ICH Q7 專家問答（5）廠房和設施

Section4: Buildings and Facilities廠房和設施

1. Q：In a multi-step APImanufacturing process, can charging operations for earlier non-critical stepsbe done outdoors, as long as the last several critical steps are done indoors?

問：在一個多步反應的原料葯製造工藝中，前期一些非關鍵的反應步驟可不可以在室外進行操作？只要最後的幾步關鍵步驟在室內進行就可以了？

UnderSection 4.1 of Q7A, it is very clear that where the equipment itself (e.g.,closed or contained systems) provides adequate protection of the material, suchequipment can be located outdoors. That is not restrictive at all as to steps.It depends on whether the equipment provides adequate protection of thematerial.

答：在Q7A指南第4.1章節下，清楚的說當設備自身（例如是密封或是閉合的系統）可以為物料提供足夠的保護，這樣的設備就可以放在室外。對反應的步驟前後根本沒有約束。這是由設備可不可以為物料提供足夠的保護來決定的。

2. Q：What is the expectedfrequency of testing of High Purity Water systems, such as Purified Water withEndotoxin Control: daily, weekly, bi-weekly, monthly, etc., for point of usesampling?

問：對純水系統的測試頻率有什麼期望要求？例如在使用點要求控制內毒素的純化水取樣是每天，每周，每兩周還是每個月等等？

Q7Adoes not specifically address frequency of testing of high purity watersystems. The frequency of testing for both endotoxin and microbial testing ofwater systems will vary from one company to another. A company should assesswhat is most practical for their particular operation. The frequency of testingfor both microbial and endotoxin attributes will depend upon the design of thewater system, the quality of the source water and other factors

答：Q7A指南沒有具體的說明純化水系統的測試頻率。每個公司水系統內毒素和微生物測試的頻率都不一樣。一個公司必須根據其特殊操作和具體情況來評估什麼是其最可行的方案。測試的頻率決定於水系統的設計，源水的水質和其他因素。

3.Q. For Intermediate processing, comment was made that the processing of potentiallytoxic, i.e. pesticides, was not that significant an issue. Can a company supportsuch an activity?

問：關於中間體工藝，有評論說加工有潛在毒性的物質，例如殺蟲劑，不是重要的問題。製藥公司可以允許這樣的活動嗎？

Yes.Some APIs may actually be derived from an intermediate that is a pesticide oran

herbicide.This is possible at an intermediate stage. (Section 4.4)

答：是的。有些原料葯可能是從殺蟲劑或是除草劑作為中間體製成的。這可能是一個中間體階段。（第4.4章節）

4.Q. Is Purified Water or Water for Injection the quality of water you arerequiring or recommending for use in API production?

問：你要求或是建議在原料葯生產中使用純化水或是注射用水嗎？

Asper Section 4.3, "water used in the manufacture of APIs should bedemonstrated to be suitable for its intended purpose." So, it is up to themanufacturer to determine what quality of water should be used at variousstages of the API process and establish appropriate specifications. Potablewater is the minimum quality of water to be used in API manufacturing. (Section4.3)

答：根據第4.3章節，「製造原料葯中使用的水必須證明適合其用途。」所以，是製造商自己決定在原料葯工藝的不同階段用什麼質量的水並且建立合適的規格標準。飲用水是原料葯製造中對水質量的最低要求（第4.3章節）。

5.Q. Permanently installed pipe work identification: would documentation be aP&ID, or would a process flow diagram be an adequate substitute for labelingindividual lines?

問：永久性管道的工作確認：需要用工藝管道和儀錶流程圖，或是工藝流程圖就足夠替代每個管線的標籤？

Itdepends. Q7A Section 4.2 states, "permanently installed pipe work shouldbe appropriately identified." It does not address how this should beaccomplished. It s up to the manufacturer to determine this. The identificationshould typically be visible to the persons (operators) working in that area.

答：那要看了。Q7A指南第4.2章節規定，「永久性安裝管道必須有合適的識別。」它沒有提到怎麼去做。由製造商自己決定怎麼做。一般要求現場工作的操作者可以看到這些標識。

6.Q. Which engineering steps during the planning of a new API plant should bekept, documented, and verified?

問：在計劃一個新的原料藥廠的時候，哪些工程步驟必須保存，記錄和確認？

Q7Adoes not get into that level of detail. Sound engineering and scientificpractices should dictate what data should be retained.

答：Q7A指南沒有涉及細節的程度。合理的工程、科學實踐應該確定什麼數據必須保留。

7. QDoes the manufacture of API s require the establishment of air qualitystandards, HVAC systems specifications to insure no dust migration during thecharging of components used in API manufacturing from one reactor to another?

問：原料葯製造有沒有要求建立空氣質量標準或是空調凈化系統的規格標準來確保沒有物料塵埃在原料葯製造投料的時候從一個反應罐轉移到另一個中？

Section4.2 of the guidance states that "adequate ventilation, air filtration andexhaust systems should be provided, where appropriate. These systems should bedesigned and constructed to minimize risks of contamination andcross-contamination and should include equipment for control of air pressure,microorganisms (if appropriate), dust, humidity, and temperature, as appropriateto the stage of manufacture. Particular attention should be given to areaswhere APIs are exposed to the environment." If the API process isessentially a closed-system, this would minimize the need for establishment ofair quality standards and specific area classifications.

答：本指南第4.2章節說「必須提供足夠的通風，空氣過濾和排風系統。這些系統必須根據減少污染和交叉污染的風險來設計和安裝，必須包括那些控制空氣壓力，控制微生物（如果適用），控制塵埃，濕度和溫度的設備，必須和製造階段相適應。在原料葯暴露於環境的地方必須特別注意。如果原料葯的工藝必須在一個密閉的系統中，那麼也就降低了建立空氣標準和特殊區域級別的需求。

8.Q. Drug product manufacturers rinse manufacturing equipment with purified water.Should API manufacturers rinse finishing equipment such as mills and blenderswith purified water?

問：製劑生產商用純水洗滌生產設備。原料葯生產商必須用純水來洗滌最後階段的設備，例如粉碎機和混粉機嗎？

Q7Adoes not specify the quality of water that should be used in any process orcleaning step. Once you determine what quality of water is suitable for aparticular step, you might want to use the same quality of water to rinse theequipment. (Section 4.3 & 5.2)

答：Q7A指南對任何階段的工藝或是清洗步驟沒有特別的要求。一旦你決定什麼質量的水適合一個特定階段的反應，你就可以用相同質量的水來清洗這個階段的設備（第4.3章節分和5.2章節）

9.Q. Is microbiological control in the environmental clean room necessary if theroom is not used for injectable grade products?

問：如果精烘包不用於注射級產品的生產還需要環境的微生物控制嗎？

Section4.2 states that if microbiological control is necessary, your facilities shouldbe designed to minimize the possibility of microbiological contamination.Sterile APIs are outside the scope of Q7A.

答：第4.2章節說如果微生物控制是必須的，你的設施就必須設計滿足儘可能少的微生物污染。無菌原料葯不在Q7A指南的範圍之內。

10.Q. The new EMEA note for guidance on water has some clauses around APIs and waterqualities that are tighter than the Q7A guidance. How should companiesinterpret these two guidances?

問：新的EMEA備忘錄關於水的指南中有些條款涉及原料葯，其中的水質要求比Q7A指南要緊。工業界怎麼解釋這兩個指南？

TheQ7A expert working group had extensive discussions over a number of meetingsaround the world about the quality of water, and the final wording recognizesthat in many circumstances there was not a good justification to expect morethan potable water quality.

答：Q7A指南專家工作組在全球範圍內的大量會議中充分討論了水質問題。最後措辭確認在大多數情況下沒有好的理由期望用比飲用水水質要求更高的水。

Weconsidered a lot of issues and opinions when developing this language, but thebottom line here is whenever you re asking about the quality of water, youalways have to ask what is the water being used for? If you re using potablewater at a very early process step, its impact may be minimal, even if you reusing it at a later processing step, its impact may be minimal. As per Section4.3, the manufacturer basically needs to determine that the quality of waterthey re using at any particular step is suitable for its intended purpose.

我們在開發這個措辭的時候考慮了很多問題和觀點，但是底線是當你問到水質的時候，你總是一定要問這個水用做什麼？如果你在非常前的工藝步驟中使用了飲用水，它的影響可能很小；即使你在後期的一步工藝步驟中使用了它，它的影響可能還是很小。根據第4.3章節，生產商基本上需要基於在特殊步驟使用適合其用途來決定水質。

11.Q. Regarding closed systems for APIs in the same room allowing for multiple productsto be manufactured in that same room, is that just different lots of the same productor different chemical entities or reactions?

問：關於允許多種產品在同一房間內的生產在同一房間內用於原料葯生產的密閉系統，是不是適用於相同產品的不同批號或是不同化學物實體或是反應？

Itis uncertain what the question means by the "same room" in an APIfacility.

答：這個問題中的原料葯生產廠房「相同房間」是什麼意思模糊不清。

Section4.1 states that facilities should be designed to minimize potentialcontamination and cross contamination. That s the intent. There is no reasonwhy you could not have different processes or different intermediates or APIsprocessed side-by-side in closed reactors.

第4.1部分規定設施必須設計得儘可能少的避免潛在的污染和交叉污染。這是目的。沒有理由你不能在鄰近的密閉反應釜中進行不同工藝或是不同中間體或原料葯的生產。

Obviously,a packaging operation is a different scenario. Having side-by-side packaging operationswithout some sort of a barrier or containment between the lines is not an acceptableGMP practice. The intent is to minimize cross contamination from one process toanother.

顯然，在包裝操作是一個不同的情況。沒有任何柵欄或是密封措施直接在一起包裝是不可以接受的.目的是減少一個工藝對另一個的交叉污染。

12.Q. We ve heard Europe has defined a fourth level of water purity called highly purifiedwater, which seems to be aimed toward the production of APIs. What impact willthis have on the other ICH regions and Q7A if any?

問：我們聽說歐洲定義了一個第四級別水純度叫「高純水」，看上去是針對原料葯生產的。這對其他ICH地區和Q7A指南會有什麼影響？

Q7A,like any GMP document, does not define standards. API manufacturers shouldestablish adequate specifications for process water, but Q7A does not define orspecify the use of purified water, highly purified water, or WFI. This isoutside the scope of Q7A.

答：Q7A指南，就象其他GMP文件一樣，沒有定義規格標準。原料葯製造商應該為工藝用水建立足夠的標準，但是指南本身沒有定義或是特指使用純水，高純水或是注射用水。這不在Q7A指南範圍內。

13.Q. Does the manufacturing facility need to be qualified to be at least class100,000 for API manufacturing?

問：原料葯製造中生產設施需要至少到達10萬級標準嗎？

No.See Section 4.2.

答：不用。參見第4.2章節。

14.Q. Section 4.4. For material of high pharmacological activity or toxicity,dedicated production areas should be considered unless there is validatedinactivation or cleaning validation. Is there an amount or a method fordetermining if your compound is considered highly potent?

問：第4.4章節中，對那些強藥理活性或是毒性的物料，必須考慮專用的生產區域除非有滅活驗證或是清洗驗證。有這麼一個方法來決定你的化合物是否是強活性物質嗎？

Q7Adoes not define potent or a potent compound. There are some definitions in theOSHA requirements in terms of the various containment areas. (Section 4.4)

答：Q7A指南沒有定義強活性或是強活性化合物。OSHA有些針對不同密閉區域的定義提出不同要求。（第4.4章節）

15.Q. Would validation of critical HVAC controls be expected if there were aseparate validated alarm and monitoring system?

問：如果有獨立的驗證報警和監控系統，那麼對關鍵HVAC控制的驗證有什麼期望要求？

Asper Section 4.2, all utilities that could affect product quality, to includeheat, ventilation, and air conditioning systems, should be qualified andappropriately monitored.

答：根據第4.2章節，所有的可以影響產品質量的設施，包括加熱系統，通風系統，和空調系統都必須確認且有合適的監控。

16.Q. In design and construction, is there any topic under the subtitles regardinglocal hazards because of adjacent units, adjacent companies, which are involvedin non-pharmaceutical operations? Say dyes for the textile industries or rubberindustries and the like that are located in the same chemically zonedindustrial district as the plant?

問：在設計和結構中，有沒有什麼條款涉及由於不生產藥物的鄰近單位，鄰近公司造成的區域性危害？例如和藥廠在同一個化學工業區內的紡織工業的印染廠或是橡膠工廠或是類似的其他工廠。

No.Q7A does not specifically address this issue. However, Section 4.1 states thatbuildings and facilities used to manufacture intermediates and APIs should belocated, designed and constructed to minimize contamination or cross contamination.So if you re in an area in which for, one reason or another, you believe thereis a possibility of contamination from a neighboring chemical plant, then youhave the responsibility for ensuring that the facility, equipment and theprocess is protected from potential contamination.

答：沒有。Q7A指南沒有特別說明這個問題。然而，第4.1章節說到製造中間體和原料葯的建築和設施必須位於，設計在且建造在盡量少的污染或是交叉污染的地方。所以如果你在一個地方，處於任何原因，你認為鄰近的化學工廠可能會造成污染，那麼你有責任確保設施，設備和工藝不受潛在的污染。

17.Q. If you re using electronic systems for control of materials, exactly whatphysical segregation or physical separation of products and areas is needed?

問：如果你使用電子系統來控制物料，那麼需要什麼樣的產品和區域的現實隔離？

Section4.1 states there should be defined areas or other control systems for a varietyof activities. If you have an adequate documentation or electronic system thatprovides appropriate control and handling of materials, there s not anexpectation for physical separation of the materials. In addition, Section 7.2states, "A system should be in place to identify the status of eachbatch." This can be a documentation or computer system.

答：第4.1章節說不同的活動必須有明確的區域或是其他控制系統。如果你有足夠的文件或是電子系統提供了足夠的物料控制和處理，就可沒有必要現實隔離物料。另外，第7.2章節說，「必須有一個系統來確認每批的狀態。」這可以是一個文件或是電子系統。

18.Q. For nitrogen gas, which is being used for vessel-to-vessel transfer. What qualificationis required? Anything besides IQ, OQ and PQ?

問：象氮氣這樣是容器到容器傳送使用的。需要什麼確認？除了IQ,OQ和PQ外的其他什麼嗎？

Section4.2 states, "All utilities that could affect product quality should bequalified and appropriately monitored, and action should be taken when limitsare exceeded." So in addition to qualifying a system, there should be somesort of monitoring.

答：第4.2章節說，「所有可以影響產品質量的設施必須確認和合適的監控，當超過限制的時候必須採取相應的行動。」所以除了確認系統外，還必須有一些監控措施。

19.Q. What does adequate protection in Section 4.1 and adequate filtration inSection 4.2 mean?

問：第4.1章節分的「足夠保護」和第4.2章節的「足夠過濾」意味著什麼？

Q7Adoes not address this because it s up to the manufacturer to determine what isadequate protection for their particular processes. Section 4.1 states,"Where the equipment itself, (e.g., closed or contained systems) providesadequate protection of the material, such equipment can be locatedoutdoors." If it s a reactor, and it s completely closed, that s probablyfine. If it s equipment that you are opening outside to sample or to introducematerials, you may need some temporary protection where the system is beingopened.

答：Q7A指南對這進行說明，因為這必須由製造商來決定他們的特定工藝需要什麼樣的特殊保護。第4.1章節說，「當設備自身（例如是閉合或是密閉系統）為物料提供足夠的保護，這些設備可以位於室外。」如果是一個反應釜，且是完全密閉的，那麼是可以的。如果是你在室外要打開來取樣或是投料的設備，那麼在系統打開的時候，你可能就需要一些暫時的保護措施了。

20.Q. There are several questions here that relate to standards for clean room classesand are asking about regulations or specific guidances that identify eitherwhere they re needed or about design requirements for room classifications,Class 10,000, etc.

問：這裡有些關於精烘包規格標準的問題，問到相關的葯政法規或是特殊的指南來確認什麼地方需要潔凈區或是關於精烘包設計的需求，10萬級等等。

Q7Adoes not define standards for clean room classes nor specify classes for APIprocesses or steps. Within the United States, no regulation or guidance hasbeen issued defining the types of clean rooms or room classifications for APIs.

答：Q7A指南沒有明確定義精烘包的級別，也沒有特別說明原料葯工藝或是步驟中需要的潔凈級別。在美國，對於原料葯生產沒有發布希么葯政法規或是指南來解釋其潔凈區或是精烘包的級別。

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