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TS/P 235 (REV)TO THE ISO MEMBER BODIES

2013-02-27

ISO/TS/P 235 – Cell-combined medical products

Dear Sir or Madam,

Please find attached a proposal for a new field of technical activity on Cell-combined
medical products submitted by KATS (Rep. of Korea).
According to subclause 1.5.6 of Part 1 of the ISO/IEC Directives, you are kindly invited tocomplete the ballot form (Form 02) which can be downloaded at www.iso.org/forms andsend it (preferably in Word format) to the Secretariat of the ISO Technical Management
Board at tmb@iso.org before 27 May 2013.

Yours faithfully,Sophie Clivio,
Secretary of the Technical Management Board

Encl.: TS/P 235
Form 1 (REV)Annex

TMB_CL/TSP_235

KATS

Cell-combined medical products (CCMPs)

Standardization of guidelines for the cell-combined medical products(CCMPs) which consist of therapeutic cells andbiomaterials designed to be delivered into the body to restore, replace defects and/or regenerate physiological functions isnecessary.
The standards and guidelines include the terminology, specification, procedures in producing therapeutic cell expansion,cell-biomaterial hybridization, in vitro and in vivo experiments, and clinical trials for the cell-combined medicalproducts(CCMPs).
These standards exclude 1)minimally manipulated cells/tissues/organ medical products (CTOMPs) intended fortransplantation; 2)gene therapy; 3)blood transfusion; 4)extracorporeal devices containing living cells.

Main components of the CCMPs are 1)autologous or allogeneic cells and 2) biomaterials (synthetic or natural)which are
hybridized with the cells to provide and promote cellular functions necessary for the treatment goal.
The CCMPs are manufactured in forms of 1)injectable single cell suspension or 2)artificially manufactured multicellular
structures that are named as tissue engineered medical products (TEMPs).
The standards for the CCMPs may include-terminology-categories and/or classification
the technologies of-general requirements-risk management-cell harvestment (autologous or allogeneic)-manipulation of therapeutic cells (e.g., gene modification, cell expansion)-biomaterials for CCMPs (e.g., for single cell encapsulation or TEMPs)a. bioinert or biodegradableb. synthetic or natural (autologous, allogeneic or xenogeneic)-procedures of cell hybridization with biomaterials-in vitro analysis of CCMPs (e.g., cell viability, immunology)-in vivo trial (e.g., animal experiments)-clinical trials
other technologies appropriate to manufacture CCMPs to be developed in the futurePlease refer to the Annex

TC150/SC7 (Tissue engineered medical products, TEMPs) has a very limited scope on the medical products consist oftherapeutic cells hybridized with non-biological synthetic polymers that covers only a part of the CCMP. Representative
type of CCMP is the injectable single cell suspension hybridised with natural/synthetic polymeric vehicle but that productis out of the scope of TC150/SC7. Furthermore, TEMPs manufactured by cells combined with natural polymericmaterials which provide biological functions are also out of the committee. And the TC150/SC7 is less activated since theexperts participated in TC150 are mainly from non-vital surgical implants.
TC194/SC1 (Tissue product safety) is working on standardization of preventing/protecting biologically-driven substancesfrom contamination and/or infection. In 2012, the committee published a standard document "ISO 13022 Application ofrisk management to health care products containing viable human cells" which provides requirements for viable cellmanipulation that shall be handled under aseptic condition, because it is impossible to sterilize cells with maintaining
viability. This standard is applicable to the related standards which are whithin the scope of this new technology
committee.
The scope of a new TC titled “Biotechnology” is very valuable to avoid any conflict with the proposal for a new TC of“Cell Combined Medical Products” from KATS. We could understand that TC “Biotechnology” may cover “Terms anddefinitions, Analytical methods in the realm of -omics" technologies, Computing tools,bioinformatics for international
comparability and integrability of data, Bioresources, Biobanking, Bioreactors, Metrology aspects of biotechnology (e.g.
enzymology). The subjects are mainly related to analysis technologies at the genetic levels for biopharmaceuticals, butnot to the living cell-combined medical products which are directly delivered into body. Of course, some related
technologies in the TC “Biotechnology” are applicable at the very initial step of isolating, selecting, and gene-modifying“therapeutic cells” which are combined with the biomaterials for producing CCMPs. As TC “Biotechnology” noted that
“The committee will not pursue standardization of forensic science, research, as well as applications for the agricultural-,food-, and medical industries”, it is clear that TC “CCMPs”, distinctly manufactured by Medical industries, is not underTC “Biotechnology. The new proposed TC “CCMPs” will mainly concern guidelines and standards for manufacturing
processes applied to “Medical Products” definitely different from the “Pharmaceuticals” at TC “Biotechnology”.
Of course, this new TC “CCMPs” will not pursue scopes of TC 150, 194, 198, 212, and TC “Biotechnology”, but setup
close cooperative activities through establishing official liaisons with them.
.

KATS (Kor), BSI (U.K.), ANSI (U.S.A.), JISC (Jap), DIN (Ger), Brazil, China, Holland, etc.

(In order to avoid conflict with, or duplicationof efforts of, other bodies, it is important to indicate all points of possible conflict or overlap. The result of any
communication with other interested bodies shall also be included.)ISO

TC150/SC7, TC194/SC1, TC198, TC210, TC212, VAMAS

Governmental regulatory systems on biological- medical products.
Manufacturers producing cell integrated products.
Medical clinics using therapeutic cells.

KATS is ready to invite related experts from ISO member bodies as the TC secretariat.

The CCMPs have been recently introduced, rapidly grown and expanded in medical markets, and regarded as therepresentative products that replace large part of the conventional drug or surgical implant markets that are intended to beused indistinctly. By using CCMPs, the philosophy of medical practice is changing from the conventional concept ofmedication and surgery to the personalized therapy that provides fundamental treatment of disease (including genetic
diseases oriented from the individual genetic disorders) and defects (including both anatomical and physiologicalrecoveries) to each patient. Drug is any chemical compound produced by chemical engineering or biotechnology, andsurgical implant is designed and manufactured by non-viable biomaterials.
As CTOMPs are classified into type I (cell, tissue, organ transplants or grafts which are minimally manipulated after
procurement from donors and transferred to recipients by medical practitioners) and type II (CCMP or cell-based
implants which are manufactured by hybridizing therapeutic cells with biomaterials in forms of injectable single cellsuspensions or TEMPs).
The main treatment efficacy of a CCMP comes from living cells in the product that are artificially manipulated in vitro
for each patient, and shall be under the absolutely different conditions from conventional drugs and/or surgical implants.
But it is not globally agreed that CCMPs shall be categorized in drugs (chemicals or biologics) and medical implants(made of non-viable biomaterials), and are regulated as the combination products in some nation. Differences in applying
standards between drugs and medical devices result in various embarrassments in the global trade market, andfurthermore, it is difficult to ensure the safety of the CCMPs.
In ISO TC150 (Surgical implants), SC7 (Tissue engineered medical products) is in activity, and scope of ISO TC150 SC7
declares the scaffolds only made by non-biological materials. The injectable single cell suspension products and TEMPs
consist of therapeutic cells hybridized with biological materials are in exception.
In TC194 (Biological evaluation of the medical devices), SC1 (Tissue product safety) WG 1 (Risk assessment,terminology and global aspects) has developed a standard ISO 13022 “Application of risk management to health careproducts containing viable human cells” in association with viable cellular component(s) of products regulated as
medicinal products, biologics, medical devices and active implantable medical devices or combinations thereof. It covers
viable human materials of autologous as well as allogeneic human origin, obtained from living or deceased donors. It
mainly concerns on protecting viable components of the products from extrinsic hazardous contamination. Furthermore, itdoes not include non-viable biological materials to be hybridized with cells.
Therefore, establishing a new technical committee of the cell-combined medical products(CCMPs)in ISO, and setting
global standards for the products is extremely required at present

SEO, Kwang-Hyun
Administrator
Korean Agency for Technology and StandardsFurther information to assist with understanding the requirements for the items above can be found in the Directives, Part 1,Annex C.

Annex(A listing of relevant existing documents at the international, regional and national levels)
ISO 10993-1, Evaluation of biological safety of medical instrument -- Part 1: Evaluation and Testing
ISO 10993-7:1995, Biological evaluation of medical devices -- Part 7: Ethylene oxide sterilization residuals
ISO 11607-1:2006, Packaging for terminally sterilized medical devices -- Part 1: Requirements for materials,
sterile barrier systems and packaging systems
ISO 11607-2:2006, Packaging for terminally sterilized medical devices -- Part 2: Validation requirements forforming, sealing and assembly processes
ISO 13022: 2012, Application of risk management to health care products containing viable human cells
ISO 13485:2003, Medical devices -- Quality management systems -- Requirements for regulatory purposes
ISO 14155-1:2003, Clinical investigation of medical devices for human subjects -- Part 1: General requirements
ISO 14155-2:2003, Clinical investigation of medical devices for human subjects -- Part 2: Clinical investigationplans
ISO 14630, Non-active surgical implant -- General requirements
ISO 14971:2000, Medical devices -- Application of risk management to medical devices
Korea
KSP 1600:2007 General guideline of safety test for the cell based therapeutic substances
KFDA Code of human cell/tissue/organ Bank
KFDA Code of cell engineered products
KFDA Code of biologics
United Kindom
Code of Practice for Tissue Bank
Code of Practice for Human Tissue Products
United States of America
21 CFR Parts 210 and 211 Drug Current Good Manufacturing Practices
21 CFR Part 312 IND regulations
21 CFR Parts 600-680 Biologics Regulations
21 CFR Parts 1270-1271 Human Tissue Regulations
FEDERAL REGISTER; Application of Current Statutory Authorities to Human Somatic Cell Therapy Products
and Gene Therapy Products; Notice - 10/14/1993
FEDERAL REGISTER; Human Cells, Tissues, and Cellular and Tissue-Based Products; Donor Screening andTesting, and Related Labeling; Interim Final Rule - 5/24/2005
FEDERAL REGISTER; Current Good Tissue Practice for Human Cell, Tissue, and Cellular and Tissue-Based
Product Establishments; Inspection and Enforcement; Final Rule - 11/18/2004
FEDERAL REGISTER; Eligibility Determination for Donors of Human Cells, Tissues, and Cellular and TissueBased Products; Final Rule - 5/25/2004
FEDERAL REGISTER Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment
Registration and Listing; Interim Final Rule; Correction - 1/30/2004
FEDERAL REGISTER Human Cells, Tissues, and Cellular and Tissue-Based Products; Establishment
Registration and Listing; Interim Final Rule; Opportunity for Public Comment - 1/23/2004
Guidance for Industry: MedWatch Form FDA 3500A: Mandatory Reporting of Adverse Reactions Related to
Human Cells, Tissues, and Cellular and Tissue-Based Products (HCT/Ps) - 11/30/2005
Draft Guidance for Industry: Eligibility Determination for Donors of Human Cells, Tissues, and Cellular andTissue-Based Products (HCT/Ps) - 5/20/2004
Public Health Service Guideline on Infectious Disease Issues in Xenotransplantation - 1/19/2001
Guidance for Industry: Source Animal, Product, Preclinical, and Clinical Issues Concerning the Use of
Xenotransplantation Products in Humans - 4/3/2003
Draft Guidance for Reviewers: Instructions and Template for Chemistry, Manufacturing, and Control (CMC)
Reviewers of Human Somatic Cell Therapy Investigational New Drug Applications (INDs) - 8/15/2003
ASTM F2312-04 Standard Terminology Relating to Tissue Engineered Medical Products
ASTM F2211-04 Standard Classification for Tissue Engineered Medical Products (TEMPs)
ASTM F2210-02 Standard guide for processing cells, tissues, and organs for use in tissue engineered medicalproducts

ASTM F2027-00 Standard guide for characterization and testing of substrate materials for tissue engineered
medical products
ASTM F2150-02 Standard guide for characterization and testing of biomaterial scaffolds used in tissue
engineered medical products
ASTM F2212-02 standard guide for characterization of type I collagen as starting material for surgical implantsand substrates for tissue engineered medical products (TEMPs)
ASTM F2315-03 Immobilization or encapsulation of living cells or tissue in alginate gels
ASTM F2383-05 Standard guide for assessment of adventitious agents in tissue engineered medical products
ASTM F2386-04 Standard guide for preservation of tissue engineered medical products (TEMPs)