testing for BMP-2 (ELIZA test platforms or human osteoblast cells) • In vivo testing ectopic rat assay (bone formation)

40. BONE Processing Processing usually includes • Cleaning • Washing • Can include antibiotic soaks or terminal ethylene oxide or gamma irradiation, or other sterilizing treatment • Other—Proprietary Technologies • Sampling for contaminants • Cutting, shaping, grinding

42. BONE Processing GAMMA STERILIZATION AAMI TIR37:2007 Sterilization of health care products—Radiation—Guidance on sterilization of human tissue-based products

43. BONE Processing MICROORGANISMS • Not unexpected on pre-processed tissue • Can the process remove the microorganisms? • Of particular concern: Clostridium is an anaerobic spore former; may prove difficult to detect; is difficult to remove; might result in serious morbidity or death. Other human pathogenic microorganisms (e.g. Group A Streptococcus) • Generally associated with the donor • Importance of prompt refrigeration and recovery

44. FDA GTP Guidance (2011) Preprocessing cultures are important “A disinfection or sterilization process must be validated based on the capability of that process to reduce or eliminate an expected level and mix of microorganisms on the particular products that will be put through the process. Thus, if musculoskeletal HCT/Ps are processed with bioburden in excess of the level that the process has been validated to remove or inactivate …there is no assurance that the process will result in the reduction or removal of bioburden to acceptable limits or reduce the risk of transmission of communicable disease.”

45. Microbial Testing • Recovery, incoming bioburden, pre-processing culture samples • In-processing samples • Post-processing samples – Final sterility samples • Environmental monitoring samples

46. Microbial Testing SWABS • Hard to quantify for tissues • Have to address recovery of microorganisms from tissue surface AND “recovery of recovered” microorganisms from swab to media • Swab recovery dependent on: • Type of swabbing system • Handling of swabs, e.g. need to transport • Time to incubation • More qualitative than quantitative for tissue • Use for recovery or pre processing samples and Post processing samples (final sterility)

47. Microbial Testing Bioburden • Evaluation of the levels of microbial contamination (types of organism and concentration) on the HCT/P prior to processing • Quantitative and qualitative • Use extraction method • Can also be used as a release test • Incoming bioburden in transport media may also be assessed using this method

48. Microbial Testing Destructive Testing • Immersion of representative tissue into a microbial growth medium • Incubate for growth • Determine as positive or negative for growth • Sample can be tissue intended for transplant or companion tissue • Tissue must be discarded after the test • Mostly used for final sterility testing

49. FDA GTP Guidance (2011) Sterility Claim • Not required for “361” tissues • But if you claim it, you must prove it

50. Cadaveric Tissues BONE Example from the TRG (2012) “An allograft bone product – either in a mineralized or demineralized form – intended for bone repair or replacement and regulated solely under section 361 of the Public Health Service Act is still regulated solely under section 361 of the Public Health Service Act if soaked in antibiotic during processing for the purpose of reducing the bioburden of the allograft.”[Emphasis Added]