Law Shirley, Charbonneau Flay, Iazzetta John, Perks William, Ma Nathan H, Walker Scott E
, DipPharmTech, is a Research Assistant in Quality Control in the Department of Pharmacy, Sunnybrook Health Sciences Centre, Toronto, Ontario.
, RPh, BSc(Pharm), is the Manager, Pharmacy of the Odette Cancer Centre, Sunnybrook Health Sciences Centre, Toronto, Ontario.
Can J Hosp Pharm. 2021 Winter;74(1):57-69. Epub 2021 Jan 1.
The availability of generic versions of bortezomib raises questions about the reliability of extrapolating stability data from one brand to another.
To evaluate the stability of bortezomib formulations available from Janssen, Teva Canada, Actavis Pharma, Dr. Reddy's Laboratories, Apotex, and MDA, reconstituted with 0.9% sodium chloride (normal saline) to produce solutions of either 1.0 or 2.5 mg/mL and stored over at least 21 days under refrigeration (4°C) or at room temperature (either 23°C or 25°C) in the manufacturer's original glass vials or in polypropylene syringes.
On study day 0, solutions with concentration 1.0 mg/mL or 2.5 mg/mL of the Teva, Actavis, Dr. Reddy's, Apotex, and MDA generic formulations were prepared. Three units of each type of container (glass vials and syringes) were stored at 4°C and 3 units at room temperature. Concentration and physical inspection were completed on at least 8 study days (including day 0) over a 21- to 84-day study period. Bortezomib concentrations were determined by a validated stability-indicating liquid chromatographic method with ultraviolet detection. The end point of these studies was the time to reach 90% of the initial concentration (T-90) with 95% confidence, which is expressed as "T-90", where CI refers to the confidence interval. In addition to estimating the T-90, differences in stability among products from all manufacturers were compared using multiple linear regression. Previously published data for the Janssen product were included in the overall comparisons.
In all of the studies, the analytical method separated degradation products from bortezomib, such that the concentration of bortezomib was measured specifically, accurately (deviations < 2.5%), and reproducibly (average replicate error 2.5%). During all studies, solutions retained more than 94% of the initial concentration at 4°C. The T-90 exceeded the study period for all formulations under all combinations of concentration, container, and temperature, except the 84-day study for the MDA product. Multiple linear regression showed no significant differences among manufacturers ( = 0.57).
In this study, formulations of bortezomib currently marketed in Canada (by Janssen, Teva Canada, Actavis Pharma, Dr. Reddy's Laboratories, Apotex, and MDA) were pharmaceutically equivalent and interchangeable. Given that there was no difference in stability related to manufacturer, nominal concentration, or container, we conclude that these formulations are physically and chemically stable for at least 35 days under refrigeration and at least 25 days at room temperature.
硼替佐米通用型制剂的可得性引发了关于从一个品牌推断稳定性数据到另一个品牌的可靠性问题。
评估杨森公司、加拿大梯瓦公司、阿特维斯制药公司、雷迪博士实验室、奥贝泰克公司和MDA公司提供的硼替佐米制剂的稳定性，用0.9%氯化钠（生理盐水）复溶以制备1.0或2.5mg/mL的溶液，并在制造商原装玻璃瓶或聚丙烯注射器中于冷藏（4°C）或室温（23°C或25°C）下储存至少21天。
在研究第0天，制备梯瓦、阿特维斯、雷迪博士、奥贝泰克和MDA通用型制剂浓度为1.0mg/mL或2.5mg/mL的溶液。每种类型的容器（玻璃瓶和注射器）各三个单位在4°C储存，三个单位在室温储存。在21至84天的研究期间，至少在8个研究日（包括第0天）完成浓度和外观检查。硼替佐米浓度通过经验证的带有紫外检测的稳定性指示液相色谱法测定。这些研究的终点是达到初始浓度90%（T-90）的时间，置信度为95%，表示为“T-90”，其中CI指置信区间。除了估计T-90外，还使用多元线性回归比较了所有制造商产品之间的稳定性差异。将杨森产品先前发表的数据纳入总体比较。
在所有研究中，分析方法将降解产物与硼替佐米分离，从而能够特异性、准确地（偏差<2.5%）和可重复地（平均重复误差2.5%）测量硼替佐米的浓度。在所有研究期间，溶液在4°C下保留了超过94%的初始浓度。除MDA产品的84天研究外，在浓度、容器和温度的所有组合下，所有制剂的T-90均超过研究期。多元线性回归显示各制造商之间无显著差异（P = 0.57）。
在本研究中，加拿大目前市场上销售的硼替佐米制剂（杨森、加拿大梯瓦、阿特维斯制药、雷迪博士实验室、奥贝泰克和MDA）在药学上等效且可互换。鉴于与制造商、标称浓度或容器相关的稳定性无差异，我们得出结论，这些制剂在冷藏条件下至少35天、室温下至少25天在物理和化学上是稳定的。
