近日，F(xiàn)DA對Liebel-Flarsheim的483缺陷報告中提及該公司偏差調(diào)查體系的缺陷，該公司自 2022 年以來至少有 40 項待滅菌產(chǎn)品微生物負(fù)荷超標(biāo)，但該公司的調(diào)查稱 “根本原因未確定”，或在沒有充分證據(jù)的情況下將 “人員” 或 “環(huán)境” 列為潛在來源。該公司還將根本原因研究作為持續(xù)CAPA的一部分，完成日期延至2026年。
該公司還認(rèn)為盡管待滅菌產(chǎn)品微生物符合超標(biāo)，但產(chǎn)品經(jīng)過最終滅菌，所以沒有風(fēng)險，對此FDA并不接受，F(xiàn)DA發(fā)現(xiàn)超標(biāo)微生物中還包含可能導(dǎo)致內(nèi)毒素水平升高的革蘭氏陰性菌，表示即使是最終滅菌產(chǎn)品，也必須維持適當(dāng)?shù)乃幤飞a(chǎn)環(huán)境條件，以保護產(chǎn)品免受微生物污染，從而減少滅菌難度和生物負(fù)荷過高產(chǎn)生的副產(chǎn)品（即內(nèi)毒素等）。
缺陷細(xì)節(jié)翻譯如下：
Your firm performs (b)(4) bioburden (b)(4) testing on in-process samples of your drug products (b)(4) terminal sterilization. Since 2022, despite (b)(4) steps, at least 40 (b)(4) test results exceeded your firm’s microbial action-level limits, including results of “too numerous to count” (TNTC). The bioburden included gram-negative microorganisms that may have contributed to elevated endotoxin levels. Your investigations into the excursions were inadequate and lacked scientifically justified root causes. For example, investigations stated, “root cause undetermined” or identified “personnel” or “environment” as potential sources without adequate evidence. Investigations also referenced root cause studies as part of ongoing CAPAs with completion dates through 2026.
貴公司對最終滅菌前的待滅菌產(chǎn)品進(jìn)行（b)(4) 生物負(fù)荷（b)(4) 檢測。自 2022 年以來，盡管采取了（b)(4) 措施，至少有 40 項（b)(4) 檢測結(jié)果超過了貴公司的微生物行動限水平，包括 “無法計數(shù)”（TNTC）的結(jié)果。該生物負(fù)荷包含可能導(dǎo)致內(nèi)毒素水平升高的革蘭氏陰性微生物。貴公司對這些超標(biāo)事件的調(diào)查不充分，且缺乏科學(xué)合理的根本原因分析。例如，調(diào)查稱 “根本原因未確定”，或在沒有充分證據(jù)的情況下將 “人員” 或 “環(huán)境” 列為潛在來源。調(diào)查還提及將根本原因研究作為持續(xù) CAPA 的一部分，完成日期延至 2026 年。
In your response, you state that you will assign a CAPA, including an effectiveness check, to each of the failures noted and identified during the inspection. You also state the implicated batches are not at risk due to terminal sterilization.
在貴公司的回復(fù)中，稱將為檢查中發(fā)現(xiàn)的每一項不合格情況制定 CAPA（包括有效性檢查），并表示受影響批次因已進(jìn)行最終滅菌所以沒有風(fēng)險。
Your response is inadequate. You failed to adequately investigate these excursions, and your risk assessment minimizes the potential impact to patients. Your assessment appears to rely on your (b)(4) sterilization process and does not consider factors impacting its effectiveness.
貴公司的回復(fù)不充分。貴公司未能充分調(diào)查這些超標(biāo)事件，且風(fēng)險評估低估了對患者的潛在影響。該評估似乎僅依賴貴公司的（b)(4) 滅菌工藝，未考慮影響其有效性的因素。
Appropriate environmental conditions for drug product manufacturing must be maintained to protect products from microbiological contamination, even when terminally sterilized, to minimize sterilization challenges and the byproducts of excessive bioburden.
即使是最終滅菌產(chǎn)品，也必須維持適當(dāng)?shù)乃幤飞a(chǎn)環(huán)境條件，以保護產(chǎn)品免受微生物污染，從而減少滅菌難度和生物負(fù)荷過高產(chǎn)生的副產(chǎn)品。
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