China National Standard for Halogenated Butyl Rubber Stopper for Injections (YBB00042005-2015)

This standard applies to halogenated (chlorinated or brominated) butyl rubber stoppers that come into direct contact with injections.

Appearance

Take several samples of the product and inspect them according to Table 1. The samples shall meet the specified requirements.

Identification

1. Weigh 2.0 g of the sample, cut into small pieces, place in a crucible, and uniformly cover with 2.0 g of sodium bicarbonate. Heat slowly on an electric furnace until carbonization occurs. Allow to cool, then place in a muffle furnace at 300 ℃ until completely ashed. Remove and cool to room temperature, add 10 ml of water to dissolve, filter, and take 1.5 ml of the filtrate. Acidify with nitric acid and add 1 drop of silver nitrate solution. A white or pale yellow precipitate shall form.

2. Take an appropriate amount of the sample and perform infrared spectroscopic analysis according to Method 4 in “Determination of Packaging Materials by Infrared Spectroscopy” (YBB00262004-2015). The spectrum shall be substantially consistent with the reference spectrum.

Puncture Particulate Matter

Take 10 stoppers and determine puncture particulate matter according to Method 1 in “Determination of Particulate Matter Released from Stoppers and Liners for Injections” (YBB00332004-2015). The number of released particles shall not exceed 20.

Puncture Force

Take 10 stoppers and measure the puncture force according to Method 1 in “Determination of Puncture Force of Stoppers and Liners for Injections” (YBB00322004-2015). The average puncture force shall not exceed 75 N, and no individual stopper shall exceed 80 N. No stopper shall be pushed into the vial during puncturing.

Sealing Performance and Retention of Puncture Device

Take 10 stoppers, place them in a steam sterilizer (without immersion in water) at 121 ℃ ± 2 ℃ for 30 minutes, and cool to room temperature. Separately, take 10 stoppers and corresponding glass injection vials, fill with water to the marked volume, seal with the stoppers, and cap with matching aluminum seals. Using the puncture device illustrated in Figure 1 of YBB00322004-2015, vertically puncture the stopper. Hang a 0.5 kg weight on the device for 4 hours. The puncture device shall not be dislodged, and there shall be no leakage at the puncture site.

Ash Content

Weigh 1.0 g of the sample and determine ash content according to “Determination of Ash in Rubber” (YBB00262005-2015). Residual ash shall not exceed 45%.

Volatile Sulfides

Determine volatile sulfides according to “Determination of Volatile Sulfides” (YBB00302004-2015). Results shall meet the specified requirements.

Insoluble Particles

Take an amount of intact stoppers equivalent to 100 cm² surface area and determine insoluble particles according to the “Determination of Insoluble Particles in Packaging Materials” (YBB00272004-2015) for pharmaceutical stoppers. The number of particles ≥10 μm shall not exceed 30 per 1 ml, and the number of particles ≥25 μm shall not exceed 3 per 1 ml.

Chemical Properties

Preparation of Test Solution: Take intact stoppers equivalent to 200 cm² surface area. Immerse in water at a ratio of 1:2 (sample surface area cm² : water ml), boil for 5 minutes, cool, rinse 5 times with the same volume of water. Transfer to a conical flask, add equal volume of water, and sterilize in an autoclave at 121 ℃ ± 2 ℃ for 30 minutes. Cool to room temperature to obtain the test solution. Prepare a blank solution in the same manner for comparison.

Clarity and Color: Examine the test solution according to the Chinese Pharmacopoeia (2015 Edition, General Rules 0902 and 0901). The solution shall be clear and colorless. If turbidity is observed, it shall not exceed the standard turbidity of No. 2. If coloration is observed, it shall not be deeper than Yellow-Green No. 5 standard solution.

pH Change: Measure 20 ml each of the test solution and blank solution, add 1 ml of potassium chloride solution (1:1000), and determine pH according to Chinese Pharmacopoeia (2015 Edition, General Rule 0631). The difference shall not exceed 1.0.

Absorbance: Measure the UV-Vis spectrum of the test solution (220–360 nm) with the blank as reference, according to Chinese Pharmacopoeia (2015 Edition, General Rule 0401). The maximum absorbance shall not exceed 0.1.

Oxidizable Substances: Precisely measure 20 ml of the test solution, add 20 ml of 0.002 mol/L potassium permanganate solution and 2 ml of dilute sulfuric acid, boil for 3 minutes, cool, add 0.1 g potassium iodide, and stand in the dark for 5 minutes. Titrate with 0.01 mol/L sodium thiosulfate to light brown, then add 5 drops of starch indicator and titrate to colorless. Perform the same procedure on the blank. The difference in titrant consumption shall not exceed 3.0 ml.

Non-volatile Residue: Measure 100 ml each of the test solution and blank, evaporate to dryness in pre-weighed dishes at 105 ℃ until constant weight. The difference shall not exceed 4.0 mg.

Heavy Metals: Measure 10 ml of test solution, add 2 ml of acetate buffer (pH 3.5), and determine heavy metals according to Chinese Pharmacopoeia (2015 Edition, General Rule 0821, Method 1). Heavy metals shall not exceed 1 ppm.

Ammonium Ion: Measure 10 ml of test solution, add 2 ml of alkaline mercuric iodide-potassium solution, stand for 15 minutes. No coloration shall occur. If coloration occurs, compare with control solution prepared from 31.5 mg ammonium chloride in 1000 ml ammonium-free water. The coloration shall not be deeper than 0.0002%.

Zinc Ion: Filter the test solution through a 0.45 μm membrane. Take 10 ml of filtrate, add 1 ml of 2 mol/L HCl and 3 drops of freshly prepared potassium ferrocyanide solution. No turbidity shall occur. Compare with control solution prepared from 44 mg zinc sulfate heptahydrate in 1000 ml water; the coloration shall not be deeper than 0.0003%.

Conductivity: Measure the conductivity of the test solution within 5 hours of preparation. The blank shall not exceed 3.0 μS/cm (20 ℃ ± 1 ℃). The test solution shall not exceed 40.0 μS/cm. Temperature correction shall be applied if measurement is not at 20 ℃ ± 1 ℃.

Biological Tests

Pyrogen Test: Mix the stoppers in proportion with sodium chloride injection according to irregular shape, sterilize in autoclave at 115 ℃ ± 2 ℃ for 30 minutes, and test according to “Pyrogen Test” (YBB00022003-2015). Results shall meet the requirements.

Acute Systemic Toxicity Test: Treat as above and test according to “Acute Systemic Toxicity Test” (YBB00042003-2015). Results shall meet the requirements.

Hemolysis Test: Determine according to “Hemolysis Test” (YBB00032003-2015). Hemolysis rate shall meet the requirements.

Appendix I Inspection Rules

1.Product inspection is divided into full inspection and partial inspection.

2.Full inspection shall be performed under the following circumstances:

-Product registration.

-Reproduction after a major quality incident.

3.Inspection of items excluding “**” shall be performed in the following cases:

-Supervision sampling.

-Resumption of production after discontinuation.

4.After product registration approval, if the raw material source, additives, and manufacturing process remain unchanged, inspection may exclude items marked “*” and “**”.

5.Appearance inspection shall follow “Sampling Procedures for Inspection by Attributes – Part 1: Sampling Plans Indexed by Acceptable Quality Level (AQL)” GB/T 2828.1-2012. Inspection items, levels, and acceptance quality limits are specified in Table 1.

Table 1 Classification of Appearance Defects, Inspection Level and Acceptance Quality Limit (AQL)
Inspection Item	Appearance
Inspection Level	I
Acceptance Quality Limit (AQL)	0.4	1.5	6.5
Classification of Appearance Defects	A TYPE	B TYPE	C TYPE
	· Stains or foreign matter within the needle puncture area or on surfaces in contact with the contents; · Bubbles or cracks within the needle puncture area or on the sealing surface.	· Stains, foreign matter, rubber threads, rubber particles, sponge-like defects, or burrs on the surface; · Roughness at the stopper neck portion; · Obvious rubber deficiency (short shot).	· Incompleteness or serrated edges caused by trimming; · Marks caused by the mold; · Noticeably uneven coloration.

Appendix II Reference Dimensions

According to the specifications and sizes of glass injection vials, classification management shall be implemented, and the corresponding dimensions of the vial finish and rubber stopper shall be standardized. Specific requirements are provided in Table 2.

Table 2 Specifications of Injection Vials and Corresponding Rubber Stopper Dimensions
Injection Vial Specification (ml)	Rubber Stopper Dimension (Crown Diameter, mm)
＜50	20,13
50,100	32,28,26,24,23,22,20
250	32,28,26,24,23,22
500	32,28,26,24
1000	32,28