中国药学杂志

Sampling time/month	Stability condition	Detection index	Detection method
0、3、6、12	Accelerated stability(25±2)℃	Appearance, visible foreign matter, pH, insoluble particles, purity, polymers, residual aluminum, prekallikrein activator, protein content, and abnormal toxicity	Ch.P 2020
0、6、12、18、24	Long-term stability (2-8 ℃)	Appearance, visible foreign matter, pH, insoluble particles, purity, polymers, residual aluminum, prekallikrein activator, protein content, and abnormal toxicity	Ch.P 2020

Sampling time/month	Stability condition	Detection index	Detection method
0、3、6、12	Accelerated stability(25±2)℃	Appearance, visible foreign matter, pH, insoluble particles, purity, polymers, residual aluminum, prekallikrein activator, protein content, and abnormal toxicity	Ch.P 2020
0、6、12、18、24	Long-term stability (2-8 ℃)	Appearance, visible foreign matter, pH, insoluble particles, purity, polymers, residual aluminum, prekallikrein activator, protein content, and abnormal toxicity	Ch.P 2020

Detection index	Quality standard	0 month	6 months	12 months	18 months	24 months
Appearance	Slightly viscous, yellow or green to brown clear liquid, should not appear cloudy	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity
Visible foreign matter	Comply with regulations	Qualified	Qualified	Qualified	Qualified	Qualified
Insoluble particles	≤6 000 (≥10 μm)	15	16	8	12	15
Insoluble Particles	≤600 (≥25 μm)	1	0	2	1	1
pH	6.4-7.4	7.0	7.0	7.0	6.9	7.0
Purity/%	≥96.0	97.6	97.7	97.6	97.5	97.6
Polymers/%	≤5.0	2.1	2.3	2.4	2.3	2.3
Residual aluminum content/μg·L^-1	≤200	12	9	14	12	12
Protein content/%	95.0-110.0 of the marked amount	101.0	101.1	100.9	101.2	101.1
Prekallikrein activator/IU·mL^-1	≤35	3	1	2	1	1
Abnormal toxicity	Should comply with regulations	Qualified	Qualified	Qualified	Qualified	Qualified

Detection index	Quality standard	0 month	6 months	12 months	18 months	24 months
Appearance	Slightly viscous, yellow or green to brown clear liquid, should not appear cloudy	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity
Visible foreign matter	Comply with regulations	Qualified	Qualified	Qualified	Qualified	Qualified
Insoluble particles	≤6 000 (≥10 μm)	15	16	8	12	15
Insoluble Particles	≤600 (≥25 μm)	1	0	2	1	1
pH	6.4-7.4	7.0	7.0	7.0	6.9	7.0
Purity/%	≥96.0	97.6	97.7	97.6	97.5	97.6
Polymers/%	≤5.0	2.1	2.3	2.4	2.3	2.3
Residual aluminum content/μg·L^-1	≤200	12	9	14	12	12
Protein content/%	95.0-110.0 of the marked amount	101.0	101.1	100.9	101.2	101.1
Prekallikrein activator/IU·mL^-1	≤35	3	1	2	1	1
Abnormal toxicity	Should comply with regulations	Qualified	Qualified	Qualified	Qualified	Qualified

Detection index	Quality standard	0 month	3 months	6 months	12 months
Appearance	Slightly viscous, yellow or green to brown clear liquid, should not appear cloudy	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity
Visible foreign matter	Comply with regulations	Qualified	Qualified	Qualified	Qualified
Insoluble particles	≤6 000 (≥10 μm)	16	9	12	15
Insoluble particles	≤ 600 (≥25 μm)	1	2	1	1
pH	6.4-7.4	7.0	7.0	7.0	7.0
Purity/%	≥96.0	97.6	97.6	97.5	97.6
Polymers/%	≤5.0	2.1	2.2	2.4	2.1
Residual aluminum content/μg·L^-1	≤200	12	15	22	11
Protein content/%	95.0-110.0 of the marked amount	101.0	100.7	101.1	101.1
Prekallikrein activator/IU·mL^-1	≤35	1	1	2	1
Abnormal toxicity	Comply with regulations	Qualified	Qualified	Qualified	Qualified

Detection index	Quality standard	0 month	3 months	6 months	12 months
Appearance	Slightly viscous, yellow or green to brown clear liquid, should not appear cloudy	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity
Visible foreign matter	Comply with regulations	Qualified	Qualified	Qualified	Qualified
Insoluble particles	≤6 000 (≥10 μm)	16	9	12	15
Insoluble particles	≤ 600 (≥25 μm)	1	2	1	1
pH	6.4-7.4	7.0	7.0	7.0	7.0
Purity/%	≥96.0	97.6	97.6	97.5	97.6
Polymers/%	≤5.0	2.1	2.2	2.4	2.1
Residual aluminum content/μg·L^-1	≤200	12	15	22	11
Protein content/%	95.0-110.0 of the marked amount	101.0	100.7	101.1	101.1
Prekallikrein activator/IU·mL^-1	≤35	1	1	2	1
Abnormal toxicity	Comply with regulations	Qualified	Qualified	Qualified	Qualified

Detection index	Intake standard /μg·d^-1	Source of intake standard	Maximum dosage of albumin product	Calculation of detection standard/μg·mL^-1	Content standard /μg·mL^-1
Molybdenum	≤25	[20]	75 g·d^-1,375 mL·d^{-1 2)}	25÷375=0.067	0.06
Nickel	≤25		75 g·d^-1,375 mL·d^{-1 2)}	25÷375=0.067	0.06
Methylbenzene	≤8 900¹⁾	[21]	75 g·d^-1,375 mL·d^{-1 2)}	8 900÷375=23.7	23
Cyclohexane	≤38 800¹⁾		75 g·d^-1,375 mL·d^{-1 2)}	38 800÷375=103.5	103

Detection index	Intake standard /μg·d^-1	Source of intake standard	Maximum dosage of albumin product	Calculation of detection standard/μg·mL^-1	Content standard /μg·mL^-1
Molybdenum	≤25	[20]	75 g·d^-1,375 mL·d^{-1 2)}	25÷375=0.067	0.06
Nickel	≤25		75 g·d^-1,375 mL·d^{-1 2)}	25÷375=0.067	0.06
Methylbenzene	≤8 900¹⁾	[21]	75 g·d^-1,375 mL·d^{-1 2)}	8 900÷375=23.7	23
Cyclohexane	≤38 800¹⁾		75 g·d^-1,375 mL·d^{-1 2)}	38 800÷375=103.5	103

Detection index	Standard	Long-term stability (24 months)	Accelerated stability (12 months)
Molybdenum	≤0.06	0.002±0.000	0.003±0.001
Nickel	≤0.06	0.02±0.00	0.02±0.00
Methylbenzene	≤23	Not detected(detection limit:0.01)	Not detected(detection limit:0.01)
Cyclohexane	≤103	0.001±0.001	0.003±0.001

Detection index	Standard	Long-term stability (24 months)	Accelerated stability (12 months)
Molybdenum	≤0.06	0.002±0.000	0.003±0.001
Nickel	≤0.06	0.02±0.00	0.02±0.00
Methylbenzene	≤23	Not detected(detection limit:0.01)	Not detected(detection limit:0.01)
Cyclohexane	≤103	0.001±0.001	0.003±0.001

Sample	Detection value /Pa	Detection value of 3 μm control product/Pa	Result determination
1	24.1	33.8	Qualified
2	23.5	33.8	Qualified
3	24.0	33.8	Qualified
4	22.6	33.8	Qualified
5	23.6	33.8	Qualified

Sample	Detection value /Pa	Detection value of 3 μm control product/Pa	Result determination
1	24.1	33.8	Qualified
2	23.5	33.8	Qualified
3	24.0	33.8	Qualified
4	22.6	33.8	Qualified
5	23.6	33.8	Qualified

Object	Challenge bottle	Positive control	Negative control
Grow bacteria or not	+	-	+	-	+	-
Number of bottles	0	5	5	0	0	5

Object	Challenge bottle	Positive control	Negative control
Grow bacteria or not	+	-	+	-	+	-
Number of bottles	0	5	5	0	0	5

人血白蛋白注射剂与环烯烃聚合物包装材料的相容性及包装完整性研究

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李莎 ¹ , 张齐明 ² , 雷晨瑶 ² , 魏密 ¹ , 韩祥东 ²^,^*

中国药学杂志 | 论著 2024,59(12): 1129-1134

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中国药学杂志 | 论著 2024, 59(12): 1129-1134

人血白蛋白注射剂与环烯烃聚合物包装材料的相容性及包装完整性研究

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李莎¹, 张齐明², 雷晨瑶², 魏密¹, 韩祥东²^,^*

作者信息

¹ 兰州交通大学生物与制药工程学院, 兰州 730070

² 国药集团兰州生物制药有限公司, 兰州 730046

李莎,女,博士,副教授研究方向:生物工程应用与生物制品研究

通讯作者:

*韩祥东,男,硕士,高级工程师研究方向:血液制品生产与质量控制研究 Tel:(0931)8316189

Compatibility and Packaging Integrity between Human Albumin Injection and Container of Cyclic Olefin Polymer

Sha LI¹, Qiming ZHANG², Chenyao LEI², Mi WEI¹, Xiangdong HAN²^,^*

Affiliations

¹ School of Biological and Pharmaceutical Engineering, Lanzhou Jiaotong University, Lanzhou 730070, China

² Sinopharm Lanzhou Biopharmaceuticals Co., Ltd, Lanzhou 730046, China

出版时间: 2024-06-22 doi: 10.11669/cpj.2024.12.008

文章导航

摘要

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目的探索环烯烃聚合物(COP)包材应用于人血白蛋白制品包装的可行性。方法使用COP瓶分装储存人血白蛋白制品,在长期稳定性(2~8 ℃,24个月)和加速稳定性[(25±2)℃,12个月]试验条件下,分析制品的关键质量指标和包材的浸出物指标,并检测COP包材的密封完整性。结果在两种试验条件下,制品的外观、可见异物、不溶性微粒、pH、纯度、多聚体、铝残留量、蛋白含量、激肽释放酶原激活剂和毒性指标都在质量标准范围内,符合药典要求。制品中,COP包材可能产生的浸出物钼、镍、甲苯、环己烷的含量均低于质量标准限值。COP瓶与卤化丁基橡胶塞、铝塑组合盖组装的人血白蛋白包装容器具有良好的密封完整性。结论初步试验表明COP可应用于人血白蛋白的储存和运输。

关键词

药包材 / 环烯烃聚合物 / 人血白蛋白 / 药品质量

Abstract

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OBJECTIVE To explore the feasibility of using cyclic olefin polymer (COP) as packaging material for human albumin products. METHODS Human albumin products were stored in COP bottles. Under the conditions of long-term stability (2-8 ℃ for 24 months) and accelerated stability [(25±2) ℃ for 12 months], the key quality indexes of albumin and the probable extracts of COP material were analyzed, and the seal integrity of COP packages was tested. RESULTS Under both test conditions, the appearance, visible foreign matter, numbers of insoluble particles, pH, purity, polymer content, residual aluminum content, protein content, activity of prekallikrein activator and abnormal toxicity of the albumin products all conformed to the quality standards and met the requirements of Chinese Pharmacopoeia. In the products, the contents of molybdenum, nickel, methylbenzene, and cyclohexane that may be produced by COP bottles were all lower than the quality standard limits. Moreover, the human albumin packaging container assembled by COP bottle, halogenated butyl rubber plug and aluminum-plastic combination cap showed excellent package integrity. CONCLUSION COP can be used in the storage and transport of human albumin.

Key words

pharmaceutical packaging material / cyclic olefin polymer / human albumin / drug quality

引用本文

李莎, 张齐明, 雷晨瑶, 魏密, 韩祥东. 人血白蛋白注射剂与环烯烃聚合物包装材料的相容性及包装完整性研究. 中国药学杂志, 2024 , 59 (12) : 1129 -1134 . DOI: 10.11669/cpj.2024.12.008

Sha LI, Qiming ZHANG, Chenyao LEI, Mi WEI, Xiangdong HAN. Compatibility and Packaging Integrity between Human Albumin Injection and Container of Cyclic Olefin Polymer[J]. Chinese Pharmaceutical Journal, 2024 , 59 (12) : 1129 -1134 . DOI: 10.11669/cpj.2024.12.008

正文

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药包材是直接接触药品的包装材料和容器^[1],我国的药品包装材料都严格执行相关标准^[2-3]。玻璃材料是最常用的药包材,一直以来,国内外许多无菌注射药品都采用中性硼硅玻璃瓶作为包装材料。其优点是成本低、阻隔性高、膨胀系数小、耐极冷极热性强、机械强度高、抗冲击性强、可消毒、不会产生严重环境污染等,尤其适合用于pH值偏酸、偏碱或对pH值变化敏感的水针制剂、生物制剂、疫苗和血液制品的分装储存^[4-6]。

人血白蛋白作为血液制品的主要品种,在临床治疗中有广泛的应用,主要适应证包括出血性休克、外伤性休克、烧伤、成人型呼吸窘迫综合征、肝硬化伴有腹水或水肿以及恶性肿瘤等^[7-9]。然而,人血白蛋白在玻璃瓶中长期储存的过程中,往往观察到制品中的铝元素含量逐渐上升,原因之一就是受玻璃瓶本身材质限制,以及温度、制品含有的枸橼酸离子等因素的影响,玻璃中的铝元素会逐渐释放到制品中^[10-12]。有研究表明,铝在人体内的过量积累,与包括阿尔茨海默病在内的多种疾病的发生具有相关性^[13-14]。因此,近年来,中硼硅玻璃用于血液制品包装材料的局限性日益凸显,国家和地方药检院多次市场抽检人血白蛋白制品,关注铝残留量等指标^[15]。国外厂家已经研究使用其他材质用于血液制品的包装,并已完成上市。与此同时,近年来,环烯烃聚合物(cyclic olefin polymers, COP)作为一种具有优越性能的新型包装材料也引起了市场的广泛关注。COP是一类具有环内碳碳双键的、非晶性透明高分子材料,由环烯烃单体(如降冰片烯)通过开环易位聚合(ROMP),再对聚合物中的不饱和双键进行氢化得到^[16-18]。

本研究首次将COP包材应用于人血白蛋白的分装储存,在长期稳定性(2~8 ℃)和加速稳定性[(25±2)℃]试验条件下,分析储存于COP瓶中的人血白蛋白关键质量指标及包材浸出物指标,检测COP瓶与卤化丁基橡胶塞、铝塑组合盖组装的人血白蛋白包装容器的密封完整性,以评估COP药包材应用于人血白蛋白分装储存的可行性,为后续国内血液制品行业包装材料的升级换代提供数据支持。

1 仪器及试药

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1.1 材料及试剂

人血白蛋白(批号:202111042,国药集团兰州生物制药有限公司);COP瓶(江苏永兴医药包装有限公司);药用卤化丁基橡胶塞(江苏华兰药用新材料股份有限公司);铝塑组合盖(上海久正医用包装材料有限公司);体积分数2% HNO₃溶液;1 mg·L^-1甲苯、环己烷标准溶液。

1.2 仪器

澄明度检测仪(YB-3型,天津市博宇通达仪器有限公司);pH计[S20型,梅特勒——托利多仪器(上海)有限公司];微粒分析仪(GWF-8JA型,天津天河分析仪器有限公司);电泳仪(G26型,INTERLAB);原子吸收光谱仪(PA900T型,PerkinElmer);酶标仪(MK3型,Thermo);自动定氮仪(Kjeltec 8400型,FOSS);电子秤(JM-B30002型用于豚鼠体质量称量,JM-B20002型用于小鼠体质量称量,诸暨超泽衡器);高效液相色谱仪(1260型)、电感耦合等离子体质谱仪(7850型)、气相色谱质谱联用仪(8890-5977B型)(美国Agilent公司);微泄漏密封性测试仪(Leak-S型,济南三泉中石实验仪器有限公司);生化培养箱(LRH-250F型,上海一恒科学仪器/科技有限公司)。

2 人血白蛋白关键质量指标分析

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2.1 试验方法

将人血白蛋白制品无菌分装至COP瓶中,开展长期稳定性(2~8 ℃,24个月)和加速稳定性[(25±2)℃,12个月]试验。检测分析不同储存时间的人血白蛋白制品关键质量指标(表1)。该部分检测分析由国药集团兰州生物制药有限公司QC实验室承担,因各指标均按照2020年版《中国药典》三部^[19]规定的方法进行检测,且所有检测方法均在实验室开展了精密度、专属性、定量限或检测限的方法学确认,证明了各检测方法在特定实验室条件下的适用性和检测结果的稳定性,故所有时间点的检测指标均只检测1次。

2.2 结果分析

2.2.1 长期稳定性试验条件下人血白蛋白制品的稳定性

采用无菌COP瓶分装储存人血白蛋白,在2~8 ℃条件下进行了24个月的长期稳定性试验,每隔6个月取样测定,pH、纯度、多聚体、铝残留量、蛋白含量及激肽释放酶原激活剂均无明显变化,可见异物和毒性指标也符合规定。所有检测指标都在质量标准范围内,符合药典要求(表2),表明人血白蛋白制品使用COP瓶在2~8 ℃保存过程中具有很好的稳定性。

2.2.2 加速稳定性试验条件下人血白蛋白制品的稳定性

采用无菌COP瓶分装储存人血白蛋白,在(25±2) ℃条件下进行了12个月的加速稳定性试验,每隔3个月取样测定,制品的pH值、纯度、多聚体、铝残留量、蛋白含量及激肽释放酶原激活剂均无明显变化,可见异物和毒性指标也符合规定。所有检测指标都在质量标准范围内,符合药典要求(表3),表明人血白蛋白制品使用COP瓶在(25±2) ℃保存过程中具有很好的稳定性。

3 COP包材浸出物分析

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3.1 试验方法

根据COP瓶生产过程所使用的原料和催化剂信息,确定需要进行检测分析的目标浸出物包括钼、镍、甲苯及环己烷。对上述长期稳定性和加速稳定性试验终点样品的COP包材浸出物进行检测,根据相关标准(表4),判断浸出物含量是否影响长期储存药品的安全性。

3.1.1 人血白蛋白中钼、镍含量的测定

参照《GB/T 37837-2019四极杆电感耦合等离子体质谱法通则》^[22],采用电感耦合等离子体质谱法(ICP-MS)测定。配制标准溶液,制作标准曲线。取人血白蛋白供试品1 mL加体积分数2% HNO₃溶液9 mL,涡旋混匀后静置4 h以上,以4 000 r·min^-1离心30 min,取上清,进样测定。

仪器工作参数:分析模式为全定量模式,反应池模式为He模式0.45 mL·min^-1,重复扫描100次,重复测定3次,样品引入60 s,测定时间40 s,样品引入泵速0.3 r·s^-1,积分时间0.3 s。

3.1.2 人血白蛋白中甲苯、环己烷含量的测定

采用气相色谱-质谱联用法(GC-MS)测定。

色谱条件:VF-624MS色谱柱(0.25 mm×30 mm,1.4 μm),载气为He(≥99.999%),流量1.5 mL·min^-1(恒流模式),进样口温度:200 ℃,辅助加热温度220 ℃,分流比25∶1,溶剂延迟2 min,柱升温程序:起始40 ℃保持6.5 min,以10 ℃·min^-1升温至200 ℃,保持10 min。

质谱条件:离子源为EI四极杆温度150 ℃,离子源温度230 ℃,扫描范围m/z 30~400,定量环温度100 ℃,传输线温度110 ℃,检测器为MSD。

3.2 结果分析

采用COP瓶分装的人血白蛋白在(25±2)℃和2~8 ℃条件下分别保存了12和24个月。检测结果显示,制品中钼、镍、甲苯及环己烷的含量均低于质量标准限值(表5),表现出良好的化学稳定性。

4 容器密封完整性分析

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采用无损的物理完整性测试方法^[23]进行检测:通过抽真空的方式检测包材系统密封完整性。检测点为长期稳定性开始和最终试验样品。

采用微生物侵入试验^[23]进行检测:即在COP瓶中灌注细菌培养基,密封后浸泡于大肠杆菌培养液中一定时间,检测培养基内是否长菌。

4.1 试验方法

4.1.1 真空衰减法

将不锈钢实体瓶阴性样品放入测试腔中,校准仪器。然后将阴性样品取出,再重新装载,打开流量计,模拟相当于3 μm孔径标准流量计差压。测试完成后,关闭流量计。再次取出阴性样品并重新装载,重复操作20次以上,直至最后测试6次差压值波动在2.5 Pa之内,表示差压平稳,即可进入正常测试。随机抽取5瓶人血白蛋白供试品进行测试,以3 μm孔径的流量计差压为标准,所有供试品差压小于该标准即符合要求。

4.1.2 微生物浸泡法

胰酪大豆胨液体培养基(TSB)接种大肠杆菌新鲜培养物,置于30~35 ℃培养24~48 h。培养基出现混浊时取样,用比浊法检测菌液浓度。当菌悬液浓度达到≥10⁶ CFU·mL^-1时备用。准备15个半量装载胰酪大豆胨液体培养基的COP瓶,随机抽取5瓶完全浸入菌液中,浸没时间不少于4 h。浸没结束后将COP瓶擦拭消毒,然后将每瓶来回翻转,确保容器的内表面和胶塞内表面跟培养基完全接触即为挑战瓶。另取5瓶不浸入菌液作阴性对照。另在剩余5瓶中接种0.1 mL的大肠杆菌(<100 CFU·mL^-1)作阳性对照。将挑战瓶、阳性对照瓶、阴性对照瓶一同放置在30~35 ℃培养7 d,观察瓶内培养基是否混浊长菌。如挑战瓶的污染数为0,阳性对照瓶混浊长菌,阴性对照瓶均无菌生长,则此次容器密封完整性试验合格。

4.2 结果分析

真空衰减法随机抽取5瓶人血白蛋白制品,差压均小于模拟3 μm孔径标准流量计差压(表6),且微生物浸泡法检测中,5瓶挑战瓶均未长菌(表7)。2种检测方法均表明COP瓶与卤化丁基橡胶塞和铝塑组合盖组装的人血白蛋白包装容器具有良好的密封完整性。

5 结论与讨论

收起

COP作为一种新型高分子材料,主要有以下特点:①高强度、高刚性,不易破损;②高耐热性,玻璃化温度达140~170 ℃,满足无菌工艺的要求;③原材料纯度高,可浸出物和可萃取物极少,可长期保持生物制品的纯度,从而更好地保障患者安全;④透明性和光泽度高,经高压蒸汽灭菌后仍能保持高透明性,满足生物制品后期外观检查等需要;⑤耐酸碱、耐有机溶剂,适用于各种pH的生物制品和药液储存;⑥气密性好,保证生物制品长期储存过程中的有效物质浓度稳定;⑦具有优异的挤出成型性及热成型性,保证了包材易于批量生产;⑧优良的抑菌性能。因此,COP作为包材能够满足生物制品生产工艺的需求,保障产品质量安全稳定,在生物医药领域具有潜在的应用价值^[24-25]。

本研究首次使用COP材质的西林瓶,在长期(2~8 ℃)和加速[(25±2) ℃]稳定性试验条件下储存人血白蛋白,监测到制品的质量指标均在合格范围内,且无异常趋势(表2~3)。试验终点检测人血白蛋白制品中是否存在COP包材生产过程中可能产生的浸出物钼、镍、甲苯和环己烷,测定结果也远低于质量标准限值(表5)。表明COP作为药包材,符合药品安全性要求。此外,传统的玻璃瓶使用的原材料为石英砂,因其自身特性,在长期储存药液的过程中会释放铝元素,影响药品质量和用药安全。本研究中,通过加速稳定性和长期稳定性试验,检测COP瓶储存的人血白蛋白注射剂中铝元素含量的变化情况,均显示其含量稳定,无升高趋势(表2~3)。相较于传统的玻璃瓶,COP材料成分明确且单一,不含铝元素,从根本上可以解决长期储存生物制品过程中,铝元素含量升高的风险。因此,本研究初步表明,COP作为一种新型材料可以应用于血液制品的储存和运输。

药包材长期接触药品,会直接影响药品在储存、运输环节的质量指标,因此,寻找成分更加明确、质量更加稳定的包装材料一直都是制药行业重点关注的领域。2014年8月4日,全球首个软袋白蛋白——Flexbumin获得了美国FDA批准,Flexbumin(USP,5%溶液)采用由4层特殊结构组成的专有Galaxy柔性容器包装,实现了白蛋白包材新的突破^[26]。而本研究首次将COP这一新型的高分子医用材料应用于人血白蛋白的包装和储存,为血液制品寻找新的包装材料提供了思路。

需要指出的是,本研究仅是针对COP用于人血白蛋白包装材料的初步探索,证明了COP材质良好的化学稳定性和应用于血液制品的初步可行性。为更加全面评估COP用于人血白蛋白及其他血液制品包装的安全性,还需按照国家相关法规要求,开展更加全面的研究和评价。

基金

收起

甘肃省青年科技基金计划资助(21JR7RA322)
兰州交通大学“大学生创新创业训练计划”项目资助(DC2410732CX0326)

参考文献

收起

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2024年第59卷第12期

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文章信息

doi: 10.11669/cpj.2024.12.008

接收时间：2023-12-13
首发时间：2025-11-25
出版时间：2024-06-22

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文章信息

作者

出版历史

收稿日期：2023-12-13

基金

甘肃省青年科技基金计划资助(21JR7RA322)

兰州交通大学“大学生创新创业训练计划”项目资助(DC2410732CX0326)

作者信息

¹ 兰州交通大学生物与制药工程学院, 兰州 730070

² 国药集团兰州生物制药有限公司, 兰州 730046

通讯作者:

*韩祥东,男,硕士,高级工程师研究方向:血液制品生产与质量控制研究 Tel:(0931)8316189

参考文献

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2种不同金属材料的力学参数

科 Family	属数 Number of genus	种数 Number of species	占总种数比例 Percentage of total species (%)	属 Genus	种数 Number of species	占总种数比例 Percentage of total species (%)
鹅膏菌科Amanitaceae	2	11	5.26	鹅膏菌属 Amanita	10	4.78
小菇科 Mycenaceae	2	12	5.74	丝盖伞属 Inocybe	5	2.39
多孔菌科 Polyporaceae	8	14	6.70	蜡蘑属 Laccaria	5	2.39
红菇科 Russulaceae	3	23	11.00	小皮伞属 Marasmius	6	2.87
				小菇属 Mycena	11	5.26
				光柄菇属 Pluteus	5	2.39
				红菇属 Russula	17	8.13
				栓菌属 Trametes	5	2.39

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RefWorks
TxT

Sampling time/month	Stability condition	Detection index	Detection method
0、3、6、12	Accelerated stability(25±2)℃	Appearance, visible foreign matter, pH, insoluble particles, purity, polymers, residual aluminum, prekallikrein activator, protein content, and abnormal toxicity	Ch.P 2020
0、6、12、18、24	Long-term stability (2-8 ℃)	Appearance, visible foreign matter, pH, insoluble particles, purity, polymers, residual aluminum, prekallikrein activator, protein content, and abnormal toxicity	Ch.P 2020

Sampling time/month

Stability condition

Detection index

Detection method

0、3、6、12

Accelerated stability(25±2)℃

Appearance, visible foreign matter, pH, insoluble particles, purity, polymers, residual aluminum, prekallikrein activator, protein content, and abnormal toxicity

Ch.P 2020

0、6、12、18、24

Long-term stability (2-8 ℃)

Appearance, visible foreign matter, pH, insoluble particles, purity, polymers, residual aluminum, prekallikrein activator, protein content, and abnormal toxicity

Ch.P 2020

Detection index	Quality standard	0 month	6 months	12 months	18 months	24 months
Appearance	Slightly viscous, yellow or green to brown clear liquid, should not appear cloudy	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity
Visible foreign matter	Comply with regulations	Qualified	Qualified	Qualified	Qualified	Qualified
Insoluble particles	≤6 000 (≥10 μm)	15	16	8	12	15
Insoluble Particles	≤600 (≥25 μm)	1	0	2	1	1
pH	6.4-7.4	7.0	7.0	7.0	6.9	7.0
Purity/%	≥96.0	97.6	97.7	97.6	97.5	97.6
Polymers/%	≤5.0	2.1	2.3	2.4	2.3	2.3
Residual aluminum content/μg·L^-1	≤200	12	9	14	12	12
Protein content/%	95.0-110.0 of the marked amount	101.0	101.1	100.9	101.2	101.1
Prekallikrein activator/IU·mL^-1	≤35	3	1	2	1	1
Abnormal toxicity	Should comply with regulations	Qualified	Qualified	Qualified	Qualified	Qualified

Detection index

Quality standard

0 month

6 months

12 months

18 months

24 months

Appearance

Slightly viscous, yellow or green to brown clear liquid, should not appear cloudy

Yellow clear
liquid, no
turbidity

Visible foreign matter

Comply with regulations

Qualified

Insoluble particles

≤6 000 (≥10 μm)

Insoluble Particles

≤600 (≥25 μm)

6.4-7.4

7.0

6.9

7.0

Purity/%

≥96.0

97.6

97.7

97.6

97.5

97.6

Polymers/%

≤5.0

2.1

2.3

2.4

2.3

Residual aluminum content/μg·L^-1

≤200

Protein content/%

95.0-110.0 of the marked amount

101.0

101.1

100.9

101.2

101.1

Prekallikrein activator/IU·mL^-1

≤35

Abnormal toxicity

Should comply with regulations

Qualified

Detection index	Quality standard	0 month	3 months	6 months	12 months
Appearance	Slightly viscous, yellow or green to brown clear liquid, should not appear cloudy	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity	Yellow clear liquid, no turbidity
Visible foreign matter	Comply with regulations	Qualified	Qualified	Qualified	Qualified
Insoluble particles	≤6 000 (≥10 μm)	16	9	12	15
Insoluble particles	≤ 600 (≥25 μm)	1	2	1	1
pH	6.4-7.4	7.0	7.0	7.0	7.0
Purity/%	≥96.0	97.6	97.6	97.5	97.6
Polymers/%	≤5.0	2.1	2.2	2.4	2.1
Residual aluminum content/μg·L^-1	≤200	12	15	22	11
Protein content/%	95.0-110.0 of the marked amount	101.0	100.7	101.1	101.1
Prekallikrein activator/IU·mL^-1	≤35	1	1	2	1
Abnormal toxicity	Comply with regulations	Qualified	Qualified	Qualified	Qualified

Detection index

Quality standard

0 month

3 months

6 months

12 months

Appearance

Slightly viscous, yellow or green to brown clear liquid, should not appear cloudy

Yellow clear
liquid, no
turbidity

Visible foreign matter

Comply with regulations

Qualified

Insoluble particles

≤6 000 (≥10 μm)

Insoluble particles

≤ 600 (≥25 μm)

6.4-7.4

7.0

Purity/%

≥96.0

97.6

97.5

97.6

Polymers/%

≤5.0

2.1

2.2

2.4

2.1

Residual aluminum content/μg·L^-1

≤200

Protein content/%

95.0-110.0 of the marked amount

101.0

100.7

101.1

Prekallikrein activator/IU·mL^-1

≤35

Abnormal toxicity

Comply with regulations

Qualified

Detection index	Intake standard /μg·d^-1	Source of intake standard	Maximum dosage of albumin product	Calculation of detection standard/μg·mL^-1	Content standard /μg·mL^-1
Molybdenum	≤25	[20]	75 g·d^-1,375 mL·d^{-1 2)}	25÷375=0.067	0.06
Nickel	≤25		75 g·d^-1,375 mL·d^{-1 2)}	25÷375=0.067	0.06
Methylbenzene	≤8 900¹⁾	[21]	75 g·d^-1,375 mL·d^{-1 2)}	8 900÷375=23.7	23
Cyclohexane	≤38 800¹⁾		75 g·d^-1,375 mL·d^{-1 2)}	38 800÷375=103.5	103

Detection
index

Intake standard
/μg·d^-1

Source of intake
standard

Maximum dosage of
albumin product

Calculation of detection
standard/μg·mL^-1

Content standard
/μg·mL^-1

Molybdenum

≤25

[20]

75 g·d^-1,375 mL·d^{-1 2)}

25÷375=0.067

0.06

Nickel

≤25

75 g·d^-1,375 mL·d^{-1 2)}

25÷375=0.067

0.06

Methylbenzene

≤8 900¹⁾

[21]

75 g·d^-1,375 mL·d^{-1 2)}

8 900÷375=23.7

Cyclohexane

≤38 800¹⁾

75 g·d^-1,375 mL·d^{-1 2)}

38 800÷375=103.5

103

Detection index	Standard	Long-term stability (24 months)	Accelerated stability (12 months)
Molybdenum	≤0.06	0.002±0.000	0.003±0.001
Nickel	≤0.06	0.02±0.00	0.02±0.00
Methylbenzene	≤23	Not detected(detection limit:0.01)	Not detected(detection limit:0.01)
Cyclohexane	≤103	0.001±0.001	0.003±0.001

Detection index

Standard

Long-term stability (24 months)

Accelerated stability (12 months)

Molybdenum

≤0.06

0.002±0.000

0.003±0.001

Nickel

≤0.06

0.02±0.00

Methylbenzene

≤23

Not detected(detection limit:0.01)

Cyclohexane

≤103

0.001±0.001

0.003±0.001

Sample	Detection value /Pa	Detection value of 3 μm control product/Pa	Result determination
1	24.1	33.8	Qualified
2	23.5	33.8	Qualified
3	24.0	33.8	Qualified
4	22.6	33.8	Qualified
5	23.6	33.8	Qualified

Sample

Detection
value
/Pa

Detection value
of 3 μm control
product/Pa

Result
determination

24.1

33.8

Qualified

23.5

33.8

Qualified

24.0

33.8

Qualified

22.6

33.8

Qualified

23.6

33.8

Qualified

Object	Challenge bottle	Positive control	Negative control
Grow bacteria or not	+	-	+	-	+	-
Number of bottles	0	5	5	0	0	5

Object

Challenge
bottle

Positive
control

Negative
control

Grow bacteria or not

Number of bottles