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YY/T 1571-2017: Tissue engineering medical device products—Sodium hyaluronate
YY/T 1571-2017
YY
PHARMACEUTICAL INDUSTRY STANDARD
OF THE PEOPLE’S REPUBLIC OF CHINA
ICS 11.040.40
C 45
Replacing YY/T 0606.9-2007
Tissue engineering medical device products - Sodium
hyaluronate
组织工程医疗器械产品 透明质酸钠
ISSUED ON: MAY 02, 2017
IMPLEMENTED ON: APRIL 01, 2018
Issued by: China Food and Drug Administration
Table of Contents
Foreword ... 3
1 Scope ... 6
2 Normative references ... 6
3 Terms and definitions ... 7
4 Classification ... 7
5 Requirements ... 8
6 Test methods ... 10
7 Marking ... 14
8 Packaging, transportation and storage ... 15
Appendix A (Normative) Determination of sodium hyaluronate content ... 16
Appendix B (Normative) Determination of protein content ... 19
Appendix C (Normative) Determination of residual ethanol (headspace gas
chromatography) ... 21
Appendix D (Informative) Determination of residual quaternary ammonium salt
(cetylpyridinium chloride) ... 23
Appendix E (Normative) Determination of weight-average molecular weight and
molecular weight distribution coefficient ... 26
References ... 28
Tissue engineering medical device products - Sodium
hyaluronate
1 Scope
This Standard specifies the requirements and test methods for sodium hyaluronate used
in surgical implants and tissue engineering medical device products.
This Standard applies to the preparation of sodium hyaluronate for tissue engineering
medical device products and their scaffold materials.
2 Normative references
The following referenced documents are indispensable for the application of this
document. For dated references, only the edition cited applies to this document. For
undated references, the latest edition (including any amendment) applies to this
document.
GB/T 191, Packaging - Pictorial marking for handling of goods
GB/T 14518, Determination of the pH of adhesives
GB/T 16886.1, Biological evaluation of medical devices - Part 1: Evaluation and
testing within a risk management process (GB/T 16886.1-2011, ISO 10993-1:2009,
IDT)
GB 18278 (all parts), Sterilization of health care products - Moist heat
GB 18279 (all parts), Sterilization of health care products - Ethylene oxide
GB 18280 (all parts), Sterilization of health care products - Radiation
YY/T 0313, Medical polymer products - Requirement for package and information
supplied by manufacturer
YY/T 0606.25, Tissue engineered medical product - Part 25: Quantification of
remnant DNA in biological materials utilizing animal tissues and their derivatives:
Fluorescence method
YY/T 0771.1, Medical devices utilizing animal tissues and their derivatives - Part 1:
Application of risk management (YY/T 0771.1-2009, ISO 22442-1:2007, IDT)
5 Requirements
5.1 Appearance
White or off-white powder or granular or fibrous solid, without any visible foreign
matter.
5.2 Identification
Typical Fourier transform infrared spectrum (FT-IR) frequencies (cm-1) of sodium
hyaluronate are 3 275 ~ 3 390(b), 1 615(s), 1 405(m), 1 377(m), 1 150, 1 077, 1 045(s),
946(m), 893(w). The wavenumber error of the measured band in the fingerprint area
shall be less than the specified value ±5 cm-1 (0.5%).
Note: s, strong; m, medium; w, weak; b, broad.
5.3 Sodium hyaluronate content
Based on the dry product, the content of sodium hyaluronate shall be 95.0% ~ 105.0%
(mass fraction).
5.4 pH
The pH of the 0.5% concentration solution shall be 5.0 ~ 8.5.
5.5 Intrinsic viscosity
It shall be 90% ~ 120% of its marked value.
5.6 Protein content
It shall not exceed 0.1% (mass fraction).
5.7 Nucleic acid content
5.7.1 Bacterial fermentation method
For solution of the concentration 0.33%, the absorbance value (OD value) at the
wavelength of 260 nm shall not exceed 0.5.
5.7.2 Tissue extraction method
In accordance with YY/T 0606.25, the limit value of residual DNA is given according
to the possible intended use.
5.8 Heavy metal content
It shall not exceed 10 μg/g (mass fraction).
The number of bacterial colonies per 1 g of the test product shall not exceed 102 CFU;
the number of mold and yeast colonies shall not exceed 20 CFU. Staphylococcus aureus,
Pseudomonas aeruginosa and Escherichia coli shall not be detected.
Note: If sodium hyaluronate is provided in a non-sterile manner, this item shall be tested;
if the final product is required to be sterile, it should be sterilized to meet the
sterile requirements.
5.19 Bacterial endotoxins
The amount of endotoxin contained per 1 mg of sodium hyaluronate shall be less than
0.05 EU.
5.20 Raw material safety
5.20.1 The sodium hyaluronate prepared by the bacterial fermentation method shall be
tested for hemolytic streptolysin, and the result shall be free from hemolytic ring.
5.20.2 The sodium hyaluronate prepared by the tissue extraction method shall be
subjected to safety evaluation and quality control in accordance with the requirements
of the series industry standards for medical devices utilizing animal tissues and their
derivatives (YY/T 0771.1, YY/T 0771.2, YY/T 0771.3).
5.21 Biological evaluation
The sodium hyaluronate shall be subjected to biological evaluation according to the
requirements of GB/T 16886.1; sodium hyaluronate shall not release substances that
have adverse effects on the human body.
6 Test methods
6.1 Appearance
Perform direct observation with the naked eye, which shall comply with the provisions
of 5.1.
6.2 Fourier transform infrared spectrum (FT-IR)
Prepare the sample by the potassium bromide tablet method, and determine according
to the method specified in the general rule 0402 of the Pharmacopoeia of the People’s
Republic of China (2015 Edition, Volume IV), which shall meet the requirements of 5.2.
6.3 Determination of sodium hyaluronate content
Measure according to the method specified in Appendix A, which shall comply with
the provisions of 5.3.
6.4 pH determination
According to the method stipulated in the general rule 0831 of Pharmacopoeia of the
People’s Republic of China (2015 Edition, Volume IV), take 0.5 g of this product, use
phosphorus pentoxide as a desiccant, and dry it at 105 °C for 6 h for determination,
which shall meet the requirements of 5.10.
6.11 Determination of quaternary ammonium residues
Measure by referring to the method specified in Appendix D, which shall comply with
the provisions of 5.11.
6.12 Determination of sulfated mucopolysaccharides
Test solution: Take about 50.0 mg of this product (based on the dry product); add 1.0
mL of perchloric acid to a stoppered test tube (length is 5 cm; inner diameter is 1.6 cm);
dissolve it; use it as the test solution.
Control solution: Weigh 0.149 g of anhydrous sodium sulfate; add water to dilute to
100 mL, to dissolve it. Then, take 10.0 mL of the above solution; add water to dilute to
100 mL, to obtain it; take 1.0 mL of the solution; put it in a stoppered test tube; heat
and evaporate to dryness at 90 °C ~ 95 °C; then, add 1.0 mL of perchloric acid as a
control solution.
For both the test solution and the control solution, use glass wool to plug the test tube;
heat at 180 °C until clear (about 12 h); then, cool to room temperature. Add 3.0 mL of
33.3 g/L barium chloride solution respectively; shake after sealing; place for 30 min.
After shaking, follow the method specified in the general rule 0401 of Pharmacopoeia
of the People’s Republic of China (2015 Edition, Volume IV); use water as a blank;
measure the absorbance of the test solution and the control solution at a wavelength of
660 nm. If the absorbance of the test solution is less than the absorbance of the control
solution, it meet the requirements of 5.12.
6.13 Determination of iron content
Take 0.25 g of this product (based on the dry product); add 1.0 mL of nitric acid; heat
it in a water bath to dissolve; prepare 5 portions in parallel; after cooling, add water to
one part to dilute to 10 mL as the test solution, and add 0.5 mL, 1.0 mL, 1.5 mL and 2.0
mL of iron standard solution (each 1.0 mL is equivalent to 10 μg/mL iron) to the other
4 portions, respectively; then, add water to dilute to 10 mL, as the control solution;
according to the method stipulated in method II of the general rule 0406 of
Pharmacopoeia of the People’s Republic of China (2015 Edition, Volume IV), measure
it at a wavelength of 248.3 nm, which shall meet the requirements of 5.13.
6.14 Determination of chlorine content
Take 67 mg of this product; put it in a 100 mL measuring bottle; add water to dissolve
and dilute to the mark. Take 15 mL and place it in a 25 mL Nessler colorimetric tube as
the test solution; take another 10 mL of standard sodium chloride solution (1.0 mL is
equivalent to 5 μg of Cl) and 5 mL of water as the control solution. Add 1.0 mL of dilute
nitric acid (take 20 g of nitric acid and add water to dilute to 100 mL) and 1.0 mL of
silver nitrate test solution to the test solution and the control solution, respectively; mix
well; place in a dark place for 5 minutes; observe from the side on a black background.
It shall comply with the provisions of 5.14.
6.15 Determination of molecular weight and molecular weight distribution
Measure according to the method specified in Appendix E, which shall comply with the
provisions of 5.15.
6.16 Determination of clarity and color of solution
Take 0.10 g of this product (based on the dry product); add 30 mL of 0.9% sodium
chloride solution; shake to mix and dissolve, which shall meet the requirements of 5.16.
6.17 Sterility test
Measure according to the method specified in the general rule 1101 of Pharmacopoeia
of the People’s Republic of China (2015 Edition, Volume IV), which shall meet the
requirements of 5.17.
Note: If sodium hyaluronate is provided in a sterile manner, perform the test of this
item, otherwise, perform the test of 6.18.
6.18 Microbial limits
Take 5.0 g of this product; add 100 mL of sterile phosphate buffered saline (pH 7.2)
containing 45 000 units of hyaluronidase; shake and dissolve in a water bath at 42 °C
for 1 h, to obtain a 1:20 test solution. Measure according to the method specified in the
general rules 1105 and 1106 of Pharmacopoeia of the People’s Republic of China (2015
Edition, Volume IV), which shall meet the requirements of 5.18.
6.19 Bacterial endotoxin test
Use the water for detecting bacterial endotoxin to prepare 2 mg/mL sodium hyaluronate;
measure according to the method specified in the general rule 1143 of Pharmacopoeia
of the People’s Republic of China (2015 Edition, Volume IV), which shall meet the
requirements of 5.19.
6.20 Hemolytic streptolysin test
Use normal saline to prepare 2 mg/mL sodium hyaluronate; take 1 mL and inoculate it
directly on the blood agar plate medium; incubate at 37 °C for 24 h, which shall meet
the requirements of 5.20.1.
Note: This clause applies to sodium hyaluronate by bacterial fermentation method.
Appendix A
(Normative)
Determination of sodium hyaluronate content
A.1 Principle
The glucuronic acid produced by the hydrolysis of sodium hyaluronate reacts with the
carbazole reagent to produce purple red, and the depth of the generated color is directly
proportional to the content of glucuronic acid. Therefore, the content of sodium
hyaluronate is represented by the measured glucuronic acid content.
A.2 Equipment
A.2.1 Analytical balance.
A.2.2 UV spectrophotometer or equivalent equipment.
A.2.3 Vortex mixer or equivalent equipment.
A.3 Solution preparation
A.3.1 Carbazole test solution
Weigh 0.125 g of carbazole; add 100 mL of absolute ethanol to dissolve. Store in a dark
place.
A.3.2 Glucuronic acid (GA) standard solution
Accurately weigh about 0.1 g of the glucuronic acid reference substance, that has been
vacuum-dried to constant weight at 105 °C with phosphorus pentoxide, as a desiccant;
put it in a 100 mL measuring bottle; add water to dissolve and dilute it to the mark;
shake well; use it as a stock solution. Precisely measure 5.0 mL of the stock solution;
put it in a 100 mL measuring bottle; add water to make a solution containing 50 μg per
1.0 mL; shake well; store at 4 °C.
A.3.3 0.025 mol/L sodium tetraborate sulfuric acid solution
Weigh 9.54 g of sodium tetraborate (Na2B4O7·10H2O); add it to 1 L of concentrated
sulfuric acid; cover it. Shake occasionally until the sodium tetraborate is completely
dissolved. Store at room temperature.
Note: The reagents used in the test are all analytical reagents, and the sulfuric acid
should be guaranteed reagent.
A.4 Sample preparation
Appendix B
(Normative)
Determination of protein content
B.1 Principle
Foline-phenol test solution can react with the protein in the hyaluronic acid solution,
and its color depth is proportional to the protein concentration.
B.2 Equipment
Analytical balance, UV spectrophotometer or equivalent, vortex mixer or equivalent.
B.3 Solution preparation
B.3.1 Alkaline cupric tartrate test solution
Weigh 0.5 g of copper sulfate and 1.0 g of sodium tartrate in a 50 mL volumetric flask;
add water to dissolve and dilute to the mark. This is liquid A; weigh 2.0 g of anhydrous
sodium carbonate in a 50 mL volumetric flask; add 0.4 g of sodium hydroxide; add
water to dissolve and dilute to the mark, this is liquid B. Mix liquid A and liquid B at a
ratio of 1:50 and shake well. Prepare the above test solutions when needed.
B.3.2 Folin test solution (prepare as follow or purchase)
Weigh 100 g of sodium tungstate and 25 g of sodium molybdate; add 700 mL of water,
50 mL of 85% phosphoric acid and 100 mL of hydrochloric acid; put them in a flask;
heat and reflux slowly for 10 h; let cool; add 150 g of lithium sulfate, 50 mL of water
and a few drops of bromine solution; boil about 15 min, until the bromine is completely
removed; let it cool to room temperature; add water to make it 1 000 mL. Filter; use the
filtrate as a stock solution; put it in a brown bottle; store it in a refrigerator at 2 °C ~
8 °C. Before use, take the stock solution; dilute it with water at 1:1; mix well.
B.3.3 Prep...