ECA新聞：EMA發布關於使用PDE值的最終問答文件
06.06.2018
EMA publishes final Q&A Document on the use of PDE (HBEL) values
EMA發布關於使用PDE值的最終問答文件
In April 2018, the EMA published the final version of the Q&A document on the use of Health-Based Exposure Limits (HBELs) without special notice. The draft version had become necessary in 2016 because the EMA had generated uncertainty within the pharmaceutical industry with their Guideline on setting these limits (PDE values as well). The Permitted Daily Exposure (PDE) values had been defined by the EMA in a new guideline in order to mathematically decide upon the dedicated or multi-purpose use of plants. The new health-based values influence the cleaning validation threshold values as well. In short, it can be determined how much cross contamination may be tolerated from a health risk point of view by using the PDE values. For identifying and using these values, the EMA had to provide a Q&A document which has now been published in its final version. 2018年4月，EMA在沒有任何通知的情況下發布了關於如何使用基於健康的暴露限（HBELs）問答的最終版本。該問答的草案是2016年發布的，因為製藥行業內對EMA已發布的建立基於健康的暴露限的指南存在疑惑。EMA在其新指南中定義了日允許暴露限（PDE），以便於以數字為依據決定設備專用還是共用。新的基於健康的限度值也會影響清潔驗證的閾值。簡言之，通過使用PDE值，可以從健康風險的角度確定可接受的交叉污染的程度。為了識別和使用這些數值，EMA必須提供一個問答文件，現在最終版本已經公諸於世。
The document currently available mostly talks of HBELs and the term PDE is used only very occasionally. HBEL seems to be used as a general term and PDE as a part of HBEL. The threshold values described as ADE (Acceptable Daily Exposures) in ISPE Risk-MaPP would also be a sort of HBEL. When calculating the cleaning threshold values, the terms of PDE, ADE and HBEL are used interchangeably. 當前文件大多談到HBELs，而PDE這個詞僅在非常偶然的情況下使用。HBEL似乎被用作一般術語，而PDE是HBEL的一部分。在ISPE的Risk-MaPP中所描述的ADE (可接受的日暴露量) 也是HBEL的一種。計算清潔閾值時，PDE、ADE、HBEL這些術語可交替使用。
The differences between the draft and the final version of the Q&A document in brief: 該問答文件的終版和草案之間的差別主要有以下幾點：
The number of questions listed has been reduced from 14 to 13. The order and to some extent the content of the questions were also changed. 問答的數量由14條減少到13條。在某種程度上這些問題的內容也有所改變。
The statement that Health-Based Exposure Limits (HBELs) are required for all products is basically the same (question 1). In addition, these must be checked repeatedly during the product life cycle. 問題1關於對所有產品均需要建立HBEL的要求基本一致，除此之外，還應在產品的生命周期中反覆檢查。
The question of what constitutes a highly hazardous substance (question 2) is no longer included in the document. Instead, question 2 states that every substance is to be classified in a band somewhere between a low up to a very high hazard potential. This means that classifying the substances as "highly hazardous" and "non-highly hazardous" is not considered reasonable. 問題2關於高危害物質的組成在終版文件沒有再提及。取而代之的是，問題2明確指出每一種物質都應被定級在一個從低到高的危害性的某個區間。這意味著把物質定義為「高有害物質」或「非高有害物質」是不合理的。
There is a new question about how a producer should handle HBELs (question 3). Here as well, they refer to risk management processes. In case that these indicate that the specified control measures do not sufficiently protect from contamination, dedicating the production should be considered. 問題3是一個新問題，關於生產商如何處理HBELs。這裡，他們指的是風險管理程序。如果通過風險管理程序表明指定的控制措施不能充分防止污染，就應當考慮專線生產。
Another new question deals with who should develop resp. define the HBEL values (question 4). According to the current paper, this can be a person with the appropriate toxicological/pharmacological expertise who is familiar with medicinal products and with determining exposure limits (apart from occupational exposure limit, PDE limits are mentioned here as well). This is somewhat confusing, since PDE values are a subset of HBELs. 另外一個新問題（問題4）是關於誰負責開發HBEL值。根據當前的文件，應當是一個有一定的毒理學/藥理知識，熟悉藥物以及確定基於健康的暴露限（除了職業暴露限，PDE 也在此提及）的人。這裡有點令人困惑，因為PDE值是HBELs的一種。
Question no. 5 is also new: in which way are clients responsible towards contract manufacturers? It is clearly stated that the client is obliged to provide a complete HBEL assessment to the contract manufacturer or else the required data so that the contract manufacturer himself can prepare a HBEL document (or have it prepared). 問題5也是一個新問題：委託方對合同生產商的責任是什麼？這裡明確指出委託方有義務向合同生產商提供完整的HBEL評估報告或者提供相關的資料讓生產商自己評估。
Question no. 6 remains unchanged: How can threshold values for cleaning be established? While in the draft, the traditional calculations according to the 1/1000 dose or 10 ppm criterion for "non-highly hazardous" are named as an option, the new document has a different passage. For existing products, the existing limit values for cleaning shall be maintained and regarded as alert values, provided that they are significantly higher than the corresponding HBEL values. So the content stays the same: less strict HBEL values should not lead to a less well-executed cleaning. 問題6沒有變：如何建立清潔閾值？在草案中對於「非高有害物質」根據1/1000劑量或10ppm計算的傳統限度可作為一種選擇，而新文件中有不同的說法。對於現有產品，如果已有的清潔限度明顯高於相應的HBEL值的話，已有的清潔限度應繼續維持作為警戒限值。所以內容保持不變：不太嚴格的HBEL值不應導致差的清潔。
The 8th question, which is also new, is interesting as well. It deals with the "visually clean" criterion. It is possible to use this as a criterion for success in cleaning, provided that numerous preconditions are fulfilled. For instance, surface-specific threshold studies are required, all relevant surfaces must be visible (if necessary, by dismantling), light and distance must be defined and the examiners need a specific training etc. 第8個問題也是新的，也很有趣。它說的是「目視乾淨」標準。在一些先決條件滿足的情況下，可以把「目視乾淨」作為清潔成功的一個標準。例如，需要對特定表面進行閾值研究，所有相關表面必須是可視的（如需，應進行拆卸），光線和距離應明確規定，檢查人員應接受特定培訓等。
Question 9 is the former question 13. Separating a product class into a dedicated section without further measures to prevent cross contamination within this class is still not allowed. 問題9是之前的問題13。將一類產品分離到一個專門的區域，而不進行進一步的措施來防止這類產品的交叉污染，仍然是不允許的。
Question 10 is the former question 5: it is still not possible to use an LD50 value to obtain an HBEL. 問題10是之前的問題5：仍然不允許用LD50來確定HBEL。
Question 11 is the former question 7 (antiparasitic treatment); question 12 is the former question 8 (veterinary medicine), question 13 covers development products. However, it no longer addresses whether HBELs are required for them; the answer to question 1 clearly indicates that these are also required for development products. In fact, it is even pointed out that HBELs have to be reviewed periodically, if the associated data change within the product life cycle - which applies mainly to development products after all. 問題11是之前的問題7（殺寄生蟲葯），問題12是之前的問題8（獸葯），問題13涉及研發產品。然而，新問答不再強調對於這些葯是否都有必要建立HBEL；問題1的回答已表明研發產品也需要建立HBEL。該文件甚至指出HBELs需要定期審核，如果相關數據在產品生命周期內有更新，這主要適用於開發中的產品。
For more information please see the new Q&A paper on the use of HBEL resp. PDE values. 更多信息詳見the new Q&A paper on the use of HBEL resp. PDE values.
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