YY/T Translated English of Chinese Standard: YY/T

Transcription

1 Translated English of Chinese Standard: YY/T YY PHARMACEUTICAL INDUSTRY STANDARD OF THE PEOPLE S REPUBLIC OF CHINA ICS C 45 YY/T Tissue engineered medical products Part 9: Sodium hyaluronate 组织工程医疗产品第 9 部分 : 透明质酸钠 Issued on: January 31, 2007 Implemented on: January 1, 2008 Issued by: China Food and Drug Administration Page 1 of 28

2 Table of Contents Foreword Scope Normative references Terms and definitions Classification Requirements Test methods Inspection rules Marks Packaging, transportation and storage Appendix A Appendix B Appendix C Appendix D References Page 2 of 28

3 Foreword YY/T 0606 Tissue engineered medical products is divided into: Part 1: General requirements; Part 2: Terminology; Part 3: General classification; Part 4: Terminology and classification of skin substitute; Part 5: Characterization and testing of substrates and scaffolds; Part 6: Type I collagen; Part 7: Chitosan; Part 8: Alginate; Part 9: Sodium hyaluronate; Part 10: In vivo assessment of implantable devices intended to repair or regenerate articular cartilage; Part 12: Guide for processing cells, tissues, and organs; Part 13: Product conservation; Part 16: Guide for gel immobilization or microencapsulation of alginates in the living cells or tissues. This Part is the Part 9 of YY/T The Appendixes A, B and C of this Part are normative; while the Appendix D is informative. This Part was proposed by China Food and Drug Administration. This Part shall be under the jurisdiction of the National Institute for the Control of Pharmaceutical and Biological Products. Drafting organizations of this Part: Shanghai Qisheng Institute of Biomaterial and Technology, and Medical Device Testing Center of the National Institute for the Control of Pharmaceutical and Biological Products. Main drafters of this Part: Gu Qisheng, Huang Zhiben, and Xi Tingfei. Page 3 of 28

4 Tissue engineered medical products Part 9: Sodium hyaluronate 1 Scope This Part of YY/T 0606 specifies the requirements, test methods, testing rules, marks, packaging, transportation and storage of the sodium hyaluronate used in surgical implants and tissue engineered medical products. This Part applies to the sodium hyaluronate which can be used for preparing the surgical implants and tissue engineered medical products. 2 Normative references The provisions in the following documents become the provisions of this Part through reference in this Part of YY/T For dated references, the subsequent amendments (excluding corrections) or revisions do not apply to this Part. However, parties who reach an agreement based on this Part are encouraged to study if the latest versions of these documents are applicable. For undated references, the latest versions apply to this Part. GB Packaging Pictorial marking for handling of goods (eqv ISO 780:1997) GB/T Determination of the ph of adhesives (neq NFT :1972) GB/T Biological evaluation of medical devices Part 1: Evaluation and testing (idt ISO :1997) GB/T Biological evaluation of medical devices Part 3: Tests for genotoxicity, carcinogenicity and reproductive toxicity (idt ISO :1992) GB/T Biological evaluation of medical devices Part 4: Selection of tests for interactions with blood (ISO :2002, IDT) GB/T Biological evaluation of medical devices Part 5: Test for in vitro cytotoxicity (ISO :1999, IDT) GB/T Biological evaluation of medical devices Part 6: Tests Page 4 of 28

5 for local effects after implantation (idt ISO :1994) GB/T Biological evaluation of medical devices Part 10: Tests for irritation and delayed-type hypersensitivity (ISO :2002, IDT) GB/T Biological evaluation of medical devices Part 11: Tests for systemic toxicity (idt ISO :1993) GB/T Biological evaluation of medical devices Part 12: Sample preparation and reference materials (ISO :2002, IDT) YY/T Package, label, transport and storage for medical polymer products YY Medical devices Symbols to be used with medical device labels, labelling and information to be supplied (ISO 15233:2000, IDT) Pharmacopoeia of People s Republic of China (2005 Edition, Volume 2) 3 Terms and definitions The following terms and definitions apply to this Part of YY/T Hyaluronic acid It refers to the linear polysaccharide that is composed of disaccharide repeating structural units generated by connecting D-glucuronic acid and N-acetyl-Dglucosamine together via β-(1-3) glucosidic bond. Each disaccharide unit is connected with another unit via β-(1-4) glucosidic bond. 3.2 Sodium hyaluronate It refers to the sodium salt form of the hyaluronic acid. The molecular weight of its structural unit is 401. The molecular structural formula is shown in the figure below. Note: SEE Appendix D for the additional information about the hyaluronic acid. Page 5 of 28

6 5.15 Safety of raw materials The sodium hyaluronate prepared by using the bio-fermentation method shall be conducted with the hemolysis test for hemolytic streptococcus. The test results shall have no hemolytic The sodium hyaluronate prepared by using the tissue extraction method shall be conducted with relevant inspection and quarantine. The test results shall be qualified Biological properties General rules The sodium hyaluronate shall be conducted with biological evaluation according to the requirements specified in the GB/T It shall not release any substances that have adverse effects on the human bodies Cytotoxicity test The cytotoxic reaction shall not be greater than Level Intradermal reaction test The primary irritation index (PII) shall not be greater than Acute systemic toxicity There shall be no acute systemic toxicity Hemolysis test There shall be no hemolytic reaction Sensitization test There shall be no skin sensitization Subcutaneous implant test There shall be no significant differences between tissue reaction and negative control, 14 days after implantation Genotoxicity test There shall be no genotoxicity. Page 8 of 28

7 GB/T It shall conform to the provisions specified in the Article Intradermal reaction test The determination shall be conducted according to the methods specified in the GB/T It shall conform to the provisions specified in the Article Acute systemic toxicity The determination shall be conducted according to the intraperitoneal injection method specified in the GB/T It shall conform to the provisions specified in the Article Hemolysis test The determination shall be conducted according to the hemolysis test method specified in the GB/T It shall conform to the provisions specified in the Article Sensitization test The determination shall be conducted according to the maximum dose method specified in the GB/T It shall conform to the provisions specified in the Article Subcutaneous implant test PREPARE the hyaluronic acid solution according to the instructions for use. USE 3 New Zealand rabbits. Respectively SELECT 2 implant points on both sides of the rabbit s spine. CONDUCT the subcutaneous injection of 0.5mL of hyaluronic acid to each point. TAKE samples for observation after 14 days. Other test procedures shall be conducted according to the methods specified in the GB/T The test procedures shall conform to the provisions specified in the Article Genotoxicity test The determination shall be conducted according to the methods for Ames test, micronucleus test, and chromosome aberration test (mouse sperm test) specified in the GB/T It shall conform to the provisions specified in the Article Inspection rules 7.1 General rules Page 12 of 28

8 8.3 The storage and transportation marks shall conform to the provisions specified in the GB/T Packaging, transportation and storage 9.1 USE appropriate packaging to ensure the safety and effectiveness of the sodium hyaluronate products. 9.2 The packaging, transportation and storage of products shall conform to the provisions specified in the YY/T Page 14 of 28

9 Appendix B (Normative) Determination of protein content in the sodium hyaluronate B.1 Folin-phenol method B.1.1 Principle The Folin-phenol reagent solution can have colored reaction with the proteins in the solution. The color intensity is in direct proportion to the protein concentration. B.1.2 Equipment Analytical balance, UV spectrophotometer or equivalent equipment, and vortex mixer or equivalent equipment. B.1.3 Solution preparation a) Reagent A: WEIGH 1.0g of copper (II) sulfate pentahydrate (CuSO4 5H2O). ADD water to dissolve and dilute to 100mL. b) Reagent B: WEIGH 2.0g of hydrated potassium sodium tartrate (KNaC4H4O6 H2O). ADD water to dissolve and dilute to 100mL. c) Reagent C: WEIGH 25.0g of sodium carbonate and 5.0g of sodium hydroxide. ADD water to dissolve and dilute to 250mL. d) Reagent D: MIX same amount of reagent A with reagent B before using. e) Reagent E: MIX 1 share of reagent D with 10 shares of reagent C before using. f) Reagent F: TAKE Folin-phenol reagent solution for 10 times of dilution before using. Note: All the test reagents are analytical reagents. B.1.4 Standard solution preparation B Accurately WEIGH about 50mg of bovine serum albumin as reference substance after being conducted with vacuum drying by using phosphorus pentoxide. ADD water to dissolve and dilute to 250mL (about 200μg/mL). Page 18 of 28

10 Appendix C (Normative) Determination of residual amount of ethanol in the sodium hyaluronate (headspace gas chromatography) C.1 Principle USE extracting agent which is the ethanol in the water extraction samples at a certain temperature. USE chromatographic column to perform the headspace extraction of samples afterwards, so as to distinguish the ethanol to be determined from other groups. USE a hydrogen flame ionization detector for inspection. COMPARE the ethanol chromatographic peak with the chromatographic peak obtained from external standard substances. C.2 Equipment C.2.1 The gas chromatograph equipped with hydrogen flame ionization detector and capillary column system. According to the requirements for the ethanol determined by using instruments, the signals generated at the lowest detectable concentration shall be greater than 2 times the instrument noise. C.2.2 Chromatographic data processor. C.2.3 Silica capillary column: SE-30 50m 0.53mm 3.0μm, or other chromatographic columns with the same isolation effects. C.2.4 1,000μL microprocessor, and 100μL microprocessor. C mL headspace bottle. C.2.6 Thermostatic drying oven. C.2.7 Absolute ethanol: chromatographic pure. C.3 Preparation of standard ethanol stock solution TAKE a 100mL flask which is dry on the outside. ADD about 60mL of distilled water. PLUG the bottle stopper. Accurately WEIGH to 0.1mg. USE an 100μL micro-syringe to inject about 60μL of chromatographic pure absolute ethanol. Gently SHAKE well without plugging the bottle stopper. WEIGH after plugging the bottle stopper. The difference between two weights represents the weight of absolute ethanol in the solution. ADD water to the scale, so as to prepare Page 22 of 28

11 500μg/mL stock solution. STORE the stock solution below 4 C. The expiry date is 1 month. C.4 Sample preparation Accurately WEIGH 0.1g of sodium hyaluronate. ADD 0.85% normal saline to prepare 1.0% hydrogel. Accurately WEIGH 1g of hydrogel. PLACE it in a 10mL headspace bottle afterwards. ADD 1mL of distilled water. SEAL the bottle stopper. PLACE the bottle in a thermostatic drying oven at 80 C for 20min. C.5 Operating conditions C.5.1 Column temperature: 50 C. KEEP the temperature for 2min. INCREASE to 160 C at the rate of 10 C/min. KEEP for 5min. C.5.2 Vaporization temperature for detection: 180 C. C.5.3 Carrier gas: nitrogen, 0.03MPa, 25cm/s. C.6 Determination methods C.6.1 USE stock solution to prepare the standard solution with five series of concentrations between 100μg/mL and 500μg/mL. Respectively TAKE 1mL of solution. ADD the solution to a 10mL headspace bottle. ADD 1.0mL of distilled water afterwards. MIX evenly. PLACE the headspace bottle in a thermostatic drying oven at 80 C for 20min. C.6.2 Rapidly EXTRACT 100μL of headspace gas from the balanced standard samples and test samples in succession. INJECT the headspace gas into the gas chromatograph under the specified conditions for chromatographic analysis. NOTE down peak height or area. Note 1: The operation is better to be conducted by one person during one analysis. USE the same syringe in the meantime. Note 2: The syringe shall be pre-heated to the same temperature with the sample at constant temperature. Note 3: Each sample (including standard sample) shall be conducted with multiple repeated analysis within the shortest possible time. The relative standard deviation shall not be greater than 10% within the concentration range of 0.01mg/mL. C.7 Result calculation C.7.1 USE the data determined by standard samples and the linear regression equation to calculate the standard curve (X: ethanol concentration, μg/ml; Y: peak height or area). Page 23 of 28

12 Appendix D (Informative) Background information D.1 Basic principle D.1.1 The application of natural existing polymers in biomedical science, pharmaceuticals, and tissue engineered medical products (TEMPs) has been increased with each passing day. This standard guide plans to provide guidance for the superficial characteristics and test parameters of the hyaluronic acid used for these purposes. The understanding with regard to the physical and chemical properties of hyaluronic acid, such as molecular weight, will help final users select correct hyaluronic acid used for specific purposes. The understanding of these parameters shall also make sure that the users can demand to obtain the materials which are similar to the records obtained from the suppliers. Eventually, the properties of hyaluronic acid determine that the hyaluronic acid applies to some kind of application or the functionality of final products. Other confirmed tests can also replace this guide to conduct the tests with the same purpose. However, none of these tests is suitable for the superficial characteristics and function confirmation of the final products. D.2 Background D.2.1 The hyaluronic acid is a kind of unbranched polysaccharide considering glucuronic acid and N-acetylglucosamine as structural unit by means of repeated alternation. The polymer chain is definitely long in natural state. However, it will shorten in the process of manufacturing. The hyaluronic acid is the simplest mucopolysaccharide without sulfate group, which is the element of all body fluid and tissues. The high-concentration hyaluronic acid exists in the vitreous humor of eyes and synovial fluid. The hyaluronic acid solution is very thick and smooth. The molecular weight of commercial hyaluronic acid might vary between g/mol and g/mol, equivalent to the degree of polymerization (DP) of about Page 25 of 28

13 References [1] YY Medical sodium hyaluronate gel [2] ASTM F Standard Guide for Characterization and Testing of Hyaluronan as Starting Materials Intended for Use in Biomedical and Tissue Engineered Medical Product Applications [3] MEDDEV rev2 Guidelines for the evaluation of the medical devices with regard to the animal-derived materials containing viruses and infectious pathogens involved END Page 28 of 28