疫苗用氢氧化铝佐剂的质量研究

Quality study of aluminum hydroxide adjuvant for vaccine

目的 建立与国际标准一致的氢氧化铝佐剂的质量标准。方法 制备10批疫苗用氢氧化铝佐剂，按照中国药典2015年版进行外观、氯化钠含量、渗透压摩尔浓度、氢氧化铝含量、pH值的检测。参照欧洲药典第8版开展溶解度和内毒素含量检测，鉴别试验、沉降试验、无菌检查、牛血清白蛋白吸附力试验以及氯化物、硫酸盐、硝酸盐、铵盐、铁盐、砷盐、重金属等7项杂质13个检测项目的测定。参照丹麦铝佐剂对粒径、比表面积、等电点、黏度和抗原吸附率进行检测。对检定结果进行统计分析，初步确定与欧洲药典相关联的质量标准。结果 10批氢氧化铝佐剂的外观、无菌试验、内毒素含量、溶解度、鉴别试验、沉降试验、牛血清白蛋白吸附力、杂质和抗原吸附率的检测结果均合格。佐剂的氯化钠含量均值为1.01%，渗透压摩尔浓度均值为309 mOsmol/kg，氢氧化铝含量均值为4.7 mg/ml；佐剂灭菌前、后的pH值均值分别为6.3、5.8；佐剂的粒径DV50全部〈10 μm；平均比表面积为1 386 m^2/kg，等电点为10.3，黏度为1.2 mPa·s。检测结果均符合质控合格范围。结论 初步建立了符合欧洲药典第8版的氢氧化铝佐剂质量控制标准。

Objective To establish quality standards in line with international standards for aluminum hydroxide adjuvant. Methods Ten batches of aluminum hydroxide adjuvant for vaccine were prepared and tested for appearance, sodium chloride content, osmolality, aluminum hydroxide content, and pH according to Chinese pharmacopoeia 2015 edition. Adjuvants were measured for solubility and endotoxin content, and subjected to identification test, sedimentation test, sterility test, bovine serum albumin （BSA） adsorption test as well as 13 inspection items of seven reference （chloride, sulfate, nitrate, ammonium salt, iron salt, arsenic salt, heavy metal） impurity tests according to European pharmacopoeia 8th ed （EP）. The particle size, specific surface area, isoelectric point, viscosity and antigen adsorption rate were detected with reference to the Danish aluminum adjuvant. Test results were statistically analyzed to establish preliminary quality standards in accordance with EP. Results The adjuvants’ appearance, sterility, endotoxin content, solubility, identification test, sedimentation test, BSA adsorption test, and 7 impurity tests all qualified. The average sodium chloride content was 1.01%, average osmolality was 309 mOsmol/kg, average aluminum hydroxide content was 4.7 mg/ml, and average pH was 6.3 before and 5.8 after sterilization. The particle size （DV50） of adjuvant was 〈10 μm, average specific surface area was 1 386 m^2/kg, isoelectric point was 10.3, and viscosity was 1.2 mPa·s. All test results were within respective quality control range. Conclusion Preliminary quality control standards for aluminum hydroxide adjuvant are established in accordance with EP.