ECA官網(wǎng)最近昨日掛出關(guān)于WHO公布驗證指南（草案）的新聞，并對這份指南（草案）進(jìn)行了解讀，評價其為工藝驗證總指南。關(guān)于這份草案的本公眾號已于6月26日對其中英文對照版進(jìn)行公示，有興趣的可以查看6月26日推送的文章——《WHO驗證指南2016（草案）》，下面是這份指南的解讀：
At the end of 2015, the WHO adapted its Appendix 7 to the latest technological standards. Appendix 7 provides support with regard to non-sterile process validation. Now, further changes to WHO guidelines are in sight. On
2015年底，WHO采納了其最近技術(shù)標(biāo)準(zhǔn)附錄7。附錄7為非無菌工藝驗證提供了支持?，F(xiàn)在，WHO指南有了進(jìn)一步變化。變化之一是關(guān)于工藝驗證的指南，現(xiàn)在草案已發(fā)布，征求意見截止日期為2016年7月12日。這里是對此草案的一些分析。
The draft contains 21 pages divided into 13 chapters and on
草案包括21頁，分為13章和參考文獻(xiàn)。
The guideline serves as a sort of umbrella guideline and should replace in the future Annex 4 of the WHO Technical Report Series No. 937 from 2006. In so far, the draft refers to other guidelines about the topic validation which will thus have to be updated too as subordinated guidelines (Appendices). The following appendices are named:
該指南是類似傘樣的指南，將來會替代2006年WHO技術(shù)報告第937號中的附錄4。到目前為止，草案提到了其它關(guān)于驗證專題的指南，而這些指南作為附屬指南（附錄）也將必須進(jìn)行更新。其中列出了以下附錄：
Appendix 1 Validation of HVAC systems (currently already available as a revised draft)
附錄1 HVAC系統(tǒng)的驗證（現(xiàn)在修訂后的草案可以獲?。?/span>
Appendix 2 Validation of water systems for pharmaceutical use (will be replaced by cross-reference to WHO Guidelines on water for pharmaceutical use for consideration in qualification of water purification systems)
附錄2 制藥用水系統(tǒng)的驗證（將通過對WHO制藥用水指南水純化系統(tǒng)確認(rèn)考慮的交叉索引被替代）
Appendix 3 Cleaning Validation
附錄3 清潔驗證
Appendix 4 Analytical method validation
附錄4 分析方法驗證
Appendix 5 Validation of computerized systems
附錄5 計算機(jī)化系統(tǒng)驗證
Appendix 6 Qualification of systems and equipment
附錄6 系統(tǒng)和設(shè)備的確認(rèn)
The introduction describes validation as an essential part of GMP and GCP. Validation also includes qualification and a lifecycle comprising an 'on
概述中將驗證描述為GMP和GCP的基本部分。驗證也包括確認(rèn)和持續(xù)改進(jìn)“持續(xù)審核”的生命周期。驗證活動的必要性、范圍和深度應(yīng)基于質(zhì)量風(fēng)險管理原則。
The following resources are listed:
列出了以下資源：
Time 時間
Finances 資金
Personnel (multidisciplinary team).
人員（多學(xué)科團(tuán)隊）。
So far, a summary of the introduction.
以下是簡單介紹。
The chapter “Scope“ points out that the draft describes an overall validation concept which could be applicable to the manufacture and control of starting materials and finished pharmaceutical products. The qualification aspects included in the document could also apply to premises, equipment, utilities and systems.
“范圍”一章指出草案描述了總體驗證概念，它可以應(yīng)用于原料和制劑的生產(chǎn)和控制。確認(rèn)方面包括在文件中，也可以應(yīng)用于設(shè)施、設(shè)備、公用設(shè)施和系統(tǒng)。
Made up of three pages, the glossary is very extensive. It is interesting to see that this chapter offers a definition for the terms 'Commissioning' and “Good Engineering Practice”. The definition for process validation is very close to that of the FDA. Performance qualification is described as applicable to equipment and systems. In the context of systems, the term “process validation” could also be used. There is also a own definition for the term “validation“ (“Act
術(shù)語有3頁，它非常廣泛。有意思的是看到此章提供了關(guān)于術(shù)語“調(diào)試”和“良好工程規(guī)范”的定義。對工藝驗證的定義與FDA非常接近。性能確認(rèn)則被描繪為適用于設(shè)備和系統(tǒng)。在系統(tǒng)的上下文中，術(shù)語“工藝驗證”也可以使用。還有一個自己定義的術(shù)語“驗證”（“證明和文件記錄所有工藝、程序或方法實際并一致地獲得預(yù)期結(jié)果的活動”）。術(shù)語“回顧性驗證”現(xiàn)在沒有列出了，而“再驗證”—也是定期（再）驗證的意思。
Chapter 4 addresses the relationship between validation and qualification. “Qualification and validation are essentially the same” whereby qualification is normally used in relation to equipment and utilities, and validation in relation to systems and processes.
第4章講了驗證和確認(rèn)之間的關(guān)系?！按_認(rèn)和驗證0本質(zhì)上是一樣的”，但確認(rèn)一般用于設(shè)備和公用系統(tǒng)，而驗證則用于系統(tǒng)和工藝。
Chapter 5 “Validation” and its subchapter “Approaches to validation” include some interesting requirements. Where appropriate, statistical calculations should be used to deliver the scientific proof that the process, systems and other related aspects are appropriately validated. Moreover, the senior management is explicitly spoken to with respect to the availability of resources. Both the management and the persons responsible for quality assurance should be actively involved in the validation activities as well as in the authorization of protocols and reports. Regarding the topic risk management which should be used, it is referred to a specific WHO guideline. Where necessary, worst-case tests or so-called 'challenge tests' should be performed like for example stress load tests and volume verification tests in computer systems.
第5章“驗證”及其子章節(jié)“驗證方法”包括一些有意思的要求。適當(dāng)時，統(tǒng)計學(xué)計算應(yīng)用于傳遞科學(xué)證據(jù)證明工藝、系統(tǒng)和其他相關(guān)方面經(jīng)過適當(dāng)?shù)尿炞C。還有，明確說明了高級管理層負(fù)責(zé)保證資源。管理層和QA負(fù)責(zé)人應(yīng)主動參與驗證活動，以及方案和報告的批準(zhǔn)。當(dāng)講到需要應(yīng)用的風(fēng)險管理時，指南引用了具體的WHO指南。必要時，應(yīng)進(jìn)行最差條件測試或所謂的“挑戰(zhàn)試驗”，如在計算機(jī)系統(tǒng)中增加負(fù)載測試，以及容量核查。
The documents needed to accompany the validation activities (Chapter 6) include among other things protocols and reports as well as a validation master plan. By means of own (superordinate?) plans, it should be ensured that a validation review is available which guarantees the maintenance of the validated status. The next chapters look at the validation master plan, protocols and reports.
驗證活動所需的文件（第5章）包括方案和報告以及驗證主計劃。通過自己的（上級？）計劃，應(yīng)保證對驗證都有審核，確保維持驗證狀態(tài)。下幾章講的是驗證主計劃、方案和報告。
A validation master plan – concise and clear - should be available (Chapter 7). However, 28 minimum requirements are listed. On
應(yīng)該制訂有驗證主計劃---簡潔明了（第7章）。其中列出了28個最低要求內(nèi)容。公司要注意數(shù)字大主要是因為對于確認(rèn)活動來說，每個設(shè)施、設(shè)備、公用系統(tǒng)確認(rèn)的子項目都相應(yīng)地列入了。這同樣適用于驗證活動（清潔、工藝、分析方法和計算機(jī)化系統(tǒng)）。驗證主計劃應(yīng)定期審核，GMP狀態(tài)應(yīng)保持更新。
The minimum requirements concerning the validation and qualification protocols are fairly detailed too (15 items). Chapter 8 also points out that there should be a description of how results should be analysed (including statistical analyses where appropriate).
關(guān)于驗證和確認(rèn)方案的最低要求也很詳細(xì)（15項）。第8章還指出應(yīng)該描述結(jié)果要如何分析（適當(dāng)時包括統(tǒng)計學(xué)分析）。
Also in the following Chapter 9 on qualification and validation reports, the focus of reporting is put on statistical analyses where possible. The final approval of reports should be done by the quality assurance department.
在后面的第9章確認(rèn)和驗證報告里，主要講的可能時統(tǒng)計學(xué)分析的報告。報告最終應(yīng)由質(zhì)量保證部門來批準(zhǔn)。
Chapter 10 Qualification 第10章 確認(rèn)
Made up of almost 3.5 pages, Chapter 10 (Qualification) is relatively extensive. It suggests that there are different approaches to qualification. The V-Model for Direct Impact Systems is given as an example. Yet, the model presents abbreviations which are not explained (e.g. UAT). “Normally” – quoting the text – ?qualification should be completed before process validation is performed”. 'Normally', qualification should begin with user requirement specifications (URS). Depending on the object considered, the following steps are: FAT, SAT, DQ, IQ, OQ, PQ. According to the document though, major equipment and critical systems may require at least URS, DQ, IQ, OQ, PQ. Now, there may be some equipment which on
第10章（確認(rèn)）總共有近3頁半，內(nèi)容相對廣泛。它建議了不同的確認(rèn)方法。例如，直接影響系統(tǒng)采用V型方式。這種模型代表意思沒有解釋（例如，UAT）。“一般”—引用其中方案—“確認(rèn)應(yīng)在工藝驗證之前完成”。“一般”，確認(rèn)應(yīng)從用戶需求規(guī)范（URS）開始。根據(jù)考慮的對象不同，可以考慮以下各步：FAT、SAT、DQ、IQ、OQ、PQ。根據(jù)文件要求，主要設(shè)備和關(guān)鍵系統(tǒng)應(yīng)該要求至少有URS、DQ、IQ、OQ、PQ?，F(xiàn)在，可能有些設(shè)備只要求IQ和OQ，如果這樣就能顯示設(shè)備的性能的話。指南中明確提到每一個確認(rèn)階段應(yīng)在下一個開始之前完成。一個WHO自己的段落說明了計算機(jī)系統(tǒng)系統(tǒng)要求用戶和功能性要求標(biāo)準(zhǔn)，設(shè)計和參數(shù)設(shè)置標(biāo)準(zhǔn)。講了這些系統(tǒng)也需要的測試。除此之外，還引用了相關(guān)的WHO關(guān)于計算機(jī)化系統(tǒng)驗證的文件。指南不像附錄15那么明確，它指出URS應(yīng)是下一個確認(rèn)階段的起始點。對于FAT、SAT、DQ、IQ、OQ、DQ的各個確認(rèn)階段則是這么說，適當(dāng)時，FAT和SAT應(yīng)列為“應(yīng)做”的項目。對于OQ，要求做最差情形研究，如果使用了統(tǒng)計學(xué)方法做測試，則要描述該統(tǒng)計學(xué)方法。應(yīng)收集適當(dāng)時間段和/或定期審核和監(jiān)測測試結(jié)果和持續(xù)工藝核查來證明設(shè)備操作是一致的。
The subchapter “Requalification” expressly mentions that full requalification is not required for the replacement of parts but a 'like for like' replacement. Where items of equipment haven’t been used for a longer period of time, requalification may have to be considered.
子章節(jié)“再確認(rèn)”提到在更換部件時并不需要全面再驗證，但采用相似的全設(shè)備替代時則需要。如果設(shè)備很長時間沒有使用，則必須考慮再確認(rèn)。
Another subchapter on revalidation points out that where periodic revalidation is performed, this should be done within defined cycles. Periodic revalidation should be considered when small process changes occur over a longer period of time. The frequency and extent of revalidation should be determined on a risk-based approach taking into account historical da
另一個再驗證的子章節(jié)指出如果實施定期再驗證，則需要在指定的周期內(nèi)進(jìn)行。如果在很長時間內(nèi)有一些小的工藝變更發(fā)生，則考慮進(jìn)行定期再驗證。再驗證的頻次和深度應(yīng)基于風(fēng)險方法結(jié)合歷史數(shù)據(jù)來決定。
Within on
子章節(jié)“工藝驗證”只有一個子章節(jié)，講了其它工藝驗證指南里的新方法和傳統(tǒng)方法。另一個段落專門講的是傳統(tǒng)工藝驗證和應(yīng)用傳統(tǒng)工藝驗證方法時驗證的前提條件（例如，通過產(chǎn)品質(zhì)量審核）。
Chapter 11 and 12 第11章和第12章
The contents of Chapter 11 (Change Management – on
第11章的內(nèi)容（變更管理---僅3個段落）和第12章（偏差管理，只有一段）相比于第13章校正和核對的內(nèi)容（1頁）要少許多。這里，強(qiáng)調(diào)了定期校正，并且可以追溯到校正的測量器具的必要性。IQ被認(rèn)為是設(shè)備校正和核查的一個適當(dāng)?shù)拇_認(rèn)階段。不管是裝置還是儀器，其校正均應(yīng)基于其影響性或風(fēng)險評估。
Conclusion: 結(jié)論
Although this guideline has been thought as superordinate guideline for other validation and qualification guidelines, it has – in its current draft status – relatively little relation to the validation lifecycle approach as required in Annex 15 and FDA’s process validation guideline. There are no references to development which represents the basis for a modern validation approach. Still, periodic revalidation is basically required. Interestingly, references to the application of statistical methods – where appropriate – recur again and again. Another interesting aspect is the mention of “GEP” and “Commissioning“ in the glossary whereby no further explanation is given as for the V-Model. In the course of qualification tests, conditional approvals (as mentioned in Annex 15) are not intended. The specification according to which a 'like for like' replacement requires requalification is very interesting. This is a contrast to PIC/S’s document “PI 006-3, Recommendations on Validation Master Plan, Installation and Operational Qualification, Non-Sterile Process Validation, Cleaning Validation” in which a 'like-for-like' replacement normally doesn’t require requalification. All in all, a closer alignment with other process validation guidelines would be preferable.
盡管此指南作為其它驗證和確認(rèn)指南的附屬指南，它---在現(xiàn)在草案狀態(tài)下---與附錄15和FDA工藝驗證指南中所要求的驗證生命周期方法的聯(lián)系還是相對較少。其中沒有引用代表現(xiàn)代驗證方法基礎(chǔ)的發(fā)展。定期再驗證仍然是基本要求。有意思的是，再三講到統(tǒng)計學(xué)方法的應(yīng)用---適當(dāng)時。另一個有意思的方面是在術(shù)語中提到了“GEP”和“調(diào)試”，而對V模型沒有給出進(jìn)一步解釋。在確認(rèn)測試中，有條件批準(zhǔn)（在附錄15中提到）是不允許的。根據(jù)指南的意思，“相似設(shè)備”替換需要進(jìn)行再驗證很有意思。這與PIC/S的“PI 006-3，驗證主計劃、安裝和運(yùn)行確認(rèn)、非無菌工藝驗證、清潔驗證的建議”是相反的，在該份文件中說“相似設(shè)備”的替換一般并不需要進(jìn)行再驗證。總而言之，如果此指南能夠與其它工藝驗證指南一致將會更好。
