注射劑之無菌充填確效研究

隨著人們對醫學常識認知水準的不斷提高，大眾對藥品之有效性及安全性的顧慮也隨之提升。就用藥之安全性而言，外用劑型優於口服劑、口服劑優於注射劑，因為注射劑之用藥風險最高，它也格外受到重視。為了達到用藥的安全性，注射劑的產品必須達到無菌的程度；而就其製程來說，可分為最終滅菌法或無菌操作方式兩種分式。最終滅菌法之無菌性保證(Sterility assurance level-SAL)可達到1×10-6，而無菌操作法之無菌性保證卻只能達到1×10-3，故衛生主管單位及藥廠對於無菌操作製程要求非常嚴格。為確保使用無菌操作法生產線之無菌性及安全性，每年至少需執行二次製程模擬試驗(或稱之為無菌充填確效及培養基充填試驗)，藉以證明該生產線所生產的藥品是無菌的。無菌充填確效的目的在於透過系統性模擬驗證及各種挑戰性試驗，確認製程、設備或流程不被微生物及異物汙染，以符合無菌操作系統之設計要求所必須進行一項定期驗證活動。為確保無菌充填確效驗證之有效性，避免發生許多偽陽性或偽陰性之偏差影響，本研究首先回顧相關文獻及國內外標準規範，然後以乾粉注射劑生產線做實例驗證，從無菌性、細菌內毒素及不溶性微粒子等因子於製程中變化之探討，制定一套新的無菌充填確效執行流程及驗證方式，提供以無菌操作生產注射劑之藥廠在執行相關確效時有效之參考，藉以提升無菌操作產品品質。

關鍵字

無菌操作；製程模擬試驗；無菌充填確效；培養基充填試驗

並列摘要

Since the general level of peoples’ acknowledged of the medial knowledge keep increasing, the concern of the effectiveness and safety of medicine is also increasing. From the aspect of the safety of medication, external use products are better than internal use products and internal use products are better than injection use products. Because of its highest risk of medication, injection use products are mostly focused. In order to maintain the safety of medication, injection use products must be sterile. From the manufacturing process perspective, there are two ways for producing the injection use products: operations for terminally sterilized and operations for aseptic preparations. The sterility assurance level (SAL) of the operations for terminally sterilized can reach 1×10-6 while the SAL of the operations for aseptic preparations can only reach 1×10-3, therefore, health related departments of the government has very strict regulation toward the sterile manufacturing process. To assure the sterility and safety of the operations for aseptic preparations, at least two process simulation test (also named validation of aseptic fill or media fill) are performed annually to verify that the products produced from the process is sterile. The purpose of validation of aseptic fill or media fill is a periodic verification activity of meeting the design requirement of the operations for aseptic preparations system to assure the process and equipment will not be contaminated by any microbiological or foreign objects by systematic simulation and different kinds of challenging tests. To maintain the effectiveness of the validation of aseptic fill and prevent the influence of false-positive or false-negative bias, this paper first review the related literature and the domestic and foreign countries’ standards. Then, the process and verification method of standard validation of aseptic fill are constructed to provide a guidance of producing the sterile injection use products for the pharmaceutical company and also increase the quality of these products. In this paper, an example of powder for injection is also presented. The performance measure developed in this paper for the sterile production process to assure the sterility requirement and reduce the production risk of the sterile production process is applied to that example and proved for its contribution.