清潔可以說是藥品生產中的關鍵工藝。傳統的清潔驗證程序只關注於單一的驗證，來證明清潔方法可以按預期工作。然而，隨著行業實踐的發展，更好的方法是將清潔驗證視為一個生命周期，將其重點從單一的清潔驗證擴展到清潔開發階段和持續清潔驗證階段，涉及到清潔方法使用的整個生命期間。
2020年，ISPE發布了清潔驗證方面新的指南，名為「清潔驗證生命周期——應用、方法和控制」。在該指南中，對於「清潔驗證生命周期」這一概念進行了闡述。
生命周期的模型
The cleaning validation lifecycle follows the model defined by FDA, the concepts defined in the EMA Process Validation Guideline, and other regulatory bodies for process validation.
清潔驗證生命周期可以遵循工藝驗證的概念，這來自FDA界定的模型、EMA工藝驗證指南和其它監管機構界定的概念。
「Although the rigor of process design and the timing of implementation for some 『stages』 may differ, the science and risk-based methodology described in the FDA guidance is equally applicable to cleaning processes.」
「儘管工藝設計的嚴謹性和某些「階段」的實施時間可能不同，但FDA指南中描述的科學和基於風險的方法同樣適用於清潔工藝。"
For existing operations and processes, the introduction of new products or residues may require an assessment of the suitability of existing cleaning method designs, rather than forcing a new design of cleaning methods.
對於現有的操作和工藝，引入新產品或殘留物可能需要評估現有清潔方法設計的適用性，而不是強制採用新的清潔方法設計。
The main elements of the FDA lifecycle model are illustrated in Figure below. The lifecycle model adopts the principles of Quality by Design, which states that quality cannot be assessed by testing alone. Therefore, processes need to be developed, critical parameters need to be identified, and the cleaning process monitored to verify ongoing performance and ensure quality output. The quality output expected from a cleaning process is the achievement of consistent cleaning of manufacturing product contact surfaces at a target cleanliness level that represents no harm to patients or impact to product quality (safety, identity, strength, potency).
FDA生命周期模型的主要要素如下圖所示。生命周期模型採用「質量源於設計」原則，該原則指出不能僅通過測試來評估質量。因此，需要開發工藝，需要確定關鍵參數，並監測清潔工藝以驗證持續性能並確保質量輸出。清潔工藝的預期質量輸出是：在目標清潔度水平上實現對生產產品接觸面的一致清潔，對患者無害或對產品質量（安全性、鑑別、強度、活性）無影響。
圖：FDA工藝驗證生命周期模型
The lifecycle approach for cleaning validation is more comprehensive than the traditional approach as application of the lifecycle ensures that the cleaning process remains in a state of control and provides a logical progression for gaining knowledge for process improvements.
與傳統方法相比，清潔驗證的生命周期方法更為全面，因為生命周期的應用可確保清潔工藝保持可控狀態，並為獲得工藝改進的知識提供了邏輯進展。
Implementing a lifecycle approach can be challenging for legacy products where the development of the cleaning process may not be fully documented. However, a company can benefit from understanding the cleaning process parameters and design constraints when dealing with cleaning method changes or investigating failures. Better knowledge of the cleaning process provides the tools necessary to assess potential manufacturing cross- contamination risks and helps to ensure a compliant and effective cleaning program.
對於可能未充分記錄清潔工藝開發的舊產品，實施生命周期方法可能具有挑戰性。然而，在處理清潔方法變更或調查故障時，公司可以從了解清潔工藝參數和設計限制中獲益。對清潔工藝的更深入了解，為評估潛在的生產交叉汙染風險提供了必要的工具，並有助於確保清潔計劃的合規性和有效性。
階段1-清潔工藝設計
Stage 1 – Cleaning Process Design: Typical activities include creating a cleaning validation plan, selecting cleaning agents, determining Health-Based Exposure Limits (HBEL), defining critical parameters following Quality Risk Management principles, characterizing residues, evaluating parameter interactions, completing recovery studies, selecting validated analytical methods, reviewing equipment design, grouping equipment, defining limits and acceptance criteria.
階段1-清潔工藝設計：典型活動包括創建清潔驗證計劃、選擇清潔劑、確定基於健康的暴露限度（HBEL）、根據質量風險管理原則界定關鍵參數、表徵殘留物、評估參數相互作用、完成回收率研究、選擇已驗證的分析方法、審核設備設計、分組設備、界定限度和可接受標準。
階段2-清潔工藝確認
Stage 2 – Cleaning Process Qualification: Typical activities include conducting next phases of the validation plan, qualifying equipment, reviewing utilities readiness, qualifying suppliers, selecting sampling site, justifying number of qualification runs, creating a cleaning qualification protocol, training personnel, executing the cleaning qualification protocol, and issuing the final validation report.
階段2-清潔工藝確認：典型活動包括執行驗證計劃的下一階段、確認設備、審核公用設施準備情況、確認供應商、選擇取樣點、確認運行次數、創建清潔確認方案、培訓人員、執行清潔確認方案和發布最終驗證報告。
Knowledge gained during this stage may require going back to Stage 1 for further development. Otherwise, proceed to Stage 3.
在此階段獲得的知識可能需要返回階段1進行進一步開發。否則，進行階段3。
階段3-持續清潔確認
Stage 3 – Continued Cleaning Verification (Ongoing Cleaning Verification): Typical activities include establishing periodic reviews, determining extension of PV sampling and testing, monitoring process capabilities, reviewing deviations and changes.
階段3-持續清潔確認：典型活動包括建立定期回顧、確定PV取樣和檢測的擴展、監測工藝能力、審查偏差和變更。
Knowledge gained during this stage may require going back to Stage 1 for further development or for revalidation at Stage 2.
在該階段獲得的知識可能需要返回階段1，進行進一步開發；或在階段2進行再驗證。
It is possible to introduce changes to previous stages in the lifecycle model based on knowledge gained during the execution of each stage. Risk-based approaches and assessments are conducted throughout the lifecycle, especially during Stage 1 and Stage 2 of the model.
可以根據每個階段執行過程中獲得的知識，在生命周期模型的早期階段引入變更。基於風險的方法和評估在整個生命周期中進行，特別是在模型的第1階段和第2階段。
參考：
Cleaning Validation Lifecycle Applications, Methods, and Controls. August, 2020. International Society for Pharmacoepidemiology (ISPE).
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