滅菌バリデーションの考え方の誕生
無菌とは
滅菌は無菌性を達成するためのプロセス、すなわち、すべての微生物を殺滅または除去するプロセスである。
無菌とは、すべての微生物が存在しないことをいう。
微生物の死滅特性は指数関数で表される。
従って生育微生物の存在は、確率で表され、この確率が非常に低い数値に減少したとしても0にはならない。
そこで、滅菌は確率的な概念として運用される。
あらかじめ無菌性保証水準(sterility assurance level:SAL)を設定し、単位あたりの被滅菌物に生存する微生物の数と種類(バイオバーデン)およびそのD値(致死速度:Decimal Reduction Time)からSALの達成される滅菌条件を計算して実施する。
滅菌の概念
現在ではSALとして10-6(100万分の1)が国際的に採用されており、日本薬局方においても同じ概念が「最終滅菌法」として採用されている。
これは、滅菌操作後、被滅菌物に微生物の生存する確率が100万分の1であることを意味する。
![](https://rkcl-ibis.s3-ap-northeast-1.amazonaws.com/a13.hm-f.jp/226/html_upload/img_226_20210927_102439_TXeaS.png)
無菌性保証の考え方
一般に、微生物は指数関数的に減少する。
確率論的に、微生物の存在が「ゼロ」となることはない。
そこで、「無菌性保証レベル(SAL 10-n)」を設定し、確率的な概念を導入した。
原則として「無菌性保証レベル(SAL)10-6」を「滅菌」と定めた。
「無菌性保証レベル(SAL)10-6」とは、滅菌した製品中に微生物が生き残る確率が100万分の1以下であることを表している。
無菌性の保証とは、目的とする製品を製造するため、滅菌プロセスが、具体的かつ検証可能な原則10-6以下の無菌性保証水準を達成すること。
しかしながら、無菌試験ではSAL10-2までしか保証できない。
無菌試験で滅菌の定義であるSAL10-6を保証しようとすると、100万個の製品に対して無菌試験を実施する必要がある。
第18改正日本薬局方は、無菌試験について以下のように記載している。
無菌試験法は、無菌であることが求められている原薬または製剤に適用される。
本試験に適合する結果が得られても、それは単に本試験条件下で調べた検体中に汚染微生物が検出されなかったことを示しているだけである。
すなわち「無菌試験に合格すること=無菌であることの証明」ではないことを示している。
FDAワーニングレター
2016年に日本のある無菌製剤を製造している企業において FDA査察 が実施された。
その際に滅菌バリデーション等の不備を指摘され、FDA Form 483が発行された。
当該企業は、 FDA に対する回答として、無菌試験において合格したロットのみを米国に輸出していると回答した。
結果的にこの回答が問題となり、ワーニングレターが発行された。
滅菌は非破壊検査では無菌性を確認することができない特殊工程であるため、滅菌バリデーションの実施が必須である。
無菌試験は抜き取り試験である。
10-6以下の無菌性保証水準は、物理的および微生物学的手法に基づく滅菌工程のバリデーションを通して証明できるものであり、無菌試験法によって証明できるものではない。
無菌試験ではSAL10-2までしか保証できない。
「無菌試験に合格すること=無菌であることの証明」ではない。
無菌性の保証は、無菌試験の保証限度をはるかに超えた高いレベルで行われている。
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