Erwinia chrysanthemi l-asparaginase (ErA) has been used for the treatment of acute lymphoblastic leukaemia (ALL) for decades, and its safety and efficacy have been well demonstrated. ErA drug substance and drug product contain a small proportion of acidic isoforms, with a known mechanism of formation, which have been shown to be minor conformational variants retaining enzymatic activity and function. Specifications for these acidic isoforms were set with an extremely limited data set, and with further manufacturing experience, it can now be demonstrated that they were set too tightly. Here, we consider the ability of the manufacturing process to meet the current acidic isoforms specifications, as well as clinical outcomes from drug product containing a higher proportion of isoforms. Compared with the historical clinical experience with the drug, there appeared to be no difference in the rate of adverse event reporting (e.g., hypersensitivity or other events) when drug product with relatively higher acidic isoforms was administered. ErA acidic isoforms comprise part of the ErA product and appear to have no clinical relevance, so a realignment of process capability and specification may be warranted. Biopharmaceutical developers should exercise caution when setting specifications with limited data, to avoid process capability pitfalls later.

腐 升-天冬酰胺酶（ErA）已用于治疗急性淋巴细胞白血病（ALL）数十年，其安全性和有效性已得到充分证明。ErA原料药和药物含有少量的酸性同工型，具有已知的形成机理，已证明是保留酶活性和功能的微小构象变体。这些酸性同工型的规格设定的数据集极为有限，并且具有进一步的制造经验，现在可以证明它们设定得太紧。在这里，我们考虑制造过程满足当前酸性同工型规格的能力，以及包含更高同工型比例的药品的临床结果。与该药物的历史临床经验相比，当服用具有相对较高酸性异构体的药物产品时，不良事件报告（例如，超敏反应或其他事件）的发生率似乎没有差异。ErA酸性同工型是ErA产品的一部分，似乎与临床没有关联，因此可能需要对工艺能力和规格进行重新调整。生物制药开发人员在使用有限的数据设置规格时应谨慎行事，以免日后出现工艺能力陷阱。