藥品儲(chǔ)運(yùn)溫度驗(yàn)證與偏差處理相關(guān)問題

藥品儲(chǔ)運(yùn)過程中經(jīng)常出現(xiàn)溫度超標(biāo)的情況，基于用藥安全和藥品穩(wěn)定有效等方面考慮，藥品儲(chǔ)運(yùn)過程中的溫度控制和運(yùn)輸驗(yàn)證尤為重要。本文匯總了中國(guó)、歐盟、美國(guó)對(duì)藥品儲(chǔ)運(yùn)過程中溫度超標(biāo)相關(guān)的問題的態(tài)度，供大家參考。

 

中國(guó)GMP：

問題：對(duì)于30℃以下儲(chǔ)存的產(chǎn)品（成品），在夏天運(yùn)輸過程會(huì)超過30℃，像此類藥品還需對(duì)運(yùn)輸條件確認(rèn)嗎？另外對(duì)運(yùn)輸條件的確認(rèn)以什么方式體現(xiàn)合適？

答：需要。對(duì)運(yùn)輸條件進(jìn)行評(píng)估。

點(diǎn)評(píng)：對(duì)運(yùn)輸條件進(jìn)行評(píng)估是通過運(yùn)輸驗(yàn)證來實(shí)現(xiàn)的？簡(jiǎn)單地說，就是按正常的運(yùn)輸、包裝條件下，用溫、濕度記錄儀等儀器證實(shí)整個(gè)運(yùn)輸過程的條件滿足產(chǎn)品的要求。對(duì)于出現(xiàn)的短時(shí)間的背離可以通過長(zhǎng)期、加速穩(wěn)定性數(shù)據(jù)予以評(píng)估。

 

問題：2～8℃保存的產(chǎn)品，如企業(yè)有加速實(shí)驗(yàn)數(shù)據(jù)，短期常溫運(yùn)輸對(duì)產(chǎn)品質(zhì)量無影響，可以不用冷鏈嗎？

答：不可以。必須在冷鏈條件下運(yùn)輸，

點(diǎn)評(píng)：冷鏈條件運(yùn)輸時(shí)出現(xiàn)的短時(shí)間背離按偏差處理。可用加速實(shí)驗(yàn)數(shù)據(jù)評(píng)估，但不允許直接用常溫運(yùn)輸條件運(yùn)輸。

 

問題：運(yùn)輸條件是否與貯存條件一致？

答：運(yùn)輸條件應(yīng)當(dāng)滿足儲(chǔ)存條件。

點(diǎn)評(píng)：運(yùn)輸條件應(yīng)滿足儲(chǔ)存條件，如果在運(yùn)輸途中出現(xiàn)了偏離，可以依據(jù)相應(yīng)的穩(wěn)定性數(shù)據(jù)進(jìn)行評(píng)估，確定偏離對(duì)產(chǎn)品的影響。

 

問題165：產(chǎn)品規(guī)定儲(chǔ)存條件為陰涼處，在運(yùn)輸過程中是否必須采取措施將運(yùn)輸溫度控制在20℃以下？

答：在不影響產(chǎn)品質(zhì)量的情況下，運(yùn)輸過程中的溫度可以在20℃以上，需要有相應(yīng)的穩(wěn)定性數(shù)據(jù)作為支持，必須采取必要的控制措施。

點(diǎn)評(píng)：運(yùn)輸過程中的溫度是否可以在20℃以上，溫度可以偏離多長(zhǎng)時(shí)間，最大可偏離的溫度上限，這些都需要有相應(yīng)的穩(wěn)定性數(shù)據(jù)作為支持。同時(shí)可以通過運(yùn)輸驗(yàn)證證實(shí)在最惡劣條件下產(chǎn)品可能經(jīng)受的最大溫度變化和時(shí)間長(zhǎng)短，結(jié)合穩(wěn)定性數(shù)據(jù)做合理的判斷。

 

問題：疫苗的運(yùn)輸條件如何監(jiān)控？

答：疫苗產(chǎn)品的冷鏈運(yùn)輸，應(yīng)該配備全過程連續(xù)溫度記錄裝置，由接收方在驗(yàn)收產(chǎn)品時(shí)對(duì)運(yùn)輸過程的溫度記錄結(jié)果進(jìn)行確認(rèn)。

點(diǎn)評(píng)：依據(jù)《中國(guó)藥典》三部的要求，生物制品貯存溫度通常為2～8℃，運(yùn)輸過程需注意快速、冷鏈、防凍結(jié)，因此疫苗產(chǎn)品的運(yùn)輸應(yīng)采用適當(dāng)?shù)谋�溫（或控溫）措施，且需�?jīng)過最差條件驗(yàn)證，并建議對(duì)運(yùn)輸過程配備連續(xù)溫度記錄裝置，記載每一發(fā)運(yùn)單位的溫度變化情況，由接收方在驗(yàn)收產(chǎn)品時(shí)對(duì)運(yùn)輸過程的溫度記錄結(jié)果進(jìn)行確認(rèn)，發(fā)運(yùn)單位也應(yīng)對(duì)此結(jié)果定期進(jìn)行評(píng)估。

 

問題：請(qǐng)問在《確認(rèn)與驗(yàn)證》附錄中關(guān)于運(yùn)輸確認(rèn)的要求中第一條即第三十四條指出：“對(duì)運(yùn)輸有特殊要求的物料和產(chǎn)品，其運(yùn)輸條件應(yīng)當(dāng)符合相應(yīng)的批準(zhǔn)文件、質(zhì)量標(biāo)準(zhǔn)中的規(guī)定或企業(yè)（或供應(yīng)商）的要求”是否可以理解為對(duì)于運(yùn)輸有特殊要求的物料和產(chǎn)品才需要進(jìn)行運(yùn)輸確認(rèn)？要求陰涼條件存儲(chǔ)的物料或產(chǎn)品是否屬于特殊要求？

答：你好，一般產(chǎn)品也應(yīng)進(jìn)行運(yùn)輸確認(rèn)，但有特殊要求的物料和產(chǎn)品應(yīng)嚴(yán)格按照附錄“確認(rèn)與驗(yàn)證”第七章的要求進(jìn)行。

 

問題：尊敬的老師您好！想咨詢您關(guān)于冷鏈運(yùn)輸（2～8℃）過程溫度記錄的相關(guān)問題：

1）冷鏈運(yùn)輸過程中如果出現(xiàn)溫度超出范圍，企業(yè)會(huì)根據(jù)產(chǎn)品特性及穩(wěn)定性研究對(duì)超出范圍的情況進(jìn)行評(píng)估以支持產(chǎn)品處置（接受或拒絕）。目前了解到行業(yè)廣泛采用這種方式。

2）根據(jù)2015版中國(guó)藥典和GB/T8170-2008數(shù)值修約規(guī)則與極限數(shù)值的標(biāo)識(shí)和判定，當(dāng)冷鏈運(yùn)輸溫度處于1.5-8.5度之間（運(yùn)輸過程溫度記錄儀通常到小數(shù)點(diǎn)后一位）均符合（2～8℃）要求。

想請(qǐng)教老師您對(duì)于上述兩個(gè)問題的解讀，謝謝！

答：你好。關(guān)于第一個(gè)問題你的理解是對(duì)的，當(dāng)有超出情況時(shí)，應(yīng)根據(jù)產(chǎn)品特性及穩(wěn)定性研究數(shù)據(jù)對(duì)其進(jìn)行評(píng)估。

第二個(gè)問題，在GMP管理中，產(chǎn)品的儲(chǔ)存條件和運(yùn)輸條件首先應(yīng)適用于產(chǎn)品特性，而不是一概而論，如果你的產(chǎn)品對(duì)溫度要求嚴(yán)格，你可以在2-8℃之內(nèi)定出超趨勢(shì)報(bào)警，如3-7℃報(bào)警。你如果要將溫度放在1.5-8.5度之間，那么你的穩(wěn)定性試驗(yàn)條件也應(yīng)與此相適應(yīng)。總之，我們的管理?xiàng)l件要有數(shù)據(jù)的支持。

 

 

歐盟GDP：

文獻(xiàn)1：

“The application of MeanKinetic Temperature (MKT) to temperature monitoring of wholesale products isonly appropriate where an acceptable MKT value is provided by the MA holder fora specific product, and the recording of temperature can be confirmed to beconsistent and complete from the moment of leaving the manufacturer’s premises.In practice the application of MKT fails where a complete chain of temperaturerecording cannot be allocated to a specific consignment of a product. Attemptsto apply MKT have been proposed by wholesalers as an alternative to havingadequate temperature control within their warehouses as well as attempting todowngrade the impact of temperature excursions. The use of MKT in the wholesaleenvironment without robust supporting information and methodology is thereforediscouraged”.

“只有在上市許可證持有人對(duì)特定產(chǎn)品提供了可接受的平均動(dòng)力學(xué)溫度值（MKT），且自產(chǎn)品離開生產(chǎn)商廠房后溫度記錄與實(shí)際相符且完整，才可以使用MKT對(duì)批發(fā)產(chǎn)品進(jìn)行溫度監(jiān)控。事實(shí)上，如果一個(gè)產(chǎn)品沒有相應(yīng)的完整溫度記錄，是不能使用MKT的。批發(fā)商建議嘗試使用MKT，把MKT作為對(duì)倉(cāng)庫(kù)溫度進(jìn)出充分控制的一種選擇，同時(shí)也作為嘗試降低溫度劇增所造成的影響的一個(gè)途徑。如果沒有有力的支持信息和方法，批發(fā)商是不允許使用MKT的。

——MHRA博客：冷藏藥品的良好分銷規(guī)范(ＧＤＰ)

Refrigeratedmedicinal products, part 2: Transportation, packing, temperature management,the use of third party couriers and returns – some things to consider

有關(guān)冷藏藥品的第二部分：運(yùn)輸、包裝、溫度控制、第三方運(yùn)輸?shù)氖褂靡约巴素涍^程中的注意事項(xiàng)

 

文獻(xiàn)2：

Question:concerning chapter 9 – transportation, 9.2.(1), can we deviate from storageconditions if the manufacturer agrees to the transportation of the productwithin a certain temperature range (2°-25°c) for a limited time frame of 6hours?

Answer: No.Storage temperature limits as described by the manufacturer or on the outerpackaging need to be respected for each stage of transport during the wholetransport chain.

問題：關(guān)于第9章---運(yùn)輸中，9.2.（1），如果生產(chǎn)商允許產(chǎn)品在一定6小時(shí)內(nèi)，在一定溫度范圍內(nèi)（2°-25°C）運(yùn)輸，我們的存貯條件是否可以允許偏差？

答：不允許。在整個(gè)運(yùn)輸鏈中各運(yùn)輸環(huán)節(jié)均需要遵守生產(chǎn)商所描述的，或外包裝上描述的存貯溫度限度。

——GOOD DISTRIBUTION PRACTICE FOR MEDICINALPRODUCTS FOR HUMAN USE

QUESTIONS ANDANSWERS

VERSION 1.0

人用藥GDP問答版本號(hào)1.0

 

文獻(xiàn)3：

The EU Good Distribution Practice (GDP) Guidelines (2013/C 343/01) revisedin 2013 reflect the requirements and expectations of the authorities during thetransport and distribution of medicinal products in a very detailed way.Nevertheless, there are still questions and insecurities.

2013年修訂后的歐盟GDP指南（2013/C343/01）以非常詳細(xì)的方式反映了官方對(duì)于藥品運(yùn)輸和銷售的期望和要求。不過，還是有一些問題不太清楚。

Especiallyquestions on temperature control during transport are recurring. This questionis examined in detail in a corresponding questions and answers paper of the German ZLG (Zentralstelleder L?nder für Gesundheitsschutz bei Arzneimitteln und Medizinprodukten/Central Authority of the German Federal L?nder for Health Protection RegardingMedicinal Products and Medical Devices) (in German language).

特別是關(guān)于運(yùn)輸途中的溫度問題再次被提出。這個(gè)問題在“德國(guó)ZLG問答”中有了一些詳細(xì)的解答，不過是德文的。（據(jù)德國(guó)同事介紹，ZLG是德國(guó)藥品和醫(yī)療器械負(fù)責(zé)審批類的機(jī)構(gòu)）

Here, it isstated that a temperature control is not required for each transport:

其中說明了并不是每一次運(yùn)輸中都要求對(duì)溫度進(jìn)行控制：

"If noconstant monitoring of temperature is carried out during the transport ofmedicinal products a risk assessmentmust be made of thetransportation routes. This includes especially the travel duration includingspecial aspects of the route, the time of year and day, including the weatherforecast, the vehicles used and their equipment. The results of this riskassessment have to be part of the transportation planning."

“如果在藥品運(yùn)輸中沒有實(shí)施持續(xù)的溫度監(jiān)控，則必須對(duì)運(yùn)輸路線進(jìn)行風(fēng)險(xiǎn)評(píng)估。評(píng)估特別要包括運(yùn)輸時(shí)間，包括路線的特殊問題，季節(jié)和天數(shù)，包括天氣預(yù)報(bào)，所用的貨車及其裝備。該風(fēng)險(xiǎn)評(píng)估的結(jié)果必須成為運(yùn)輸計(jì)劃的一部分。”

But at the sametime this means that monitoring has to be done if no risk assessment wascarried out or if the risk assessment led to the result that a temperaturecontrol is necessary.

但同時(shí)，這也表示如果沒有進(jìn)行風(fēng)險(xiǎn)評(píng)估，那就必須進(jìn)行監(jiān)控，或者如果風(fēng)險(xiǎn)評(píng)估結(jié)論是需要對(duì)溫度進(jìn)行控制，那也必須進(jìn)行監(jiān)控。

According to theZLG document a lot of things have to be considered when carrying out the riskassessment:

根據(jù)ZLG文件，在進(jìn)行風(fēng)險(xiǎn)評(píng)估時(shí)必須要考慮很多問題：

·        The mean kinetic temperature (MKT) cannot be used. The reason is that it does not takeinto consideration effects "that may lead to irreversible quality defectseven when certain temperature limits that are established during stabilitystudies in connection with the marketing authorisation are exceeded only for ashort time. And it does not take into consideration the possible formation offissures in the glass of ampoules and injection bottles at temperatures aroundthe freezing point. Furthermore, calculation of the MKT requires that the temperatureprofiles of all transports are known that have been carried out previously. Butusually this data is not available ...." 

·        不能使用平均動(dòng)力學(xué)溫度（MKT）。理由是它沒有考慮到影響“可能會(huì)引起不可逆的質(zhì)量缺陷，即使在穩(wěn)定性研究期間已建立了與上市許可相關(guān)聯(lián)的特定溫度限度只是超出了很短的時(shí)間。它沒有考慮在冷凍點(diǎn)上下的溫度可能會(huì)使得安瓿和注射用瓶的玻璃產(chǎn)生龜裂。另外，MKT計(jì)算需要知道之前已實(shí)施的所有運(yùn)輸過程中的溫度概況。但通常這些數(shù)據(jù)是無法獲得的……”

·        In order to assess deviations "appropriateprocedures" must be established. 

·        為了評(píng)估偏差，必須建立“適當(dāng)?shù)某绦?/span>”

·        Storage conditions must generally be respected alsoduring transportation. "Only in cases that according to the packagingor the confirmed written information given by the manufacturer, thepharmaceutical entrepreneur or the marketing authorisation holder. a transportwithin the aforementioned temperature range will not reduce the quality"this temperature range can be handled more generously. It has been demonstratedfor example "in connection with the marketing authorisation of medicinalproducts on the labelling of which only storage between +2 and +8 °C isindicated that they remain sufficiently stable even if the temperature rises upto +25 °C for a short time."

在運(yùn)輸過程中必須遵守存貯條件。“只有當(dāng)根據(jù)生產(chǎn)商、藥品企業(yè)或上市許可持有人提供的包裝或確認(rèn)的書面信息，在上述溫度范圍內(nèi)的運(yùn)輸將不會(huì)降低質(zhì)量”，這樣的溫度范圍才可能更靈活。例如，已證明“與藥品上市許可相關(guān)的標(biāo)簽說明只能存貯在+2到+8 °C，即使溫度在短時(shí)間內(nèi)高至 +25°C其質(zhì)量仍保持足夠穩(wěn)定。”

——GMPNews

22/04/2015

GDP:Is Temperature Control required for each Transport?

GDP:是不是每次運(yùn)輸均需要對(duì)溫度進(jìn)行控制？

 

 

美國(guó)USP：

10.30.40. ControlledCold Temperature

受控的冷藏溫度

 “Controlled cold temperature” is defined astemperature maintained thermostatically between 2° and 8° (36° and 46° F), thatallows for excursions in temperature between 0° and 15° (32° and 59° F) thatmay be experienced during storage, shipping, and distribution such that theallowable calculated mean kinetic temperature（MKT） is not more than 8°(46° F). Transient spikes up to 25° (77° F) may bepermitted if the manufacturer so instructs and provided that such spikes do notexceed 24 hours unless support

溫度保持在2°和8°（36°和46℉）之間。在儲(chǔ)存、運(yùn)輸、分銷過程中，允許溫度在0°至15°（32°和59℉）之間波動(dòng)，但平均動(dòng)力學(xué)溫度（MKT）不超過8°（46℉）。片刻最高溫度允許達(dá)到25°（77℉），超過溫度的最長(zhǎng)時(shí)間不得過24小時(shí)，除非穩(wěn)定性數(shù)據(jù)或是其他廠商的說明支持。

 

10.30.60.Controlled Room Temperature

受控的室溫

 “Controlled room temperature” indicates atemperature maintained thermostatically that encompasses the usual and customaryworking environment of 20° to 25° (68° to 77°F); that results in a mean kinetictemperature(MKT) calculated to be not more than 25°; and that allows forexcursions between 15° and 30° (59° and 86°F) that are experienced inpharmacies, hospitals, and warehouses. Provided the mean kinetic temperatureremains in the allowed range, transient spikes up to 40° are permitted as longas they do not exceed 24 hours.

Spikes above 40°may be permitted if the manufacturer so instructs. Articles may be labeled for storageat “controlled room temperature” or at “up to 25°”, or other wording based onthe same mean kinetic temperature. The mean kinetic temperature is a calculatedvalue that may be used as an isothermal storage temperature that simulates thenonisothermal effects of storage temperature variations. (See alsoPharmaceutical Stability 〈1150〉.)

受控的室溫指通常維持在20℃~25℃（68℉~77℉）恒定溫度，其MKT值不應(yīng)超過25℃，并且根據(jù)經(jīng)驗(yàn)，允許在藥房、醫(yī)院和倉(cāng)庫(kù)偏移至15℃~30℃（59℉~86℉）。維持MKT在規(guī)定的范圍，即使短暫的達(dá)到40℃并且不超過24小時(shí)也是允許的。如果超過40℃則需要制造商另外說明。說明書中可以注明儲(chǔ)存在受控的室溫或最高25℃或其他基于同樣MKT值的溫度。平均動(dòng)力學(xué)溫度（MKT）指用一個(gè)等溫儲(chǔ)存溫度計(jì)算值來模擬各種不同的儲(chǔ)存溫度的影響。

 

An article forwhich storage at controlled room temperature is directed may, alternatively, bestored and distributed in a cool place, unless otherwise specified in theindividual monograph or on the label.

如果說明書規(guī)定了在受控的室溫下儲(chǔ)存，那么同樣也可以在陰涼條件下（cool，8℃~15℃）儲(chǔ)存和運(yùn)輸，除非在USP各論或產(chǎn)品標(biāo)簽上有單獨(dú)的特殊規(guī)定。

 

10.30.30. Cool

陰涼

Any temperature between8° and 15° (46° and 59°F) is“cool.” An article for which storage in a coolplace is directed may, alternatively, be stored and distributed in arefrigerator,unless otherwise specified by the individual monograph.

陰涼溫度是指8℃~15℃之間（46℉~59℉）。如果說明書中規(guī)定了在陰涼條件下儲(chǔ)存，那么同樣也可以在冷藏條件下儲(chǔ)存和運(yùn)輸，除非在USP各論中有單獨(dú)的特殊規(guī)定。

——USP  GENERAL NOTICES AND REQUIREMENTS凡例

 

綜上，對(duì)各國(guó)對(duì)藥品儲(chǔ)運(yùn)過程中溫度超標(biāo)的態(tài)度如下：

國(guó)家	溫度偏差
中國(guó)	1、可以通過長(zhǎng)期、加速穩(wěn)定性數(shù)據(jù)評(píng)估溫度偏差 2、不允許以加速試驗(yàn)數(shù)據(jù)評(píng)估結(jié)果為依據(jù)直接放寬儲(chǔ)運(yùn)條件 3、運(yùn)輸驗(yàn)證（考慮最差條件）
歐盟	1、使用MKT評(píng)估溫度偏差需要有足夠信息支持 2、并不是每一次運(yùn)輸中都要求對(duì)溫度進(jìn)行監(jiān)控，但要進(jìn)行風(fēng)險(xiǎn)評(píng)估 3、如果沒有風(fēng)險(xiǎn)評(píng)估，那就必須進(jìn)行溫度監(jiān)控 不能使用MKT作為降低風(fēng)險(xiǎn)的措施
美國(guó)	1、允許計(jì)算MKT來評(píng)價(jià)儲(chǔ)運(yùn)條件是否符合（藥典特別規(guī)定的品種除外） 2、允許低溫（指低于規(guī)定儲(chǔ)存溫度）儲(chǔ)運(yùn)。