Standards for Tissue Engineered Medical Products (TEMPs) January 22, 2014

TISSUE ENGINEERING Volume 11, Number 9/10, 2005 © Mary Ann Liebert, Inc.

Editorial Standardized Experimental Procedures in Tissue Engineering: Cure or Curse?

Professor Alan J. Russell

What Is a Standard?

“A standard is a common language that promotes the flow of goods between buyer and seller and protects the general welfare.”

ASTM Examples: • Medical & Surgical Materials & Devices • Anesthetic & Respiratory Equipment • Environment Site Assessment • Jet Fuel

Why Are Standards Important?

• • • • • AID in design, manufacturing, performance, operation and maintenance ADVANCE safety, health, quality INCREASE public interest, product certainty, and information availability TRANSFER technology to the marketplace via standards, handbooks, manuals, and training PASSPORTS to the global market

How Are Standards Used?

• • • • Developed voluntarily and used voluntarily Means of communication and quality assurance Government agencies reference them in codes, certification, regulations, and laws • Over 3,400 ASTM International standards are used as the basis for national standards by reference in regulation in over 75 countries Used by thousands of individuals/companies/agencies globally to declare conformance/compliance (design and marketing), coordinate research, coordinate product

TEMPs Challenges

• • • TEMPs = tissue engineered medical products Complex emerging field Priority for standards within the field of tissue engineering and regenerative medicine is not established • Global coordination remains uncertain

Standards Organizations

• • • • • • ASTM International ISO (International Organization for Standardization) IEC (International Electrotechnical Commission) ITU (International Telecommunication Union) ANSI (American National Standards Institute) IEEE (Institution of Electrical Engineers)

ASTM International

• • • • • • • ASTM provides the structure, resources, forum and technical expertise required to develop standards ASTM provides the organization required to publish and disseminate standards ASTM – Previously American Standards for Testing and Materials Organized as a set of ‘Technical Committees’ covering all broad topics of interest (140) A Technical Committee may have ‘Divisions’ containing a cluster of sub-committees covering a topic area A Technical Committee may have several – many ‘Sub committees’ – focused on a particular broad topic Each Sub-committee has task groups, each being responsible for developing a particular standard

ASTM F04 Division IV – Tissue Engineered Medical Products

• Objective – Establish standards and guides for use in tissue engineered medical products. – Consensus based approach, involving Industry, Academia, Federal groups – Involvement of international regulatory interests • Meetings two times per year (May and November)

TEMPs Standards Characteristics

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Assured patient safety

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Function related

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Provide reproducible results

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Realistic assessment(s)

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Requirements should be consistent between different products with similar objectives

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Develop through consensus

TEMPs Opportunities for Standards

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Increased efficiency for Research and Product Development

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Reduced costs of product development and manufacture

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Increased manufacturing efficiency

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Improved clinical effectiveness

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Reduced regulatory hurdles and timelines

6 Types of ASTM Standards Documents

Type of Standard Definition Guide Test Method Practice Specification Terminology Classification

An organized collection of information or series of options that does not recommend a specific course of action A definitive procedure that produces a test result A set of instructions for performing one or more specific operations that does not produce a test result An explicit set of requirements to be satisfied by a material, product, system or service A document composed of terms, definitions of terms, descriptions of terms, nomenclature, and explanations of abbreviations, acronyms & symbols Systematic arrangement or division of materials, products, systems, or services into groups based on similar characteristics such as origin, composition, properties, or use

Total Active

23 7 0 0 0 0 30

ASTM F4.04 Tissue Engineered Medical Products

6 Subcommittees with

30

published standards • F4.41 Classification & Terminology for TEMPs (2) • F4.42 Biomaterials & Biomolecules for TEMPs (16) • F4.43 Cells & Tissue Engineered Constructs (6) • F4.44 Assessment of TEMPs (5) • F4.45 Adventitious Agents Safety (1) • F4.46 Cell Signaling (0)

Approved TEMPs Standards: F04.41 Classification & Terminology for TEMPs

1.

2.

F2311-08 Standard Guide for Classification of Therapeutic Skin Substitutes F2312-11 Standard Terminology Relating to Tissue Engineered Medical Products

1.

Approved TEMPs Standards: F04.42 Biomaterials and Biomolecules for TEMPs

F2027-08 Standard Guide for Characterization and Testing of Raw or Starting Biomaterials for Tissue-Engineered Medical Products 2.

3.

4.

5.

6.

7.

F2064-00(2006)e1 Standard Guide for Characterization and Testing of Alginates as Starting Materials Intended for Use in Biomedical and Tissue-Engineered Medical Product Applications F2103-11 Standard Guide for Characterization and Testing of Chitosan Salts as Starting Materials Intended for Use in Biomedical and Tissue-Engineered Medical Product Applications F2131-02(2012) Standard Test Method for In Vitro Biological Activity of Recombinant Human Bone Morphogenetic Protein-2 (rhBMP-2) Using the W-20 Mouse Stromal Cell Line F2150-13 Standard Guide for Characterization and Testing of Biomaterial Scaffolds Used in Tissue-Engineered Medical Products F2212-11 Standard Guide for Characterization of Type I Collagen as Starting Material for Surgical Implants and Substrates for Tissue Engineered Medical Products (TEMPs) F2259-10(2012)e1 Standard Test Method for Determining the Chemical Composition and Sequence in Alginate by Proton Nuclear Magnetic Resonance (1H NMR) Spectroscopy 8.

9.

F2260-03(2012)e1 Standard Test Method for Determining Degree of Deacetylation in Chitosan Salts by Proton Nuclear Magnetic Resonance (1H NMR) Spectroscopy F2347-11 Standard Guide for Characterization and Testing of Hyaluronan as Starting Materials Intended for Use in Biomedical and Tissue Engineered Medical Product Applications 10. F2450-10 Standard Guide for Assessing Microstructure of Polymeric Scaffolds for Use in Tissue Engineered Medical Products 11. F2602-13 Standard Test Method for Determining the Molar Mass of Chitosan and Chitosan Salts by Size Exclusion Chromatography with Multi-angle Light Scattering Detection (SEC-MALS) 12. F2603-06(2012) Standard Guide for Interpreting Images of Polymeric Tissue Scaffolds 13. F2605-08e1 Standard Test Method for Determining the Molar Mass of Sodium Alginate by Size Exclusion Chromatography with Multi-angle Light Scattering Detection (SEC-MALS) 14. F2791-09 Standard Guide for Assessment of Surface Texture of Non-Porous Biomaterials in Two Dimensions 15. F2883-11 Standard Guide for Characterization of Ceramic and Mineral Based Scaffolds Used for Tissue-Engineered Medical Products (TEMPs) and as Devices for Surgical Implant Applications 16. F2900-11 Standard Guide for Characterization of Hydrogels used in Regenerative Medicine

Approved TEMPs Standards:

F04.43 Cells and TE Constructs

1. F2149-01(2007) Standard Test Method for Automated Analyses of Cells-the Electrical Sensing Zone Method of Enumerating and Sizing Single Cell Suspensions 2. F2210-02(2010) Standard Guide for Processing Cells, Tissues, and Organs for Use in Tissue Engineered Medical Products 3. F2315-11 Standard Guide for Immobilization or Encapsulation of Living Cells or Tissue in Alginate Gels 4. F2664-11 Standard Guide for Assessing the Attachment of Cells to Biomaterial Surfaces by Physical Methods 5. F2739-08 Standard Guide for Quantitating Cell Viability Within Biomaterial Scaffolds 6. F2944-12 Standard Test Method for Automated Colony Forming Unit (CFU) Assays Colonies in Culture — Image Acquisition and Analysis Method for Enumerating and Characterizing Cells and

Approved TEMPs Standards: F04.44 Assessment for TEMPs

1.

2.

3.

4.

5.

F2451-05(2010) Standard Guide for In Vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage F2529-13 Standard Guide for In Vivo Evaluation of Osteoinductive Potential for Materials Containing Demineralized Bone (DBM) F2721-09 Standard Guide for Pre-clinical In Vivo Evaluation in Critical Size Segmental Bone Defects F2884-12 Standard Guide for Pre-clinical In Vivo Evaluation of Spinal Fusion F2903-11 Standard Guide for Tissue Engineered Medical Products (TEMPs) for Reinforcement of Tendon and Ligament Surgical Repair

Approved TEMPs Standards: F04.45 Adventitious Agents Safety

1.

F2383-11 Standard Guide for Assessment of Adventitious Agents in Tissue Engineered Medical Products (TEMPs)

Approved TEMPs Standards: F04.46 Cell Signaling

This is a new subcommittee and does not have any published standards yet.

TEMPS Standards Used in a 510K Submission to FDA - A Living Example

• • •

X-Repair (Synthasome):

Woven, degradable mesh (poly-L-lactic acid) Augments surgical repair of tendons & soft tissues Received 510k clearance in 2009

Standards Used in 510k Application:

• ASTM D3786 Standard Test Method for Bursting Strength of Textile Fabrics - Diaphragm Bursting Strength Tester Method • ASTM D5035 Standard Test Method for Breaking Force & Elongation of Textile Fabrics (Strip Method) • ASTM D5587 Standard Test Method for Tearing Strength of Fabrics by Trapezoid Procedure • ASTM F1635-11 Standard Test Method for in vitro Degradation Testing of Hydrolytically Degradable Polymer Resins and Fabricated Forms for Surgical Implants  • ASTM F2211 Standard Classification for Tissue Engineered Medical Products (TEMPs) • ASTM F2312 Standard Terminology Relating to TEMPs • ASTM F2027 Standard Guide for Characterization and Testing of Raw or Starting Biomaterials for Tissue-Engineered Medical Products • ASTM F2150 Standard Guide for Characterization of Biomaterial Scaffolds Used in TEMPs • ISO 10993 Biological Evaluation of Medical Devices • ISO 11135 Sterilization of Health Care Products

F2451 - 05 (2010) Standard Guide for in vivo Assessment of Implantable Devices Intended to Repair or Regenerate Articular Cartilage

• • • • Consensus document developed over two years with input from academics, companies, clinicians, and FDA Approved in 2005 Used in applications to the FDA Key document referenced in FDA guidance document for articular cartilage repair: – “Guidance for Industry: Preparation of IDEs and INDs for Products Intended to Repair or Replace Knee Cartilage”

Standards Opportunities for Animal Models

• • • • • • • • • • Standard guides for pre clinical in-vivo evaluation of cranio-facial defects – Cranial – Facial – Neurological Standardization of surgical procedures Standard guide for assessing scarring, healing & regeneration of the skin – Surgical incisions – – Open wound defects Burns – Skin regeneration Wound infection Rapid screening model for cartilage repair Tendon (mobility, lack of scarring, scaffold materials) Ligament (focus on strength) Muscle (focus on function and mass, fibrosis) Soft tissue augmentation Standard practice/guide for nerve repair

Standards Opportunities for Clinical Studies

• • Assessment of clinical outcomes – – Measurement of patient-reported outcomes Measurement of clinically relevant biomechanical functions • Identification and coding of clinical conditions Current standards of care for managing various conditions

Standards Opportunities for Cells & Tissue Engineered Constructs

• • • • • • Standard guide to normal versus dystrophic mineralization Standard guide for cellular alkaline phosphatase activity Standard guide for characterization of osteoblasts and other lineages Standard guide for characterization of progenitor populations (proliferation, differentiation, purity, viability) Standard for apoptosis Standardize terminology regarding MSCs/progenitors (what is it now, what can it become, and what does it do)

Standards Opportunities for Biomaterials

• • • • • • • • • • • • Standard guide to host response Cell attachment Mechanical properties Porosity Loading Cell-mediated degradation Cell and scaffold tracking in vivo Vascular supply Innervation Assessing sensory and autonomic function Biointegration Biomaterial behavior in a contaminated/infected environment (Performance standards for biofilm formation)

Standards Opportunities for Adventitious Agents & Safety

• • • Exuberant inflammatory responses Tumorgenicity Toxicity for cell based constructs – Assessing cell viability – Biodistribution of cells after implantation

Standards Opportunities for Cell Signaling

• • • • • • • Apoptosis mechanism Cell signaling mechanism-based assays for stress/cytotoxicity – Greater predictive capability compared to live/dead Controlled extracellular matrix preparations for systematic studies – Expected physical and chemical properties of protocols and response from cells Criteria for evaluating cells after storage – Integrity with genetics, response to environment, ‘health’ Quantitative methods for cell area determination – Robust benchmarking protocol for fixing, staining and analyzing morphologies of cells in a population Criteria for qualifying a cell-based assay – What criteria are required for assuring a robust, reproducible, and valid biomarker assay(s) relevant to biological interpretation Fluorescent labels

Future Plans for TEMPs

• • • • • • • Continue standards development Increase involvement by individuals and groups Continue and encourage international cooperation Prioritize standard developments for pre-clinical and clinical assessment Spur selective safety document development Refine strategy Continue coordination with ISO/international partners

Summary

• • • • • • • • • • • TEMPs are already on the market addressing previously unmet clinical needs New TEMPs will continue to be developed for use Commerce needs to gain approval by multiple regulatory agencies globally The need for International Standards will increase Consensus standards are being developed TEMPs standards are being used Standards are an integral component of all industries Standard development is an active and ongoing process within TERM Standards are a valuable and necessary component of applications to the FDA Standards enhance efficiency of research, product development & manufacturing Risk: If you don’t develop (or participate in) the standard, someone else will

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Additional Resources

www.astm.org

www.iso.org

www.nist.gov/srm Plant AL, Horowitz E. Symposium on metrology and standards for cell signaling: impact on tissue engineering, National Institute for Standards and Technology, October 14-15, 2003. Tissue Engineering, 2005, 11, 985-90.

Russell AJ. Standardized experimental procedures in tissue engineering: cure or curse. Tissue Engineering, 2005, 11, vii-vix.

Messenger MP, Tomlins PE. Regenerative medicine: a snapshot of the current regulatory environment and standards. Advanced Healthcare Materials, 2011, 23, H10-H17.

Leitner E, Bischoff P. Setting standards for technologies in regenerative medicine. Biomedical Technology (Berlin), 2012, 57, 1051-1054.

Yokoi M, Hattori K, Narikawa K et al. Feasibility and limitations of the round robin test for assessment of in vitro chondrogenesis evaluation protocol in a tissue-engineered medical product. Journal of Tissue Engineering and Regenerative Medicine, 2012, 6, 550-8.

American Academy of Orthopaedic Surgeons. Position Statement: Consensus Standards for Medical Devices. Rosemont, IL, 2013.

U.S. Food & Drug Administration. Guidance for Industry and FDA Staff: Frequently Asked Questions on Recognition of Consensus Standards. White Oak, MD: 2007.