當(dāng)實(shí)驗(yàn)室工藝在放大生產(chǎn)后出現(xiàn)意外的雜質(zhì)，問(wèn)題根源可能并非工藝本身，而是工廠的海拔高度，本文將通過(guò)Takeda公司的一個(gè)真實(shí)案例，揭示高海拔環(huán)境如何通過(guò)影響溶劑沸點(diǎn)與反應(yīng)器操作，進(jìn)而引發(fā)雜質(zhì)與殘留金屬含量超標(biāo)的關(guān)鍵細(xì)節(jié)。具體內(nèi)容如下：
From Lab to Plant: Managing Operational Environment During Scale-Up
從實(shí)驗(yàn)室到工廠：放大生產(chǎn)過(guò)程中管理操作環(huán)境
Scale-up comes with its challenges, with adaptations to the process, materials and equipment often anticipated. Though these challenges can result from equipment, raw material differences, and process variability, operational environments must be a major focus during lab trials, as Yuhei Yamamoto and his team at Takeda learned in a recent experience.
工藝放大過(guò)程會(huì)伴隨諸多挑戰(zhàn)，通常需要對(duì)工藝、物料和設(shè)備進(jìn)行調(diào)整。盡管這些挑戰(zhàn)可能由設(shè)備問(wèn)題、原輔料差異及工藝變異性導(dǎo)致，但操作環(huán)境必須成為實(shí)驗(yàn)室試驗(yàn)期間的重點(diǎn)關(guān)注對(duì)象，正如 Yuhei Yamamoto 及其在 Takeda 的團(tuán)隊(duì)在近期一次實(shí)踐中所認(rèn)識(shí)到的那樣。
Yamamoto and his lab team took their Suzuki-Miyaura coupling reaction to new heights (literally), and published the lessons they learned from their scale-up with a contract manufacturing organization (CMO) at a higher altitude. CMOs at higher elevations are certainly not the norm; however, the research can help those with palladium-catalyzed reactions recognize early considerations and avoid unforeseen complications during scale-up.
Yamamoto 及其實(shí)驗(yàn)室團(tuán)隊(duì)將其鈴木 - 宮浦偶聯(lián)反應(yīng)（Suzuki-Miyaura coupling reaction）提升到了新的高度 —— 而且是從字面意義上來(lái)說(shuō)。他們與一家位于更高海拔的合同生產(chǎn)組織（contract manufacturing organization, CMO）合作進(jìn)行工藝放大，并將從中吸取的經(jīng)驗(yàn)教訓(xùn)整理發(fā)表。高海拔地區(qū)的 CMO 當(dāng)然并非普遍情況；不過(guò)，這項(xiàng)研究可為從事鈀催化反應(yīng)（palladium-catalyzed reactions）的研究者提供幫助，助力他們識(shí)別工藝放大前期需考慮的因素，避免過(guò)程中出現(xiàn)不可預(yù)見(jiàn)的問(wèn)題。
Troubleshooting Cause and Solutions
故障原因與解決方案
Palladium is sensitive to temperature and oxygen. To maintain the internal conditions of the reaction, the CMO (at a higher altitude) needed to use a pressure reactor.
鈀對(duì)溫度和氧氣敏感。為了維持反應(yīng)的內(nèi)部條件，位于高海拔地區(qū)的合同生產(chǎn)組織（CMO）需要使用加壓反應(yīng)器。
“Reaction temperature was an important factor and needed to be maintained at 85–95 °C. At high altitude, the solvent refluxed at 80 °C, and the reaction would not go to completion at this temperature. The CMO used a reactor that could be pressurized, allowing the internal temperature to reach 85–95 °C,” explained Yamamoto.
反應(yīng)溫度是一個(gè)重要因素，需要維持在 85–95°C。在高海拔地區(qū)，溶劑在 80°C 時(shí)回流，而在此溫度下反應(yīng)無(wú)法進(jìn)行完全。合同生產(chǎn)組織使用了可加壓的反應(yīng)器，使內(nèi)部溫度能夠達(dá)到 85–95°C 。
The researchers established solid reaction conditions in their lab; however, when the CMO performed the reaction at a higher altitude using the pressure reactor, the crystals had elevated levels of palladium. “The release test of the compound included impurity levels and residual palladium, and this was identified by checking the master batch record and comparing it to the laboratory procedure and data to identify any differences,” added Yamamoto.
研究人員在實(shí)驗(yàn)室中確定了可靠的反應(yīng)條件；然而，當(dāng)合同生產(chǎn)組織在高海拔地區(qū)使用加壓反應(yīng)器進(jìn)行反應(yīng)時(shí)，晶體中的鈀含量升高了。該化合物的放行測(cè)試包括雜質(zhì)水平和殘留鈀含量，這是通過(guò)檢查主批記錄并將其與實(shí)驗(yàn)室流程和數(shù)據(jù)進(jìn)行比較以識(shí)別任何差異來(lái)確定的。
Impurities are not uncommon with Suzuki-Miyaura coupling, according to Yamamoto. Dehalogenation, homo-coupling and oxidation can all produce impurities, but the out-of-expectation (OOE) levels of related substances led to concern. “Many parameters can affect impurity formation. If we consider which conditions cause impurity issues during scale-up, they include the presence of air (or oxygen), mixing efficiency, nitrogen flow, heating efficiency, and reaction temperature,” explained Yamamoto.
據(jù)Yamamoto介紹，鈴木 - 宮浦偶聯(lián)反應(yīng)中出現(xiàn)雜質(zhì)并不罕見(jiàn)。脫鹵、自身偶聯(lián)和氧化都可能產(chǎn)生雜質(zhì)，但相關(guān)物質(zhì)的超出預(yù)期（OOE）水平引發(fā)了擔(dān)憂。許多參數(shù)都會(huì)影響雜質(zhì)的形成。如果我們考慮在放大生產(chǎn)過(guò)程中哪些條件會(huì)導(dǎo)致雜質(zhì)問(wèn)題，這些條件包括空氣（或氧氣）的存在、混合效率、氮?dú)饬?、加熱效率和反?yīng)溫度。
His team investigated stirring efficiency, jacket temperature, reaction pressure and presence/absence of oxygen to determine the cause of the excess palladium.
他的團(tuán)隊(duì)調(diào)查了攪拌效率、夾套溫度、反應(yīng)壓力以及氧氣的存在與否，以確定鈀過(guò)量的原因。
The research team deduced that the elevated impurities from the reaction were caused by a high external temperature. They found that there were local hot spots near the high-temperature jacket.
研究團(tuán)隊(duì)推斷，反應(yīng)中雜質(zhì)升高是由較高的外部溫度引起的。他們發(fā)現(xiàn)高溫夾套附近存在局部熱點(diǎn)。
To tackle the crystal quality, the scientists noted that the jacket temperature needed to be below 105 °C. This measure helped to reduce impurities from the reaction. However, the strict aerobic conditions prevented them from removing the palladium after the reaction, and they needed to add air.
為了解決晶體質(zhì)量問(wèn)題，科學(xué)家們指出夾套溫度需要低于 105°C。這一措施有助于減少反應(yīng)產(chǎn)生的雜質(zhì)。然而，嚴(yán)格的需氧條件使他們無(wú)法在反應(yīng)后去除鈀，因此他們需要通入空氣。
Since adding air directly was not advisable, the team added air via O?/N? bubbling. This was integrated after the reaction to facilitate palladium removal and enhance crystal quality.
由于直接通入空氣不可取，團(tuán)隊(duì)通過(guò) O?/N?鼓泡的方式通入空氣。這一步驟在反應(yīng)后進(jìn)行，以促進(jìn)鈀的去除并提高晶體質(zhì)量。
Lessons Learned
經(jīng)驗(yàn)教訓(xùn)
In their research, the scientists emphasized the importance of mimicking the equipment and environments to be used for manufacturing. In this case, having utilized the pressure reactor in the process would have highlighted impurities that led to earlier process refinement.
在他們的研究中，科學(xué)家們強(qiáng)調(diào)了模擬生產(chǎn)中將要使用的設(shè)備和環(huán)境的重要性。在這種情況下，如果在過(guò)程中使用了加壓反應(yīng)器，就會(huì)更早地發(fā)現(xiàn)雜質(zhì)，從而更早地對(duì)工藝進(jìn)行優(yōu)化。
Yamamoto continued that other reactions at high altitude should take heed. “This issue is not limited to the S-M reaction and can occur with any reaction if the decrease in boiling point at high altitude is not considered. Therefore, it is recommended that, when running reactions at reflux or high temperature, a pressure reactor should be used in the lab and relevant data should be collected,” he furthered. Altitude is not a concern for reactions that do not require high temperatures or reflux.
Yamamoto繼續(xù)表示，高海拔地區(qū)的其他反應(yīng)也應(yīng)引起注意。“這個(gè)問(wèn)題不僅限于鈴木 - 宮浦反應(yīng)，如果不考慮高海拔地區(qū)沸點(diǎn)的降低，任何反應(yīng)都可能出現(xiàn)這種情況。因此，建議在進(jìn)行回流或高溫反應(yīng)時(shí)，實(shí)驗(yàn)室應(yīng)使用加壓反應(yīng)器并收集相關(guān)數(shù)據(jù)，” 他進(jìn)一步說(shuō)道。對(duì)于不需要高溫或回流的反應(yīng)，海拔高度不是問(wèn)題。
Good communication is the key, according to Yamamoto, concluding, “For manufacturers at high altitude, I recommend maintaining good communication with laboratory chemists, especially if the lab chemists are located at normal altitude.”
Yamamoto總結(jié)道，良好的溝通是關(guān)鍵：“對(duì)于高海拔地區(qū)的制造商，我建議與實(shí)驗(yàn)室化學(xué)家保持良好的溝通，尤其是當(dāng)實(shí)驗(yàn)室化學(xué)家位于正常海拔地區(qū)時(shí)。”
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