冷凍瓶——5 個關(guān)鍵注意事項

Freezing bottles – 5 critical considerations
冷凍瓶——5 個關(guān)鍵注意事項
Claus Exenberger
September 25, 2025
 
Freezing drug substances to ultra-cold temperatures is a standard step in biopharmaceutical manufacturing. Yet, beyond simply cooling, it’s the critical quality attributes (CQA), like product safety, consistency, and process efficiency, that truly define success in biopharma. When preparing to freeze drug substances in sterile bottles, it’s essential to weigh several key factors. These considerations help ensure the freezing process not only preserves product integrity but also supports reliable and productive operations.
將原料藥冷凍至超低溫是生物制藥生產(chǎn)的標準步驟。然而，除了簡單的冷卻之外，關(guān)鍵質(zhì)量屬性 (CQA)，例如產(chǎn)品安全性、一致性和工藝效率，才是真正決定生物制藥成功的關(guān)鍵。在準備將原料藥冷凍于無菌瓶中時，必須權(quán)衡幾個關(guān)鍵因素。這些考慮因素有助于確保冷凍過程不僅能保持產(chǎn)品完整性，還能支持可靠且高效的操作。
 
1. Secure product quality with controlled freezing通過控制冷凍來確保產(chǎn)品質(zhì)量
Controlled and uniform freezing is essential to avoid cryoconcentration – a phenomenon where solutes concentrate unevenly due to ice formation from the outside in. This can lead to protein denaturation and pH shifts, which ultimately impact drug stability and efficacy. Studies show that the “volcano effect" in bottles, where solutes are pushed to the center and top, can cause significant concentration gradients. Manufacturers can minimize these risks by controlling the freezing rate and temperature profile throughout the freezing process including the solidification phase. Product integrity stems from a controlled freezing which can be adapted depending on the specifications of the drug substance, such as cell-based or mAbs.
受控且均勻的冷凍對于避免低溫濃縮至關(guān)重要——低溫濃縮是一種溶質(zhì)由于從外部向內(nèi)結(jié)冰而濃縮不均勻的現(xiàn)象。這會導(dǎo)致蛋白質(zhì)變性和 pH 值變化，最終影響藥物的穩(wěn)定性和療效。研究表明，瓶中的“火山效應(yīng)"（溶質(zhì)被推到中心和頂部）會導(dǎo)致明顯的濃度梯度。制造商可以通過控制整個冷凍過程（包括凝固階段）的冷凍速率和溫度曲線來最大限度地降低這些風(fēng)險。產(chǎn)品完整性源于受控冷凍，可根據(jù)藥物物質(zhì)（例如基于細胞或單克隆抗體）的規(guī)格進行調(diào)整。
What we learnt about controlled bottle freezing
我們對受控瓶冷凍的了解
 
 
Figure 1: Visualization of the volcano effect in bottles occurring in uncontrolled freezing, compared to consistent distribution in controlled freezing. 圖 1：不受控冷凍時瓶子中火山效應(yīng)的可視化，與受控冷凍時的一致分布進行比較。
 
2. Protect bottles for container closure integrity保護瓶子以確保容器密封的完整性
When drug substances or other raw materials, such as buffer or media, are frozen in bottles, the single-use containers must maintain their integrity. Even though they’re called rigid containers, there are vulnerable spots, particularly when the single-use container and assemblies become more brittle under sub-zero conditions. 
當(dāng)藥物或其他原材料（例如緩沖液或培養(yǎng)基）在瓶中冷凍時，一次性容器必須保持其完整性。盡管它們被稱為硬質(zhì)容器，但也存在脆弱點，尤其是在零下環(huán)境下，一次性容器和組件會變得更脆。
To prevent leakage or contamination, bottle integrity can remain secure when the assemblies are protected during cold chain handling. Bottle RoSS is the equivalent of the RoSS® shell, which is the protective shell for single-use bags. With Bottle RoSS the tubing on bottles is protected at glass-like sub-zero temperatures with the help of a soft 3D foam which hardens at frozen state.
為了防止泄漏或污染，在冷鏈處理過程中，如果組件受到保護，瓶子的完整性就能得到保障。Bottle RoSS 相當(dāng)于 RoSS® 外殼，后者是一次性包裝袋的保護殼。Bottle RoSS 采用了柔軟的 3D 泡沫，在冷凍狀態(tài)下會變硬，從而保護瓶子上的管子免受零下溫度的侵蝕。
More about Bottle RoSS
了解更多關(guān)于 Bottle RoSS 的信息
 
 
3. Static or blast freezing?靜態(tài)冷凍還是速凍？
In general, the choice between static and blast freezing for cooling drug substances in bottles depends on the container format and the sensitivity of the drug substances.
一般來說，選擇靜態(tài)冷凍還是速凍來冷卻瓶裝藥物取決于容器的規(guī)格和藥物的敏感度。
Static freezers are meant for storing drug substances at low temperatures, not for freezing them. Using them to freeze bottles can lead to issues like cryoconcentration and product degradation. Even if the freezing time is similar to other methods for small bottles, the lack of control during the critical phase transition still negatively impacts product quality.
靜態(tài)冷凍機用于低溫儲存藥物，而非冷凍。使用靜態(tài)冷凍機冷凍瓶裝藥物可能會導(dǎo)致低溫濃縮和產(chǎn)品降解等問題。即使冷凍時間與其他小瓶冷凍方法相似，關(guān)鍵相變期間的控制不足仍會對產(chǎn)品質(zhì)量產(chǎn)生負面影響。
In contrast, blast freezers with high-speed air convection technology are more effective at rapidly and uniformly freezing drug substances. This technology is particularly effective for biologics stored in bulky containers, such as bottles, as it minimizes thermal gradients and preserves product quality.
相比之下，采用高速空氣對流技術(shù)的速凍機能夠更有效地快速均勻地冷凍藥物。該技術(shù)尤其適用于儲存在大型容器（例如瓶裝）中的生物制劑，因為它可以最大限度地減少熱梯度并保持產(chǎn)品質(zhì)量。
 
 
4. Role of bottle types and sizes瓶子類型和尺寸的作用
Not all bottles are created equal. Manufacturers can choose among bottles with different types, geometry and size of the bottle, which may impact on freezing efficiency and uniformity. HDPE and PETG bottles have different features affecting the following fluid and cold chain management processes. Same with the sizes that can range up to 20L bottles.
并非所有瓶子都是一樣的。制造商可以選擇不同類型、幾何形狀和尺寸的瓶子，這可能會影響冷凍效率和均勻性。HDPE 和 PETG 瓶具有不同的特性，會影響以下流體和冷鏈管理流程。容量高達 20L 的瓶子也是如此。
Overall, rigid bottles allow for optimal airflow in blast freezers, supporting consistent freezing profiles. Larger containers may require customized airflow systems to ensure uniform temperature distribution.
總體而言，硬質(zhì)瓶可在速凍機中實現(xiàn)最佳氣流，從而支持一致的冷凍曲線。較大的容器可能需要定制的氣流系統(tǒng)，以確保均勻的溫度分布。
 
5. Think end-to-end for closed system efficiency端到端思考，提高封閉系統(tǒng)的效率
Look left and right before freezing bottles. An efficient and safe freezing process requires an aseptic closed system, beginning with the aseptic filling and filtration stages. This continues through cold chain storage and shipping with a controlled thawing process. Integrating closed systems minimizes contamination risks, streamlines workflows, and ensures that drug substances remain protected at every stage. This end-to-end strategy meets GMP-relevant quality standards, including Annex 1, and operational efficiency, making it the gold standard for working with bottles in biopharma. 
冷凍瓶子前務(wù)必仔細檢查。高效安全的冷凍流程需要無菌密閉系統(tǒng)，從無菌分裝和過濾階段開始，一直到冷鏈儲存和運輸，并采用受控解凍流程。集成密閉系統(tǒng)可最大限度地降低污染風(fēng)險，簡化工作流程，并確保藥物在每個階段都得到保護。這種端到端策略符合 GMP 相關(guān)質(zhì)量標準（包括附錄 1）和運營效率，使其成為生物制藥行業(yè)使用瓶子的黃金標準。
Interview: Trends with Single-Use Bottles in Bioprocessing – Single Use Support
訪談：生物加工中一次性瓶的趨勢——一次性支持

 
Mastering filling & freezing of bottles with Single Use Support利用一次性使用支持掌握瓶子的分裝和冷凍
Uncontrolled bottle freezing processes often struggle to scale, leading to inefficiencies and risks for critical drug substances. With RoSS.BLST, Single Use Support addresses these pain points by enabling seamless transitions from clinical to commercial production – without compromise.
不受控制的瓶裝冷凍工藝通常難以規(guī)?；?，導(dǎo)致關(guān)鍵藥物效率低下并帶來風(fēng)險。借助 RoSS.BLST，Single Use Support 解決了這些痛點，實現(xiàn)了從臨床到商業(yè)生產(chǎn)的無縫過渡，且絲毫不受影響。
Single Use Support’s end-to-end fluid management and cold chain solutions deliver scalable, aseptically closed processes for advanced fluid and cold chain management of bottles, ensuring product safety and regulatory compliance at every step. As the only provider offering fully integrated handling, filling and cooling critical liquids in bottles, Single Use Support empowers biopharma manufacturers to streamline fluid and cold chain management with bottles with compatibility, safety and efficiency.
Single Use Support 的端到端流體管理和冷鏈解決方案為先進的瓶裝流體和冷鏈管理提供可擴展、無菌封閉的流程，確保每一步的產(chǎn)品安全和合規(guī)性。作為一家提供全集成瓶裝關(guān)鍵液體處理、分裝和冷卻的供應(yīng)商，Single Use Support 使生物制藥制造商能夠使用兼具兼容性、安全性和效率的瓶子來簡化流體和冷鏈管理。