一、前言
2008 年 11 月欧盟(European Union)公布药品优良製造规范(GMP)附则1:无菌药品的製造之修订版,除了「冷冻乾燥小瓶铝盖压盖」之规定延至 2010年 3 月 1 日施行之外,其馀修订均在 2009 年 3 月 1 日生效。PIC/S 于 2009 年 1月 15 日公告相同内容的附则 1 新版本(PE 009-8 GMP 附则 1),并于公告同日生效。
与先前版本之重大差異为:
1. 洁淨室分级:重新定义洁淨室分级标准与监测要求。
2. 培养基充填允收标准:增加了对培养基允收标准的规定。这些标准引用自FDA 的无菌操作指导手册。进行「重大失败」调查时,应将最近一次成功的培养基充填以后生产的所有批次列入考虑。
3. 灭菌前的负荷菌:增加了应对每一个批次执行负荷菌(bioburden)之监测,包含经由无菌製造所生产的产品、以及最终灭菌的产品。如果最终灭菌产品採用过度灭菌的方法,其负荷菌含量分析只需在适当间隔执行。如为产品为參數放行(parametric release)时,应对每一个批次产品进行负荷菌含量分析,并且将之视为製程中试验。必要时,也应进行内毒素负荷(endotoxin burden)的量测。
4. 对冷冻乾燥小瓶在最终压盖前之环境条件的指示:增加了冷冻乾燥产品小瓶直到橡皮塞完全塞入前需保持于 A 级条件下;且铝盖捲缩工程进行应在 A/B级环境,或该工作环境空气品质符合 A 级区要求。
本次 PIC/S GMP 附则 1 修订与先前版本比较,不但考虑了当前的法规/规则,例如,EN ISO 14644 与 FDA 的无菌操作指导手册,而且也顾及国际调和化。另外,条文编号也大幅更易。
二、重要内容变动介绍:
(一)洁淨室分级与监测(Classification and Monitoring)
Number of items in the batch | Minimum number of items to be tested for each medium, unless otherwise justified and authorised* |
Parenteral preparations - Not more than 100 containers - More than 100 but not more than 500 containers - More than 500 containers |
10 percent or 4 containers, whichever is the greater 10 containers 2 percent or 20 containers, whichever is less |
Ophthalmic and other non-injectable preparations - Not more than 200 containers |
5 percent or 2 containers, whichever is the greater |
- More than 200 containers - If the product is presented in the form of single-dose containers, apply the scheme shown above for preparations for parenteral use |
10 containers |
Catgut and other surgical sutures for veterinary use | 2 percent or 5 packages whichever is the greater, up to a maximum total of 20 packages |
Bulk solid products - Up to 4 containers - More than 4 containers but not more than 50 containers - More than 50 containers |
Each container 20 percent or 4 containers, whichever is the greater 2 percent or 10 containers, whichever is the greater |
Pharmacy bulk packages of antibiotics (greater than 5 g) | 6 containers |
* If the contents of one container are enough to inoculate the two media, this column gives the number of containers needed for both the media together. |