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GB/T 45351-2025Manufacture of cell-based medical devices - Control of microbial risks during processing (English PDF)

基于细胞的医疗器械生产加工过程中微生物风险控制

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Issued by

State Administration for Market Regulation, China National Standardization Administration

Level / Type

National · Recommended

Issue date

February 28, 2025

Implementation date

September 1, 2026

Scope

GB/T 45351-2025 is the English-translated version of 基于细胞的医疗器械生产加工过程中微生物风险控制.

GB/T 45351-2025 — This document specifies the requirements for controlling microbial contamination when processing cell-based medical devices using a risk-based approach.

The minimum requirements that need to be met are set out and guidance is provided. This document applies to cell-based medical devices with or without a "sterile" label.

Refer to this document for use. This document does not apply to. --- Procurement and transportation of cell-based starting materials for processing cell-based medical devices, ---In vitro diagnostic reagents.

This document does not specify biosafety requirements. This document does not replace regulations related to the manufacturing and quality control of cell-based medical devices.

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Document preview — GB/T 45351-2025

National Standard of the People's Republic of China

ICS: 11.080.01
Classification: C 47

Issued by: State Administration for Market Regulation, China National Standardization Administration

Preface
Introduction
1 Scope
2 Normative references
3 Terms and Definitions
4 General Requirements
5 Process Definition
6 Production Environment
7 Equipment
8 People
9 Product Production
10 Process Simulation and Process Validation
11 Finished product release. Sterility test
12 Finished product release. Detection of biological contamination that cannot be determined by sterility testing
Appendix A (Informative) Typical elements of process definition
Appendix B (Informative) Examples of Microbiological Risks of Cell-Based Medicinal Products
Appendix C (Normative) Decision Tree for Application of Risk Assessment of Cell Starting Materials
Appendix D (Informative) Protective facilities
Appendix E (Normative) Starting Materials for Cell-Based Medical Devices
Appendix F (Normative) Protection requirements for purchased non-sterile starting materials before entering the production area
Reference

Foreword

This document is in accordance with the provisions of GB/T 1.1-2020 "Guidelines for standardization work Part 1: Structure and drafting rules for standardization documents" Drafting.

This document is modified to adopt ISO 18362:2016 "Microbiological risk control in the production and processing of cell-based medicinal products".

This document has the following structural adjustments compared to ISO 18362:2016.

--- Appendix A corresponds to Appendix F in ISO 18362:2016;

--- Appendix B corresponds to Appendix A in ISO 18362:2016;

--- Appendix C corresponds to Appendix B in ISO 18362:2016;

--- Appendix D corresponds to Appendix C in ISO 18362:2016;

--- Appendix E corresponds to Appendix D in ISO 18362:2016;

--- Appendix F corresponds to Appendix E in ISO 18362:2016.

The technical differences between this document and ISO 18362:2016 and their reasons are as follows.

--- The product scope of this document has been changed to limit it to cell-based medical devices (see Chapter 1) to adapt to my country's technology condition;

--- Added "Other cell-based medical products refer to this document for use" (see Chapter 1) to clarify that this document is used in other cell-based the reference for microbial risk control in the processing of medical products containing cells;

--- ISO 17665-1 (see 5.1.3) is replaced by the normative reference GB 18278.1 to adapt to my country's technical conditions;

--- ISO 11135 (see 5.1.3) is replaced by the normative reference GB 18279 to adapt to my country's technical conditions;

--- Replaced ISO 11137 (all parts) (see 5.1.3) with the normative reference GB (/T) 18280 (all parts) to adapt to Our country's technical conditions;

--- ISO 14937 (see 5.1.3) was replaced by the normative reference GB/T 19974 to adapt to my country's technical conditions;

--- ISO 14160 (see 5.1.3) was replaced by the normative reference YY0970 to adapt to my country's technical conditions;

--- ISO 20857 (see 5.1.3) was replaced by the normative reference YY/T 1276 to adapt to my country's technical conditions;

--- ISO 25424 (see 5.1.3) was replaced by the normative reference YY/T 1464 to adapt to my country's technical conditions;

--- Replaced ISO 13408-1 with the normative reference YY/T 0567.1 [see Chapter 3, 5.1.4, 5.2.3c) and Appendix C] to apply According to my country's technical conditions;

--- Replaced ISO 13408-7 with the normative reference YY/T 0567.7 [see 5.1.4, 5.2.3c) and Appendix C] to adapt to the technical requirements of my country.

Technical conditions;

--- Added normative reference document GB/T 42061 [see 9.2.1a)] to adapt to my country's technical conditions;

--- ISO 14971 [see 5.2.1a)] was replaced by the normative reference GB/T 42062 to adapt to my country's technical conditions;

--- ISO 14644-4 [see 6.4c)] was replaced by the normative reference GB/T 25915.4 to adapt to my country's technical conditions;

--- Replaced ISO 22442 (all parts) [5.2.2b), 9.2.1a)] with the normative reference YY/T 0771 (all parts), Adapt to my country's technical conditions;

--- European GMP Part II [see 9.2.1a)] has been deleted to meet the feasibility requirements of this document;

--- Deleted ICHQ7 [see 9.2.1a)] and ICHQ9 [see 5.2.1a)] to meet the feasibility requirements of this document.

The following editorial changes were made to this document.

--- Change the name of the standard to "Microbial Risk Control in the Production and Processing of Cell-based Medical Devices";

--- Incorporated the amendments to ISO 18362:2016/Amd.1.2022, the outer margins of the clauses involved are marked with vertical double Line (||) is marked;

--- Replace ISO 13485 with the informative reference GB/T 42061 (see Note 4.1);

--- Changed the description of H14 to avoid misunderstanding [see 6.6d)];

--- Deleted the European Pharmacopoeia Certificate of Suitability (CEP) (see 9.2.1) to adapt to my country's national conditions.

--- Replaced ISO 22443-3 with informative reference YY/T 0771.3 (see 9.5);

--- Replaced ISO 11737-1 with the informative reference GB/T 19973.1 (see 12.2.3);

--- Deleted the risk examples of biological products in Table B.1 (see Appendix B) to be consistent with the scope of application of the standard;

--- Changed the ISO cleanliness control level and converted it into the corresponding cleanliness level specified in my country (see Appendix D) to avoid Understanding bias;

--- Replaced ISO 14971 with the informative reference GB/T 42062 (see E.1);

--- Replaced ISO 22442 (all parts) with informative reference YY/T 0771 (all parts) (see E.1);

--- European GMP Part II (see E.1) was deleted.

Introduction

0.1 Overview

The main components of cell-based medical devices include prokaryotic/eukaryotic cells or biological entities derived from cells.

Cell-based or cell-derived starting materials used in the manufacture of biopharmaceuticals can be in a living or inactivated state and can come from human, animal, microbial, Organisms or plants. A common feature of these medical devices is that their effectiveness comes from their biological properties.

Cell-based medical devices may have certain limitations in their ability to withstand sterilization and purification processes.

This document specifies the factors that need to be considered when applying a risk-based approach to the processing of such medical devices.

factors to reduce the possibility of increasing endogenous contamination of the product and prevent the introduction of exogenous contamination into the product.

The following key factors should be considered, including process design, equipment, facilities, common media, preparation conditions, addition of buffers and reagents, and operator Training.

0.2 Cell-based medical devices labeled "sterile"

Cell-based medical devices labeled "sterile" are generally sterilized through a terminal sterilization process or processed in an aseptic manner.

Examples of cell-based medical devices that are sterilized by terminal sterilization include, but are not limited to. cancellous bone, demineralized bone matrix, catgut, Sterility assurance for these medical devices is achieved through reasonable environmental design and control, of starting materials and packaging.

This can be achieved through appropriate manufacturing process design and validation (including terminal sterilization processes and the application of reasonable on-line controls and testing).

The requirements and guidelines for the terminal sterilization process of cell-based medical devices can be found in GB 18278.1, ISO/T S17665-2, GB 18280.1, GB 18280.2, GB/T 18280.3, GB 18279, YY0970, YY/T 1276, for reference, please refer to GB/T 19974 and YY/T 1464.

Some infectious agents (such as viruses and protozoa) may require a multifaceted approach to ensure product quality and safety.

Current terminal sterilization or aseptic processing standards do not specifically address these pathogens.

Cell-based medical devices that are labeled "sterile" but cannot be terminally sterilized are generally processed aseptically.

The sterility of the device is ensured through reasonable environmental design and control, of starting materials and packaging, reasonable production process design and confirmation.

certification, process simulation [according to the requirements of YY/T 0567 (all parts)], application of reasonable online control of production process and aseptic processing conditions Starting materials and packaging materials should be sterilized using a validated sterilization process. This document does not define "sterile" the specific aseptic processing requirements for cell-based medical devices labeled "sterile" are restated.

For aseptic processing, see YY/T 0567 (all parts).

0.3 Cell-based medical devices without a "sterile" label

The processing of cell-based medical devices (such as corneal tissue or living skin grafts) that are not labeled "sterile" includes the use of Before the finished product is assembled or combined, its components may need to be treated to reduce the bioburden and thus reduce the endogenous the control measures taken to maintain product quality during the processing of such medical devices are the production and technical means may be different from those of such medical devices marked "sterile".

Some infectious agents (such as viruses and protozoa) may require a multifaceted approach to ensure product quality and Safety.

Microbiological quality assurance of cell-based medical devices without a "sterile" label is achieved through environmental control, of starting materials and packaging, this is achieved through appropriate production process design and validation, process validation and process simulation studies, and the application of appropriate process controls and testing.

Risk assessment is the basis for selecting the appropriate microbiological quality standard for cell-based medical devices that are not labeled "sterile".

The acceptability of a product is determined by the presence of microorganisms in a specified quantity of product or by the total number of microorganisms in a specified quantity of product to ensure that the finished product will not Patients pose a microbiological risk.

Cell-based medical device production Microbiological risk control during processing

1 Scope

This document specifies the requirements for controlling microbial contamination when processing cell-based medical devices using a risk-based approach.

The minimum requirements that need to be met are set out and guidance is provided.

This document applies to cell-based medical devices with or without a "sterile" label.

Refer to this document for use.

This document does not apply to.

--- Procurement and transportation of cell-based starting materials for processing cell-based medical devices,

---In vitro diagnostic reagents.

This document does not specify biosafety requirements.

This document does not replace regulations related to the manufacturing and quality control of cell-based medical devices.

2 Normative references

The contents of the following documents constitute essential clauses of this document through normative references in this document.

For referenced documents without a date, only the version corresponding to that date applies to this document; for referenced documents without a date, the latest version (including all amendments) applies to this document.

GB 18278.1 Sterilization of health care products by moist heat Part 1: Development, validation and routine control of sterilization processes for medical devices Request (GB 18278.1-2015, ISO 17665-1:2006, IDT) GB 18279 Sterilization of healthcare products - Development, validation and routine control requirements for ethylene oxide sterilization processes for medical devices (GB 18279-2023, ISO 11135:2014, IDT) GB/T 18280 (all parts) Radiation sterilization of health care products [ISO 11137 (all parts)] Note. GB 18280.1-2015 Radiation sterilization of health care products Part 1: Development, validation and routine control requirements for sterilization processes for medical devices (ISO 11137-1:2006, IDT) GB 18280.2-2015 Radiation sterilization of health care products Part 2: Establishing the sterilization dose (ISO 11137-2:2006, IDT) GB/T 18280.3-2015 Radiation sterilization of healthcare products Part 3: Guide to dose measurement (ISO 11137-3:2006, IDT) GB/T 19974 Sterilization of health care products - Characteristics of sterilization factors and development, validation and routine control of sterilization processes for medical devices General requirements (GB/T 19974-2018, ISO 14937:2009, IDT) GB/T 25915.4 Clean rooms and related controlled environments Part 4: Design, construction and start-up (GB/T 25915.4-2010, ISO 14644-4:2001,IDT) GB/T 42061 Medical device quality management system for regulatory requirements (GB/T 42062-2022, ISO 13485.

2016, IDT)

GB/T 42062 Application of Medical Device Risk Management to Medical Devices (GB/T 42062-2022, ISO 14971:2019, IDT) YY/T 0567.1-2013 Aseptic processing of health care products Part 1: General requirements (ISO 13408-1:2008, IDT) YY/T 0567.7-2016 Aseptic processing of medical care products Part 7: Alternative processing of medical devices and combination products (ISO 13408-7:2012, IDT) YY/T 0771 (all parts) Medical devices of animal origin [ISO 22442 (all parts)] Note. YY/T 0771.1-2020 Medical devices of animal origin Part 1: Application of risk management (ISO 22442-1:2015, MOD)

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This preview omits tables, figures, formulas and parts of the technical clauses. The complete document — 28 pages — is available in the English PDF.

Referenced standards

Normative references

ISO 17665 · ISO 11135 · GB/T 18280 · ISO 11137 · ISO 14937 · ISO 14644 · ISO 13485 · ISO 14971 · ISO 13408 · YY/T 0771 · ISO 22442

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