作為清潔驗證方案內容和前提之一，是要確定清潔殘留的可接受限度，即清潔驗證限度。

近30年來，就如何確定清潔驗證限度，行業和監管機構提出了多個思路和指南文件，呈現了科學化和風險化的發展態勢，這在制藥行業保守不變的氛圍下顯得很特別。

1993年 - 行業

【文件】

Fourman, G. andMullin, M, “Determining Cleaning Validation Acceptance Limits forPharmaceutical Manufacturing Operations,” PharmaceuticalTechnology

Fourman，G.和Mullin，M，“為制藥生產操作確定清潔驗證可接受限度”，制藥技術

【思路】

Any carryover of product residue shall meet the following criteria: No more than 0.001 (a factor of 10 because pharmaceuticals are often considered non-active at 1/10th of the dose, 10 to ensure the cleaning program is robust and the final 10 as a safety factor) dose of any product will appear in the maximum daily dose of another product. No more than 10 ppm of a product will appear in another product. No quantity of residue visible on the equipment.

產品的任何殘留均應滿足以下標準：

? 對于一個產品，出現在另一種產品的最大每日劑量中量，不應超過其劑量的0.001（1/10 x 1/10 x 1/10）。其中，第一個1/10系數：認為藥物在劑量的1/10下是非活性的；第二個1/10系數：以確保清潔程序是穩健的；最后一個1/10系數：作為安全系數。

? 一個產品中在另外一個產品殘留量不超過10 ppm。

? 設備上目檢不可見任何殘留物。

1993年 -FDA

【文件】

FDA Guide to Inspections Validation of Cleaning Processes

FDA清潔工藝檢驗指南

【思路】

Basis for limits must be scientifically justifiable. Mentions as examples 10 ppm, 1/1000 of the normal therapeutic dose (biological activity). Surfaces should be visibly clean.

限度依據必須在科學上是合理的。作為實例，提及10ppm，正常治療劑量的1/1000（生物活性）。表面應明顯清潔。

1998年 -PDA

【文件】

PDA Technical Report No. 29 “Points to Consider for CleaningValidation”

PDA技術報告第29號“清潔驗證要考慮的要點”

【思路】

Numerical limits should have a logical and scientific basis. Safety factors used based on the type of products and risk. Fractions of therapeutic dose for Topical Products (1/10th to 1/100th), Oral Products(1/100th to 1/1000th), Parenteral and Ophthalmic products (1/1000th to1/10,000th), Investigational products (1/10,000th to 1/100,000th).

數值限度應具有邏輯和科學依據。根據產品類型和風險使用，使用安全系數乘以治療劑量。安全系數：局部用產品（1/10至1/100），口服產品（1/100至1/1000），腸胃外和眼科產品（1/1000至1 / 10,000），研究性產品（1 / 10,000到1/100,000）。

2000年 -ICH

【文件】

ICH Q7 Good Manufacturing Practice for Active PharmaceuticalIngredients

ICH Q7活性藥物成分的GMP

【思路】

“Limits can be established based on the minimum known pharmacological, toxicological or physiological activity of the API or its most deleterious component.”

“可以根據API或其最有害的成分的最低已知藥理、毒理或生理活性，來確定限度。”

【思路】

2010年 -ISPE

【文件】

ISPE Baseline? Guide: Volume 7 – Risk-Based Manufacture of Pharmaceutical Products [Risk- MaPP] (SecondEdition)

ISPE 基準?指南：第7卷–基于風險的藥品生產[Risk-MaPP]（第二版）

【思路】

Residue limits based on Health-Based Exposure Limit (HBEL) such as Acceptable Daily Exposure (ADE) values.

基于健康的暴露限度（HBEL）的殘留限度，例如可接受的每日暴露（ADE）值。

2014年 -EMA

【文件】

EMA: Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities [

EMA指南：設定基于健康的接觸限度，以在共享設施中生產不同藥品時進行風險識別

【思路】

HBEL(Permitted Daily Exposure (PDE)) through the derivation of a safe threshold value should be employed to identify the risks of cross-contamination in shared facilities. Alternate approaches could be accepted if adequately justified.

應采用通過導出安全閾值的HBEL（允許的每日暴露量PDE）的方法，來識別共享設施中交叉污染的風險。如果有充分的理由，可以接受其它方法。

2015年 -EU

【文件】

EudraLex GMP Annex 15: Qualification and Validation, Section 10 Cleaning Validation [4]

EudraLex GMP附錄15：確認與驗證，第10節清潔驗證[4]

【思路】

Based on toxicological evaluation. References EMA 2014 Guidance onsetting HBEL.

根據毒理學評估。參考EMA 2014設置HBEL的指南。

2015年 -PIC/S

【文件】

PIC/S Guide to Good Manufacturing Practice for Medical Products, Annex 15

《PIC/S醫療產品GMP指南》，附錄15

【思路】

Limits for carryover should be based on a toxicological evaluation of the active materials. References EMA 2014 Guidance on setting HBEL.

殘留限度應基于活性物質的毒理學評估。參考EMA 2014設置HBEL的指南。

2018年 -EMA

【文件】

EMA: Questions and answers on implementation of risk-based prevention of cross-contamination in production and ‘Guideline on setting health-based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities’

EMA問答指南：關于在生產中實施基于風險的交叉污染預防，以及“設定基于健康的接觸限度，以在共享設施中生產不同藥品時進行風險識別”

【思路】

Answers commonly asked questions regarding EMA 2014 Guideline.

“HBELs should be established for all medicinal products.” “For existing products, manufacturer’s historically used cleaning limits should be retained and can be considered alert limits provided that when taking cleaning process capability into account, they provide sufficient assurance that excursions above the HBEL will be prevented.”

回答有關EMA 2014指南的常見問題。

“應該為所有藥品建立HBEL。” “對于現有產品，應保留生產商歷史上使用過的清潔限度，考慮到清潔工藝能力，這些限度可以提供足夠的保證，防止超出HBEL的偏移，可以將其視為警戒限。”

2020年 -PIC/S

【文件】

PIC/S: Questions and Answers on Implementation of Risk- Based Prevention of Cross- Contamination in Production and ‘Guideline on Setting Health-Based Exposure Limits for Use in Risk Identification in The Manufacture of Different Medicinal Products in Shared Facilities’

PIC/S問答指南：關于在生產中實施基于風險的交叉污染預防，以及“設定基于健康的接觸限度，以在共享設施中生產不同藥品時進行風險識別”

【思路】

Adoption byPIC/S of the EMA approach.

PIC/S采用EMA方法。

2020年 -WHO

【文件】

WHO: Draft Working document QAS/20.849, Points to consider on the different approaches – including HBEL – to establish carryover limits in cleaning validation for identification of contamination risks when manufacturing in shared facilities [29]

世衛組織：工作文件QAS / 20.849，不同方法（包括HBEL）的考慮要點，建立清潔驗證中的殘留限度，以識別在共用設施中生產時的污染風險[29]

【思路】

This draft document incorporates HBELs as part of the baseline approach to setting cleaning limits.

本文檔方案將HBEL納入了設置清潔限度的基準方法的一部分。

參考：Cleaning Validation Lifecycle Applications, Methods, and Controls. August, 2020. International Society for Pharmacoepidemiology (ISPE).