China National Standard for PET Bottles for Oral Solid Preparation (YBB00262002-2015)

This standard applies to plastic bottles for oral solid preparations manufactured by the injection stretch blow molding (ISBM) process, using polyethylene terephthalate (PET) as the main raw material.

Appearance
Take an appropriate quantity of the product and visually inspect it under bright natural light. The bottles shall have a uniform and consistent color without any obvious color differences. The surface of the bottle shall be smooth and flat, free from deformation and noticeable scratches. There shall be no pinholes, oil stains, or air bubbles. The bottle mouth shall be even and smooth.

Identification
(1) Infrared Spectroscopy
Take an appropriate quantity of the product and determine it in accordance with the Packaging Material Infrared Spectroscopy Method (YBB00262004-2015), Method IV. The spectrum shall be essentially consistent with the reference spectrum.

(2) Density
Take 2g of the product, add 100 mL of water, reflux for 2 hours, allow to cool, then dry at 80°C for 2 hours. Determine the density in accordance with the Density Determination Method (YBB00132003-2015). The result shall be 1.31–1.38 g/cm³.

Leak Tightness
Take an appropriate quantity of the product. Place a suitable number of glass beads into each bottle, then tightly close the cap (for test bottles with screw caps, tighten the bottle and cap using a torque wrench; the torque shall comply with Table 1). Place the bottles in a container equipped with a vacuum device, immerse them in water, evacuate to a vacuum level of 27 kPa, and maintain for 2 minutes. No water ingress or bubble formation shall be observed inside the bottles.

Table 1 Torque between Bottle and Cap
Cap Diameter (mm)	Torque (N·cm)
15-22	59-78
23-48	98-118
49-70	147-176

 

Oscillation Test
Take an appropriate quantity of the product. Fill each bottle with acidic water as an indicator, then tightly close the cap (for test bottles with screw caps, tighten the bottle and cap using a torque wrench; the torque shall comply with Table 1). Wrap bromophenol blue test paper (prepared by immersing filter paper in bromophenol blue test solution diluted fivefold, removing it after saturation and drying) tightly around the neck of the bottle. Place the bottles on a shaker (oscillation frequency: 200 ± 10 cycles per minute) and shake for 30 minutes. The bromophenol blue test paper shall show no color change.

Water Vapor Transmission Rate
Take an appropriate quantity of the product and determine it in accordance with the Water Vapor Transmission Rate Determination Method (YBB00092003-2015), Method III (2), under the conditions of temperature 25 °C ± 2 °C and relative humidity 95% ± 5%. The result shall not exceed 100 mg/24 h·L.

Acetaldehyde
Determine in accordance with the Acetaldehyde Determination Method (YBB00282004-2015), Method I. The content shall not exceed 0.0002% (2 parts per ten million).

Residue on Ignition
Take 2.0 g of the product and examine it as prescribed (Chinese Pharmacopoeia 2015 Edition, General Chapter 0841). The residue remaining shall not exceed 0.1%.

Extractables Test

Preparation of Test Solutions:
Take three portions of the product, each with an internal surface area of 600 cm² (cut into small pieces 5 cm in length and 0.3 cm in width), and place them separately into stoppered conical flasks. Add an appropriate amount of water, shake to wash the pieces, discard the water, and repeat this operation twice. After drying at 30–40 °C, immerse each portion in 200 mL of water (70 °C ± 2 °C), 65% ethanol (70 °C ± 2 °C), and n-hexane (58 °C ± 2 °C), respectively, for 24 hours. Remove and allow to cool to room temperature, then make up to the original volume with the same batch of test solvent to obtain the test solutions. Use the same batch of water, 65% ethanol, and n-hexane as blank solutions. Perform the following tests:

Oxidizable Substances
Accurately measure 20 mL of the aqueous test solution, accurately add 20 mL of potassium permanganate titrant (0.002 mol/L) and 1 mL of dilute sulfuric acid, boil for 3 minutes, and cool rapidly. Add 0.1 g of potassium iodide and allow to stand in the dark for 5 minutes. Titrate with sodium thiosulfate titrant (0.01 mol/L). Near the endpoint, add 5 drops of starch indicator solution and continue titration until colorless. Perform the same procedure using the aqueous blank solution. The difference in the volume of sodium thiosulfate titrant (0.01 mol/L) consumed between the two shall not exceed 1.5 mL.

Non-Volatile Residue
Separately take 50 mL each of the aqueous, 65% ethanol, and n-hexane test solutions and the corresponding blank solutions, and place them into tared evaporating dishes. Evaporate to dryness on a water bath, then dry at 105 °C for 2 hours. After cooling, weigh accurately.

The difference between the non-volatile residue of the aqueous test solution and its blank shall not exceed 12.0 mg.

The difference between the non-volatile residue of the 65% ethanol test solution and its blank shall not exceed 50.0 mg.

The difference between the non-volatile residue of the n-hexane test solution and its blank shall not exceed 75.0 mg.

Heavy Metals
Accurately measure 20 mL of the aqueous test solution, add 2 mL of acetate buffer solution (pH 3.5), and determine in accordance with the Heavy Metals Test (Chinese Pharmacopoeia 2015 Edition, General Chapter 0821, Method I). The heavy metals content shall not exceed 0.0001% (1 part per million).

Microbial Limits
Take several bottles of the product and add sodium chloride injection solution to half of the nominal capacity. Tightly close the caps and shake for 1 minute to obtain the test solution. Filter the test solution through a membrane and examine it as prescribed (Chinese Pharmacopoeia 2015 Edition, General Chapters 1105 and 1106).

Total aerobic microbial count: not more than 1000 cfu per bottle.

Total yeasts and molds: not more than 100 cfu per bottle.

Escherichia coli: shall not be detected per bottle.

Abnormal Toxicity*
Take several bottles of the product, wash them thoroughly with water, then take 500 cm² (based on internal surface area), cut into pieces, and add 50 mL of sodium chloride injection solution. Sterilize in an autoclave at 110 °C for 30 minutes, then remove and allow to cool for later use. Use the same batch of sodium chloride injection solution as the blank. Administer by intravenous injection and examine as prescribed (Chinese Pharmacopoeia 2015 Edition, General Chapter 1141). The result shall comply with the requirements.

Storage
Seal the inner packaging of the solid bottles with pharmaceutical polyethylene plastic bags and store in a dry and clean place.

Appendix I Inspection Rules

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

2.A full inspection shall be carried out in accordance with the requirements of this standard under any of the following circumstances:
(1) Product registration.
(2) Resumption of production after a major quality incident.
(3) Supervisory sampling inspection.
(4) Resumption of production after a production suspension.

3.After product registration approval, if there are no changes in raw material origin, additives, production process, etc., the pharmaceutical packaging material manufacturer and user enterprises may conduct inspections in accordance with the requirements of this standard, excluding the items marked with “*”.

4.The inspections for appearance, leak tightness, oscillation test, water vapor transmission rate, and microbial limits shall be carried out in accordance with the Sampling Procedures for Inspection by Attributes — Part 1: Sampling Plans Indexed by Acceptance Quality Limit (AQL) for Lot-by-Lot Inspection (GB/T 2828.1-2012). The inspection items, inspection levels, and acceptance quality limits are shown in Table 2.

Table 2 Inspection Items, Inspection Levels, and Acceptance Quality Limits
Inspection Items	Inspection Levels	Acceptance Quality Limits
Appearance	I	4.0
Leak Tightness	S-3	4.0
Oscillation Test	S-3	2.5
Water Vapor Transmission Rate	S-2	4.0
Microbial Limits	S-1	1.5

 

Note:

1.Items marked with * shall be inspected at least once every six months.

2.Caps used with the bottles may be made of different materials as needed. They shall be tested for extractables and abnormal toxicity in accordance with the standard, and shall comply with the relevant requirements of these items.