無菌過濾前的生物負荷量(Bioburden)相關要求

相信使用無菌過濾為最終滅菌手段應該都對於過濾前的IPC管制點有些印象，一定有一個檢測項目：生物負荷量 Bioburden；允收標準為 NMT 10 CFU/100 mL。不知道大家對這個規格的印象為何？這已經是典型注射用水(WFI)的檢驗規格！而在《過濾器的串接類型》內在執行無菌過濾前也都有出現這個規格，這個規格是哪裡來的呢？是哪個法規的要求？一定需要遵循嗎？

• 這個數值明確的出現在 EMA的Sterilisation of the medicinal product, active substance, excipient and primary container - Scientific guideline中並強烈建議採取這個標準：
  In most situations, a limit of NMT 10 CFU/100 ml (TAMC) would be acceptable for bioburden testing. If a pre-filter is added as a precaution only and not because the unfiltered bulk solution has a higher bioburden, this limit is applicable also before the pre-filter and is strongly recommended from a GMP point of view.
  但有的但書如下，若為起始物料帶來的，預過濾前的生物負荷量超過10 cfu /100 mL是可被接受的：
  A bioburden limit of higher than 10 CFU/100 ml before pre-filtration may be acceptable if this is due to starting material known to have inherent microbial contamination. In such cases, it should be demonstrated that the first filter is capable of achieving a bioburden of NMT 10 CFU/100 ml prior to the last filtration.
  而與微生物相關的無菌過濾前/無菌過濾後的保持時間驗證，就是用來支持數據，以確保在製程期間藥品的品質！
  
• 而PIC/S GMP ANNEX 1則是提到無菌過濾前應執行生物負荷量分析且須有合理的標準限制，未明確規範數值。
  8.80 Suitable bioburden reduction prefilters and/ or sterilising grade filters may be used at multiple points during the manufacturing process to ensure a low and controlled bioburden of the liquid prior to the final sterilising filter.
  
• FDA Guidance for Industry: Sterile Drug Products Produced By Aseptic Processing - Current Good Manufacturing Practice, September 2004則提到說無菌過濾前要設計並控制生物負荷量，並無明確建議數值。
  Manufacturing process control should be design to minimize the bioburden in the unfiltered product. In addition to increasing the challenge to the sterilizing filter, bioburden can contribute impurities (e.g., endotoxin) to, and lead to degradation of, the drug product. a prefiltration bioburden limit should be established.

綜合FDA與PICS GMP規範，皆明確指出執行無菌過濾前應執行生物負荷量的檢測，而規格建議設為NMT 10 CFU/100 mL；但若主要來源為原物料，則可以另外提出一個合理的規格去做控管。