Requirements for human haematopoietic stem/progenitor cells.

'Requirements for human haematopoietic stem/progenitor cells' is the first set of guidelines on human haematopoietic stem/progenitor cells in China, jointly drafted and agreed upon by experts from the Chinese Society for Stem Cell Research. This standard specifies the technical requirements, inspection methods, inspection rules, instructions for usage, labelling requirements, packaging requirements, storage requirements and transportation requirements for human haematopoietic stem/progenitor cells, which is applicable to the quality control for human haematopoietic stem/progenitor cells. We hope that publication of these guidelines will promote institutional establishment, acceptance and execution of proper protocols, and accelerate the international standardization of human haematopoietic stem/progenitor cells for applications.

SCOPE

This document specifies the technical requirements, test methods, test regulations, instructions for use, labelling requirements, packaging requirements, storage requirements, transportation requirements and waste disposal requirements of human haematopoietic stem/progenitor cells.

This document is applicable for the production and testing of human haematopoietic stem/progenitor cells.

This document does not apply to haematopoietic stem cells involved in the Technical management specifications for haematopoietic stem cell transplantation and Cord blood haematopoietic stem cell bank management specifications (Trial).

NORMATIVE REFERENCES

The following content constitutes indispensable articles of this standard through normative reference. For dated references, only the edition cited applies. For undated references, only the latest edition (including all amendments) applies.

GB/T 6682 Water for analytical laboratory use—Specification and test methods

WS 213 Diagnosis for hepatitis C

WS 273 Diagnosis for syphilis

WS 293 Diagnosis for HIV/AIDS

T/CSCB 0001 General requirements for stem cells

Pharmacopoeia of the People's Republic of China

National Guide to Clinical Laboratory Procedures

TERMS AND DEFINITIONS

For the purpose of this document, the terms and definitions in T/CSCB 0001, T/CSCB 0002 and following terms and definitions apply to this document.

Human haematopoietic stem cells

Stem cells that have the ability to self‐renew and differentiate into all mature blood cell types.

Human haematopoietic progenitor cells

Progenitor cells that have the ability to differentiate into multiple or a particular lineage of blood cells.

Haematopoietic colony

Cell clusters or colonies containing recognizable progeny generated from individual haematopoietic progenitor cells cultured in a semi‐solid medium containing the appropriate cytokines.

ABBREVIATIONS

BFU‐E: burst‐forming unit‐erythroid

CD: cluster of differentiation

CFU‐GEMM: colony‐forming unit‐granulocyte‐erythroid‐macrophage‐megakaryocyte

CFU‐GM: colony‐forming unit‐granulocyte‐macrophage

EBV: Epstein‐Barr virus

HBV: hepatitis B virus

HCMV: human cytomegalovirus

HCV: hepatitis C virus

HIV: human immunodeficiency virus

HTLV: human T‐cell lymphotropic virus

NOD‐SCID: non‐obese diabetic‐severe combined immunodeficient

STR: short tandem repeat

TP: treponema pallidum

TECHNICAL REQUIREMENTS

Source materials and ancillary materials

5.1.1 The requirements of T/CSCB 0001 shall be followed.

5.1.2 To ensure the safety of the donor and the donated cells, the process for donor evaluation and screening, cell collection, transportation and receipt shall be standardized.

5.1.3 The donor shall be screened for HIV, HBV, HCV, HTLV, EBV, HCMV and TP, and the results shall be documented.

Primary quality attributes

Cell morphology

Cells grown under suspended conditions shall be round and uniform in size. Cells shall be round, and exhibit high nuclear‐to‐cytoplasmic ratio, light blue cytoplasm and no granular structure in the cytoplasm after the Wright‐Giemsa staining.

Chromosome karyotype

The normal karyotype shall be 46, XY or 46, XX.

Cell viability

Shall be ≥85% before cryopreservation and ≥70% after resuscitation.

Cell markers

The expression of CD34 shall be ≥80% of the cell population.

Colony‐forming unit assays

Number of total colonies shall be ≥10 per 103 cells, and number of CFU‐GEMM colonies shall be ≥1 per 103 cells.

Haematopoietic reconstitution assays

Sixteen weeks post‐transplantation into NOD‐SCID Il2rgnull mice, human CD45+ cell reconstitution levels shall be ≥5%, and human CD45+CD19+ cells, CD45+CD3+ cells, CD45+CD33+ cells and CD45−CD235a+ cells shall be positive in total peripheral blood mononuclear cells of the recipient mice.

Microorganisms

Fungi, bacteria, mycoplasma, HIV, HBV, HCV, HTLV, EBV, HCMV and TP shall be negative.

Process control

5.3.1 The process of cell expansion, cryopreservation and resuscitation shall follow the requirements of T/CSCB 0001.

5.3.2 The identity of the cells shall match with that of donor cells by STR analysis.

TEST METHODS

Cell morphology

Observe the morphology of cells using a microscope. Cell staining shall be performed following the National Guide to Clinical Laboratory Procedures.

Chromosome karyotype

The method in the Pharmacopoeia of the People's Republic of China shall be followed.

Cell viability

The method in Appendix A shall be followed.

Cell markers

The method in Appendix B shall be followed.

Colony‐forming unit assays

The method in Appendix C shall be followed.

Haematopoietic reconstitution assays

The method in Appendix D shall be followed.

Microorganisms

Fungi

The method ‘1101 sterility test’ in the Pharmacopoeia of the People's Republic of China shall be followed.

Bacteria

The method ‘1101 sterility test’ in the Pharmacopoeia of the People's Republic of China shall be followed.

Mycoplasma

The method ‘3301 sterility test’ in the Pharmacopoeia of the People's Republic of China shall be followed.

HIV

The nucleic acid test method in WS 293 shall be followed.

HBV

The nucleic acid test method in the National Guide to Clinical Laboratory Procedures shall be followed.

HCV

The nucleic acid test method in WS 213 shall be followed.

HTLV

The nucleic acid test method in the National Guide to Clinical Laboratory Procedures shall be followed.

EBV

The nucleic acid test method in the National Guide to Clinical Laboratory Procedures shall be followed.

HCMV

The nucleic acid test method in the National Guide to Clinical Laboratory Procedures shall be followed.

TP

The nucleic acid test method in WS 273 shall be followed.

INSPECTION RULES

Sampling method

7.1.1 Cells produced from the same production cycle, same production line, same source, same passage and same method are considered to be the same batch.

7.1.2 Three smallest units of packaging shall be randomly sampled from the same batch.

Quality inspection and release

Each batch of cell preparation shall be subject to the quality inspection before release. The quality inspection items shall include all the attributes specified in 5.2. The inspection reports shall be attached.

Review inspection

Review inspection shall be performed by professional cytological testing institutions/laboratories as necessary.

Decision rules

Products that pass all requirements in 5.2 for the quality inspection and quality review inspection are considered to be qualified. Products that do not meet these criteria should be considered unqualified.

INSTRUCTION FOR USAGE

The instructions for usage shall include, but not limited to:

Product name;

Passage number;

Cell numbers;

Production date;

Lot number;

Production organization;

Storage conditions;

Shipping conditions;

Operation manual;

Execution standard number;

Manufacturing address;

Contact information;

Postal code;

Matters that need attention.

Note: Upon user’s requirement, endotoxin test results can be provided.

LABELS

The label shall include, but not limited to:

Product name;

Passage number;

Cell number;

Lot number;

Production organization;

Production date.

PACKAGE, STORAGE AND TRANSPORTATION

Package

The appropriate materials and containers shall be selected to ensure maintenance of the primary quality attributes of human haematopoietic stem/progenitor cells.

Storage

10.2.1 T/CSCB 0001 shall be followed.

10.2.2 Productions should be stored at a temperature below ‐130°C.

Transportation

10.3.1 T/CSCB 0001 shall be followed.

10.3.2 Cryopreserved cell products shall be transported in dry ice or at temperature below ‐130°C. Non‐cryopreserved cell products shall be transported at temperature between 2 and 8°C.

WASTE DISPOSALS

Waste that arises during human haematopoietic stem/progenitor cell production and detection shall be disposed according to the regulations in T/CSCB 0001.