Chan Edwin, Maa Yuh-Fun, Overcashier David, Hsu Chung C
Pharmaceutical Processing and Technology Development.
PDA J Pharm Sci Technol. 2011 Jul-Aug;65(4):363-71. doi: 10.5731/pdajpst.2011.00759.
This study is to investigate the effect of headspace air pressure in pre-filled syringes on liquid leak (dripping) from the syringe needle upon needle shield removal. Drip tests to measure drip quantity were performed on syringes manually filled with 0.5 or 1.0 mL of various aqueous solutions. Parameters assessed included temperature (filling and test), bulk storage conditions (tank pressure and the type of the pressurized gas), solution composition (pure water, 0.9% sodium chloride, and a monoclonal antibody formulation), and testing procedures. A headspace pressure analyzer was used to verify the drip test method. Results suggested that leakage is indeed caused by headspace pressure increase, and the temperature effect (ideal gas expansion) is a major, but not the only, factor. The dissolved gases in the liquid bulk prior to or during filling may contribute to leakage, as these gases could be released into the headspace due to solubility changes (in response to test temperature and pressure conditions) and cause pressure increase. Needle shield removal procedures were found to cause dripping, but liquid composition played little role. Overall, paying attention to the processing history (pressure and temperature) of the liquid bulk is the key to minimize leakage. The headspace pressure could be reduced by decreasing liquid bulk storage pressure, filling at a higher temperature, or employing lower solubility gas (e.g., helium) for bulk transfer and storage. Leakage could also be mitigated by simply holding the syringe needle pointing upward during needle shield removal.
Substantial advances in pre-filled syringe technology development, particularly in syringe filling accuracy, have been made. However, there are factors, as subtle as how the needle shield (or tip cap) is removed, that may affect dosing accuracy. We recently found that upon removal of the tip cap from a syringe held vertically with needle pointed downwards, a small amount of solution, up to 3-4% of the 1 mL filled volume or higher for filled volume of <1 mL, leaked out from the needle. This paper identified the root causes of this problem and offered solutions from the perspectives of the syringe fill process and the end user procedure. The readers will benefit from this paper by understanding how each process step prior to and during syringe filling may affect delivery performance of the pre-filled syringe device.
本研究旨在调查预充式注射器中的顶空气压对取下针帽后注射器针头漏液（滴液）的影响。对手动填充0.5或1.0 mL各种水溶液的注射器进行了测量滴液量的滴液测试。评估的参数包括温度（填充和测试时）、大容量储存条件（罐压力和加压气体类型）、溶液成分（纯水、0.9%氯化钠和单克隆抗体制剂）以及测试程序。使用顶空气压分析仪验证滴液测试方法。结果表明，泄漏确实是由顶空气压升高引起的，温度效应（理想气体膨胀）是一个主要但不是唯一的因素。填充前或填充过程中液体中的溶解气体可能导致泄漏，因为这些气体可能由于溶解度变化（响应测试温度和压力条件）而释放到顶空并导致压力升高。发现取下针帽的过程会导致滴液，但液体成分的影响很小。总体而言，关注液体的加工历史（压力和温度）是最大限度减少泄漏的关键。可以通过降低液体大容量储存压力、在较高温度下填充或使用较低溶解度的气体（如氦气）进行大容量转移和储存来降低顶空气压。在取下针帽时将注射器针头向上握住也可以减轻泄漏。
预充式注射器技术开发取得了重大进展，特别是在注射器填充精度方面。然而，一些因素，如取下针帽（或尖端帽）的方式等很细微的因素，可能会影响给药精度。我们最近发现，当从垂直握持且针头向下的注射器上取下尖端帽时，会有少量溶液从针头漏出，对于1 mL的填充体积，漏出量可达填充体积的3 - 4%或更低；对于小于1 mL的填充体积，漏出量更高。本文从注射器填充过程和终端用户操作程序的角度确定了该问题的根本原因并提供了解决方案。读者将通过了解注射器填充前和填充过程中的每个步骤如何影响预充式注射器装置的给药性能而从本文中受益。
