生物制劑的冷凍和冷鏈解決方案——最佳實(shí)踐
Freezing and cold chain solutions for biologics – best practices
生物制劑的冷凍和冷鏈解決方案——最佳實(shí)踐
Alexander Fuchs
May 6, 2024
Freezing biologics is an almost unavoidable step in the process of preserving and storing them for an extended period of time. After all, biologics encompass a diverse range of therapeutic products derived from living organisms. They include monoclonal antibodies, protein solutions, and other biotherapeutics – complex formulations engineered to treat various diseases and medical conditions. The freeze-thaw process requires close attention to formulation, cooling rates, and cryoprotective strategies to maintain the stability and efficacy of the drug product.
冷凍是生物制劑長期保存和儲存過程中幾乎不可避免的步驟。畢竟，生物制劑涵蓋了多種源自活體生物的治療產(chǎn)品，包括單克隆抗體、蛋白質(zhì)溶液和其他生物治療藥物——這些復(fù)雜的制劑旨在治療各種疾病和病癥。凍融過程需要密切關(guān)注制劑配方、冷卻速率和冷凍保護(hù)策略，以維持藥物產(chǎn)品的穩(wěn)定性和療效。
Safe cold storage of biologics is key in ensuring the efficacy and safety of pharmaceutical products throughout their lifecycle. As the demand for biopharmaceuticals continues to rise, so does the need for efficient and reliable storage solutions that maintain the integrity of the cold chain. Biologics are often highly temperature-sensitive, requiring precise control to prevent degradation and ensure potency.
生物制劑的安全冷藏是確保藥物產(chǎn)品在其整個(gè)生命周期內(nèi)療效和安全性的關(guān)鍵。隨著對生物制藥的需求持續(xù)增長，對能夠維持冷鏈完整性的高效可靠儲存解決方案的需求也日益增加。生物制劑通常對溫度高度敏感，需要精確控制溫度以防止降解并確保其效力。
In this article, we will discuss essential requirements and innovative solutions for freezing and storing biologics along the cold chain – from ultracold and cryogenic freezers to solutions for safe packaging of biologics.
本文將探討生物制劑在冷鏈中冷凍和儲存的基本要求和創(chuàng)新解決方案——從超低溫和低溫冷凍機(jī)到生物制劑的安全包裝方案。
Biologics early considerations 生物制劑早期考量
Freezing biologics demands the consideration of various critical factors to uphold their integrity and efficacy throughout the process. Some of these considerations include:
生物制劑的冷凍保存需要考慮多種關(guān)鍵因素，以確保其在整個(gè)過程中保持完整性和有效性。這些因素包括：
Container selection: Vials, cryovessels, or single-use bags – there are numerous types of containers to choose from when freezing biologics. It is important for manufacturers to consider the thermodynamic characteristics of the materials they are made of to ensure that they can endure the stress that may come with extreme temperature gradients while protecting valuable therapies, such as mAbs or mRNA vaccines.
容器選擇：冷凍保存生物制劑時(shí)，可選擇的容器類型多種多樣，例如小瓶、冷凍容器或一次性冷凍袋。生產(chǎn)商必須考慮容器材料的熱力學(xué)特性，以確保其能夠承受極端溫度梯度帶來的壓力，同時(shí)保護(hù)重要的治療藥物，例如單克隆抗體或mRNA疫苗。
However, container options do not only differ in terms of built materials, but also in regard to their size: The volume of individual units significantly impacts their freezing behavior, thus also the risk for detrimental effects of freezing like unwanted ice crystal formation or protein concentration.
然而，容器的選擇不僅體現(xiàn)在材料上，還體現(xiàn)在其尺寸上：單個(gè)容器的體積會顯著影響其冷凍性能，進(jìn)而影響冷凍過程中可能產(chǎn)生的有害影響，例如形成不必要的冰晶或蛋白質(zhì)濃縮。
Formulation and cryoprotective agents: Biologics themselves are already highly complex structures, but they are often not frozen alone, but in combination with other substances, such as cryoprotective agents (CPAs or cryoprotectants). Excipients like glycerol and glycol in formulation development play vital roles in mitigating cryoconcentration effects and sustaining the stability of proteins during freezing and thawing cycles.
制劑和冷凍保護(hù)劑：生物制劑本身就是高度復(fù)雜的結(jié)構(gòu)，但它們通常并非單獨(dú)冷凍，而是與其他物質(zhì)（例如冷凍保護(hù)劑）混合使用。在制劑研發(fā)中，甘油和乙二醇等輔料在減輕冷凍濃縮效應(yīng)和維持蛋白質(zhì)在凍融循環(huán)中的穩(wěn)定性方面發(fā)揮著至關(guān)重要的作用。
Freezing and thawing protocols: Cooling rates are a fundamental aspect in achieving desired freeze-thaw profiles and preserving protein stability. It is one of the most decisive steps in unit operation of pharmaceutical freezers, which is why the next chapter will discuss this facet in more detail. 1
凍融方案：冷卻速率是實(shí)現(xiàn)理想凍融曲線和保持蛋白質(zhì)穩(wěn)定性的關(guān)鍵因素。它是制藥冷凍機(jī)單元操作中最關(guān)鍵的步驟之一，因此下一章將更詳細(xì)地討論這一方面。
Hitting the right cooling rate and speed for biological drug substances
生物藥物的冷卻速率和速度要合適。
Hitting the optimal cooling rate is crucial when freezing biological drug substances. This rate directly impacts various aspects of the process, including ice formation, protein denaturation, and overall product stability.
在冷凍生物藥物時(shí)，達(dá)到最佳冷卻速率至關(guān)重要。該速率直接影響工藝的各個(gè)方面，包括冰的形成、蛋白質(zhì)變性和產(chǎn)品的整體穩(wěn)定性。
Since there is no cooling and thawing rate that is considered to be universally ideal, it has to be individualized for each product. This requires thorough stability studies, including characterization of all its components and the kinetics occurring during freezing.
由于不存在普遍適用的理想冷卻和解凍速率，因此必須針對每種產(chǎn)品進(jìn)行個(gè)性化設(shè)置。這需要進(jìn)行全面的穩(wěn)定性研究，包括對所有成分的表征以及冷凍過程中發(fā)生的動力學(xué)變化。
Linked to freezing rates is the time for phase transition as an even more crucial factor for protein stability: It refers to the amount of time it takes for the product to transition from the liquid to the frozen state, and determines effects like cryoconcentration, pH changes, and glass formation. 2
與冷凍速率密切相關(guān)的是相變時(shí)間，它是影響蛋白質(zhì)穩(wěn)定性的一個(gè)更為關(guān)鍵的因素：相變時(shí)間是指產(chǎn)品從液態(tài)轉(zhuǎn)變?yōu)楣虘B(tài)所需的時(shí)間，它決定了諸如冷凍濃縮、pH 值變化和玻璃態(tài)形成等效應(yīng)。
Freezing strategies for biologics 生物制劑的冷凍策略
Biotechnology knows several freezing strategies for biologics, with some of them being more eligible than others. However, it always depends on the very scope that a pharmaceutical company or CDMO has when subjecting their products to a distinct freezing method, as well as the individual product characteristics.
生物技術(shù)領(lǐng)域針對生物制劑開發(fā)了多種冷凍策略，其中一些策略比其他策略更適用。然而，最終選擇哪種冷凍方法，始終取決于制藥公司或合同研發(fā)生產(chǎn)機(jī)構(gòu)（CDMO）的具體業(yè)務(wù)范圍以及產(chǎn)品的特性。
In the following sections, we will discuss four methods to freeze biologics and biosimilars.
在接下來的章節(jié)中，我們將討論四種生物制劑和生物類似藥的冷凍方法。
Slow uncontrolled freezing 緩慢不受控制的冷凍
Slow uncontrolled freezing, characterized by gradual cooling rates and minimal control over ice crystal formation, may appear as a simple approach, but poses significant risks to protein solutions. This method often results in the formation of unwanted ice crystals, inducing denaturation and compromising product stability.
緩慢且不受控的冷凍方法，其特點(diǎn)是冷卻速率緩慢，且對冰晶形成控制甚微，看似簡單，但卻對蛋白質(zhì)溶液構(gòu)成重大風(fēng)險(xiǎn)。該方法通常會導(dǎo)致形成不必要的冰晶，從而誘發(fā)蛋白質(zhì)變性并損害產(chǎn)品穩(wěn)定性。
Furthermore, slow freezing brings an increased risk for cryoconcentration, describing an inhomogeneous distribution of protein mass within the sample. 3
此外，緩慢冷凍還會增加冷凍濃縮的風(fēng)險(xiǎn)，冷凍濃縮是指樣品中蛋白質(zhì)質(zhì)量分布不均勻。³
Lyophilization of biologics 生物制劑的凍干
Lyophilization, or freeze-drying, stands as a popular method for preserving biologics, involving freezing the product followed by ice removal under vacuum for extended frozen storage. This process utilizes buffer solutions like sucrose to minimize ice nucleation and stabilize protein formulations.
凍干，也稱冷凍干燥，是一種常用的生物制劑保存方法，其原理是將產(chǎn)品冷凍，然后在真空條件下去除冰層，從而實(shí)現(xiàn)長期冷凍保存。該過程利用蔗糖等緩沖溶液來減少冰核的形成并穩(wěn)定蛋白質(zhì)制劑。
While lyophilization offers advantages in the preservation of biopharmaceuticals, it also presents disadvantages. These may include high operational costs, longer processing times, and product loss as a result of protein denaturation. Therefore, products like pharmaceuticals based on LNPs are usually not freeze-dried. 4
雖然凍干在生物制藥的保存方面具有優(yōu)勢，但也存在一些缺點(diǎn)。這些缺點(diǎn)包括較高的操作成本、較長的處理時(shí)間以及因蛋白質(zhì)變性造成的產(chǎn)品損失。因此，像基于脂質(zhì)納米顆粒（LNP）的藥物這類產(chǎn)品通常不采用凍干工藝。
Controlled plate freezing 受控平板冷凍
Controlled plate freezing is a methodical approach to freezing biologics that involves precise regulation of freezing rates and temperature gradients. This technique is not only valuable during process development and small-scale production: With innovative plate freezing and thawing systems like RoSS.pFTU, both small and large-scale freezing of biologics is possible.
可控平板冷凍是一種系統(tǒng)化的生物制劑冷凍方法，它涉及對冷凍速率和溫度梯度的精確控制。這項(xiàng)技術(shù)不僅在工藝開發(fā)和小規(guī)模生產(chǎn)中具有價(jià)值，而且借助RoSS.pFTU等創(chuàng)新型平板冷凍和解凍系統(tǒng)，生物制劑的小規(guī)模和大規(guī)模冷凍均可實(shí)現(xiàn)。
By optimizing heat transfer and freezing time, controlled plate freezing ensures the preservation of protein stability throughout the freezing process, with a decreased risk for protein aggregation and other unwanted freezing effects.
通過優(yōu)化傳熱和冷凍時(shí)間，可控平板冷凍能夠確保蛋白質(zhì)在整個(gè)冷凍過程中保持穩(wěn)定性，并降低蛋白質(zhì)聚集和其他不良冷凍效應(yīng)的風(fēng)險(xiǎn)。
Cryogenic freezing and cryopreservation 低溫冷凍和冷凍保存
Cryogenic freezing involves the use of extremely low temperatures (down to around -180°C) for the preservation of biologics, ensuring long-term stability and viability. This method, integral to cryopreservation, safeguards the integrity of biotherapeutics over extended periods.
低溫冷凍是指利用極低溫度（低至約-180°C）保存生物制品，以確保其長期穩(wěn)定性和活性。該方法是冷凍保存不可或缺的一部分，能夠長期保障生物治療藥物的完整性。
Cryobiology plays an important role in individualizing the ideal process parameters and storage temperatures for, e.g., cell therapies, which are typically stored at around -150°C. It represents an essential preservation method in bioprocessing, when ultra-low temperatures (around -80°C) are not sufficient to preserve product quality.
低溫生物學(xué)在確定理想的工藝參數(shù)和儲存溫度方面發(fā)揮著重要作用，例如，細(xì)胞療法通常儲存在約-150°C的溫度下。當(dāng)超低溫（約-80°C）不足以保證產(chǎn)品質(zhì)量時(shí)，低溫冷凍便成為生物加工過程中必不可少的保存方法。
Control over freezing rates, though, has long been a major challenge during cryogenic freezing, due to the use of liquid nitrogen as cooling means. Single Use Support has therefore developed the first truly controlled cryogenic freezer, the RoSS.LN2F, which protects biologics from full exposure to LN2 while following adjustable freezing profiles. 5
然而，由于使用液氮作為冷卻手段，控制冷凍速率一直是低溫冷凍過程中的一大挑戰(zhàn)。因此，Single Use Support公司開發(fā)了首款真正可控的低溫冷凍機(jī)RoSS.LN2F，該設(shè)備能夠根據(jù)可調(diào)節(jié)的冷凍曲線，在避免生物制品完全暴露于液氮的情況下，保護(hù)其免受液氮的直接影響。
Freezing biologics and the advances with single-use technologies
生物制劑的冷凍保存及一次性使用技術(shù)的進(jìn)步
For cryopreservation of sensitive biologics Single Use Support is convinced of plate freezing and cryogenic freezing as two extremely favorable approaches to control the cooling and thawing process. They can ideally cater to individual product requirements in terms of cooling rates and target temperature, ensuring ideal results upon thawing.
對于敏感生物制劑的冷凍保存，Single Use Support 堅(jiān)信平板冷凍和低溫冷凍是控制冷卻和解凍過程的兩種極其理想的方法。它們能夠完美滿足不同產(chǎn)品在冷卻速率和目標(biāo)溫度方面的個(gè)性化需求，確保解凍后達(dá)到理想效果。
This is why Single Use Support offers innovative solutions for both methods, providing reliable and scalable options for controlled freezing and thawing. The plate-based freeze and thaw technology of the RoSS.pFTU platform ensures homogeneous processing with full control over the process, minimizing the formation of ice crystals and maintaining the stability of biologic substances.
因此，Single Use Support 為這兩種方法提供了創(chuàng)新解決方案，為可控的冷凍和解凍提供了可靠且可擴(kuò)展的選擇。RoSS.pFTU 平臺的平板式凍融技術(shù)可確保處理過程的均勻性，并實(shí)現(xiàn)對整個(gè)過程的完全控制，最大限度地減少冰晶的形成，從而維持生物物質(zhì)的穩(wěn)定性。
The cryogenic freezer RoSS.LN2F, on the other hand, enables pharmaceutical manufacturers to ensure long-term storage at even lower temperatures, ensuring the viability of biotherapeutics like certain cell-based products – for small and large volumes.
另一方面，低溫冷凍機(jī) RoSS.LN2F 使制藥企業(yè)能夠在更低的溫度下進(jìn)行長期儲存，從而確保某些細(xì)胞療法等生物治療藥物（無論小批量還是大批量）的活性。
Both systems work with high-quality single-use bags covered in the RoSS® Shell as protective packaging solution. And being based on a modular and vendor-agnostic setup, the solutions by Single Use Support are fully scalable, catering to both small and large scale demands when processing bulk drug substances.
這兩個(gè)系統(tǒng)均采用高品質(zhì)的一次性包裝袋，并以 RoSS® Shell 作為保護(hù)性包裝解決方案。 Single Use Support 的解決方案基于模塊化和供應(yīng)商無關(guān)的架構(gòu)，具有完全可擴(kuò)展性，能夠滿足原料藥加工過程中從小規(guī)模到大規(guī)模的各種需求。
Single Use Support couples the individual strengths of plate and cryogenic freezing with the overall advantages of single-use technologies: They allow for safe and efficient bioprocessing, with elevated flexibility, cost-effectiveness, and sustainability due to a reduction of resource consumption for manual cleaning and sterilization.
Single Use Support 將平板冷凍和低溫冷凍各自的優(yōu)勢與一次性技術(shù)的整體優(yōu)勢相結(jié)合：由于減少了人工清潔和滅菌所需的資源消耗，該方案能夠?qū)崿F(xiàn)安全高效的生物加工，并具有更高的靈活性、成本效益和可持續(xù)性。
What’s needed along the cold chain of biologics?
生物制劑冷鏈需要哪些環(huán)節(jié)？
The safe storage of biologics along the cold chain requires meticulous attention to several critical factors to ensure product integrity and efficacy. From temperature control to protection from contamination, various elements must be carefully managed to maintain the quality of biologic products throughout biomanufacturing – all in regard to regulatory compliance.
生物制劑在冷鏈中的安全儲存需要對多個(gè)關(guān)鍵因素進(jìn)行細(xì)致關(guān)注，以確保產(chǎn)品的完整性和有效性。從溫度控制到防止污染，必須精心管理各種要素，以在整個(gè)生物制藥過程中維持生物制品的質(zhì)量——所有這些都必須符合監(jiān)管要求。
What makes cold chain management of biologics and biosimilars even more complex is the need for individualized approaches, depending on the very product or intermediate that is currently being processed. Different types of biologics have unique requirements and vulnerabilities – e.g. physical stress, light or oxygen exposure. One of the most common aspects to be considered is temperature, along with bringing efficiency and safety into harmony.
生物制劑和生物類似藥的冷鏈管理之所以更加復(fù)雜，是因?yàn)樾枰鶕?jù)當(dāng)前正在加工的具體產(chǎn)品或中間體采取個(gè)性化的方法。不同類型的生物制劑具有獨(dú)特的要求和脆弱性——例如，物理應(yīng)力、光照或氧氣暴露。需要考慮的最常見因素之一是溫度，以及如何在效率和安全性之間取得平衡。
Best choice for cold storage of Biopharmaceuticals - A Comparison
生物制藥冷藏的最佳選擇——比較
Temperature control in cold storage 冷庫的溫度控制
Temperature control plays a pivotal role in the storage of biologics due to the inherent sensitivity of these products to temperature fluctuations. Biologics, such as mRNA vaccines or allogeneic stem cell therapies, often contain delicate molecular structures that can be easily compromised by exposure to inappropriate temperatures.
由于生物制品本身對溫度波動非常敏感，溫度控制在生物制品的儲存中起著至關(guān)重要的作用。例如，mRNA疫苗或異體干細(xì)胞療法等生物制品通常含有精細(xì)的分子結(jié)構(gòu)，暴露于不適宜的溫度下很容易受到破壞。
Maintaining the prescribed temperature range is critical to preserving the stability and efficacy of biologic products. Deviations from the recommended storage conditions can lead to irreversible damage, including denaturation of proteins, loss of biological activity, protein stability, and degradation of nucleic acids. These alterations can not only render the product ineffective, but also pose potential safety risks to patients.
維持規(guī)定的溫度范圍對于保持生物制品的穩(wěn)定性和有效性至關(guān)重要。偏離推薦的儲存條件會導(dǎo)致不可逆的損害，包括蛋白質(zhì)變性、生物活性喪失、蛋白質(zhì)穩(wěn)定性下降以及核酸降解。這些改變不僅會使產(chǎn)品失效，還會對患者構(gòu)成潛在的安全風(fēng)險(xiǎn)。
It is the recommended storage temperature that, being specific for each product type, makes cold chain management so complex for pharmaceutical companies and CDMOs. For instance, Fc-fusion proteins have been found to aggregate during long-term storage at -30°C; samples stored at both -70°C and -20°C, on the other hand, remained stable.
正是由于每種產(chǎn)品類型的推薦儲存溫度各不相同，才使得制藥公司和合同研發(fā)生產(chǎn)機(jī)構(gòu)（CDMO）的冷鏈管理如此復(fù)雜。例如，研究發(fā)現(xiàn)Fc融合蛋白在-30°C長期儲存期間會發(fā)生聚集；而儲存在-70°C和-20°C的樣品則保持穩(wěn)定。
Nevertheless, there are some rules of thumb regarding typical storage temperatures for biologics:
不過，關(guān)于生物制劑的典型儲存溫度，有一些經(jīng)驗(yàn)法則：
此外，生物制品的溫度敏感性不僅限于儲存，還體現(xiàn)在運(yùn)輸和處理過程中。運(yùn)輸過程中的溫度波動會對產(chǎn)品質(zhì)量產(chǎn)生不利影響，尤其是在溫度波動超出可接受范圍的情況下。
Combining efficiency and safety 兼顧效率與安全性
Achieving the delicate equilibrium between efficiency and safety is a balancing act in the storage of biologics. While optimizing storage processes for efficiency is essential to meet production demands and minimize costs, it must not compromise the safety and integrity of biologic products.
在生物制品的儲存過程中，如何在效率和安全性之間取得微妙的平衡至關(guān)重要。優(yōu)化儲存流程以提高效率對于滿足生產(chǎn)需求和降低成本至關(guān)重要，但絕不能以犧牲生物制品的安全性和完整性為代價(jià)。
Efficiency in storage entails streamlining workflows, maximizing storage capacity, and minimizing downtime. However, these optimizations must not compromise safety measures, such as temperature control, contamination prevention, and product traceability.
提高儲存效率意味著簡化工作流程、最大化儲存容量和最小化停機(jī)時(shí)間。然而，這些優(yōu)化措施絕不能影響安全措施，例如溫度控制、污染預(yù)防和產(chǎn)品可追溯性。
By integrating efficient storage practices with advanced systems and robust safety protocols, biopharmaceutical companies can ensure that biologic products are stored in optimal conditions while reducing the risk of product loss or compromise. This holistic approach to storage management not only optimizes efficiency in biomanufacturing, but also safeguards product quality and patient safety throughout the cold chain. 6 7
通過將高效的儲存實(shí)踐與先進(jìn)的系統(tǒng)和完善的安全規(guī)程相結(jié)合，生物制藥公司可以確保生物制品在最佳條件下儲存，同時(shí)降低產(chǎn)品損失或受損的風(fēng)險(xiǎn)。這種全面的儲存管理方法不僅優(yōu)化了生物制藥的效率，而且在整個(gè)冷鏈過程中保障了產(chǎn)品質(zhì)量和患者安全。
窗體底端
Managing the cold chain: The potential of single-use technologies
冷鏈管理：一次性技術(shù)的潛力
Effectively managing the cold chain presents significant challenges in the storage and transportation of biologics or biosimilars. However, single-use technologies offer immense potential in addressing these challenges and optimizing cold chain management processes.
有效管理生物制劑或生物類似藥的冷鏈在儲存和運(yùn)輸方面面臨著諸多挑戰(zhàn)。然而，一次性技術(shù)在應(yīng)對這些挑戰(zhàn)和優(yōu)化冷鏈管理流程方面展現(xiàn)出巨大的潛力。
In contrast to walk-in freezers and cold rooms, upright ultra-cold storage freezers with a customized inner shelving system allow maximized storage density and space efficiency. Combined with advanced temperature control including digital alarming management as well as long temperature holding in the case of failure, these freezers offer an elevated level of reliability and safety while being energy-effective and user-friendly.
與步入式冷凍庫和冷藏室相比，配備定制內(nèi)部擱架系統(tǒng)的立式超低溫冷凍庫能夠最大限度地提高存儲密度和空間利用率。結(jié)合先進(jìn)的溫度控制技術(shù)（包括數(shù)字報(bào)警管理）以及故障時(shí)的長時(shí)間溫度保持功能，這些冷凍庫在提供更高可靠性和安全性的同時(shí)，還兼具節(jié)能和易用性。
As not only the number of individual freezers, but also their interior can be customized according to specific needs, they are prepared to be used at different scales, making production lines ready for future changes in capacity needs.
由于不僅冷凍庫的數(shù)量，而且其內(nèi)部結(jié)構(gòu)也可以根據(jù)具體需求進(jìn)行定制，因此它們可以適應(yīng)不同規(guī)模的應(yīng)用，使生產(chǎn)線能夠應(yīng)對未來產(chǎn)能需求的變化。
Ultra-cold storage for biologics – when refrigeration is not enough
生物制劑的超低溫儲存——當(dāng)普通冷藏不足以滿足需求時(shí)
Ultra-cold storage involves temperatures around -80°C, and is crucial for preserving the efficacy and stability of biologics, such as vaccines, cell therapies, and mRNA-based drugs. These delicate biopharmaceuticals often require storage at ultra-low temperatures to prevent degradation and maintain protein stability along with therapeutic properties.
超低溫儲存是指在約-80°C的溫度下進(jìn)行儲存，對于保持生物制劑（例如疫苗、細(xì)胞療法和mRNA藥物）的療效和穩(wěn)定性至關(guān)重要。這些敏感的生物制藥產(chǎn)品通常需要在超低溫下儲存，以防止降解并維持蛋白質(zhì)穩(wěn)定性及其治療特性。
Ultra-low temperature storage can either be necessary超低溫儲存可能是必要的。
However, achieving and maintaining such extreme temperatures presents several challenges:
然而，實(shí)現(xiàn)并維持如此極端的溫度面臨著諸多挑戰(zhàn)：
Single Use Support's ultra cold storage RoSS.ULTF addresses these challenges by offering precise temperature control down to -75°C (-103°F), ensuring the integrity of stored biologics. Its modularity allows for tailored shelving systems to accommodate various sizes of bioprocess containers, maximizing storage density and providing efficient storage solutions.
Single Use Support 的超低溫存儲系統(tǒng) RoSS.ULTF 通過提供低至 -75°C (-103°F) 的精確溫度控制，有效應(yīng)對了這些挑戰(zhàn)，確保儲存的生物制品的完整性。其模塊化設(shè)計(jì)允許定制貨架系統(tǒng)，以適應(yīng)各種尺寸的生物工藝容器，從而最大限度地提高存儲密度并提供高效的存儲解決方案。
Moreover, its modularity enables easy integration into existing facilities, offering flexibility in storage location and setup. Being compatible not only with RoSS® Shells as a dedicated protective packaging solution further discussed below, but also with all other primary packagings, the RoSS.ULTF provides additional protection for single-use bioprocess containers during storage and transport.
此外，其模塊化設(shè)計(jì)使其能夠輕松集成到現(xiàn)有設(shè)施中，從而在存儲位置和設(shè)置方面提供更大的靈活性。RoSS.ULTF 不僅與下文將詳細(xì)介紹的專用保護(hù)性包裝解決方案 RoSS® Shells 兼容，而且與所有其他初級包裝兼容，可在存儲和運(yùn)輸過程中為一次性生物工藝容器提供額外的保護(hù)。
Enhanced protection during cold storage and logistics of biologics
加強(qiáng)生物制品冷藏和物流過程中的保護(hù)
Effective protection during biologic storage is crucial for maintaining potency and safety. Temperature fluctuations and environmental factors can compromise their integrity, leading to reduced efficacy or complete loss. Robust protection measures are thus essential.
在生物制劑儲存過程中，有效的保護(hù)對于維持其效力和安全性至關(guān)重要。溫度波動和環(huán)境因素會損害其完整性，導(dǎo)致效力降低甚至完全喪失。因此，強(qiáng)有力的保護(hù)措施必不可少。
The RoSS® Shell offers a solution by providing a secure enclosure for single-use bags, shielding biologics during transportation, freeze-thaw cycles, and storage. Its versatility and compatibility with various bag sizes and manufacturers ensure consistent protection from physical stress, which might lead to bag ruptures and product loss.
RoSS® Shell 提供了一種解決方案，它為一次性包裝袋提供安全的封閉空間，在運(yùn)輸、凍融循環(huán)和儲存過程中保護(hù)生物制劑。其通用性以及與各種尺寸和制造商的包裝袋的兼容性，確保了對可能導(dǎo)致包裝袋破裂和產(chǎn)品損失的物理應(yīng)力的持續(xù)保護(hù)。
Moreover, the RoSS® Shell's stackable design optimizes storage space, making it ideal for streamlining cold chain logistics. It represents a significant advancement in biologic protection, offering reliability and efficiency throughout the supply chain.
此外，RoSS® Shell 的可堆疊設(shè)計(jì)優(yōu)化了存儲空間，使其成為簡化冷鏈物流的理想之選。它代表了生物保護(hù)領(lǐng)域的一項(xiàng)重大進(jìn)步，為整個(gè)供應(yīng)鏈提供了可靠性和效率。
Putting the puzzle together – platform solutions by Single Use Support
拼圖游戲——Single Use Support 的平臺解決方案
Single Use Support integrates a suite of platform solutions tailored to the various demands of biopharmaceutical production. One of the key elements in the product portfolio is the RoSS.pFTU platform for freeze/thaw processes in the production of biologics, featuring scalable units adaptable to diverse batch sizes and bag types. This system based on plate freezing ensures meticulous control over the process of freezing biologics, safeguarding the integrity of valuable biopharmaceuticals.
Single Use Support 整合了一系列平臺解決方案，旨在滿足生物制藥生產(chǎn)的各種需求。其產(chǎn)品組合中的關(guān)鍵要素之一是 RoSS.pFTU 平臺，該平臺用于生物制劑生產(chǎn)中的凍融工藝，配備可擴(kuò)展單元，能夠適應(yīng)不同的批次大小和包裝袋類型。該系統(tǒng)基于平板凍融技術(shù)，可確保對生物制劑凍融過程進(jìn)行精確控制，從而保障珍貴生物制藥的完整性。
Should even lower temperatures be required, Single Use Support also offers RoSS.LN2F – a cryogenic freezer that is able to reach temperatures as low as -170°C in a controlled manner.
如果需要更低的溫度，Single Use Support 還提供 RoSS.LN2F——一款能夠以可控方式達(dá)到低至 -170°C 的低溫冷凍機(jī)。
Moreover, fluid management solutions for biosimilars and biologics offer unmatched versatility and efficacy, seamlessly fitting into existing manufacturing workflows. With a focus on quality, safety, and scalability, the RoSS.FILL solutions are designed for the fluid transfer of delicate substances.
此外，用于生物類似藥和生物制劑的流體管理解決方案具有無與倫比的多功能性和高效性，可無縫集成到現(xiàn)有的生產(chǎn)流程中。RoSS.FILL 解決方案專注于質(zhì)量、安全性和可擴(kuò)展性，專為易損物質(zhì)的流體轉(zhuǎn)移而設(shè)計(jì)。
In order to provide a safe and resource effective storage solution for biologics and biosimilars, Single Use Support has developed the ultra-low temperature freezer RoSS.ULTF, with customizable inner shelving and elevated temperature monitoring. It provides stable temperatures down to -75°C, protecting valuable biopharmaceuticals in different primary packaging solutions and sizes.
為了給生物制劑和生物類似藥提供安全高效的存儲方案，Single Use Support 開發(fā)了超低溫冷凍柜 RoSS.ULTF，該冷凍柜配備可定制的內(nèi)部擱架和先進(jìn)的溫度監(jiān)控系統(tǒng)。它能提供低至 -75°C 的穩(wěn)定溫度，保護(hù)采用不同初級包裝和規(guī)格的珍貴生物制藥產(chǎn)品。
With the advanced platform solutions by Single Use Support, pharmaceutical manufacturers can rely on future-proof systems that aid in mastering the complexities in storing valuable biologics safely and with precision.
憑借 Single Use Support 的先進(jìn)平臺解決方案，制藥企業(yè)可以信賴面向未來的系統(tǒng)，從而安全、精準(zhǔn)地應(yīng)對存儲珍貴生物制劑的復(fù)雜挑戰(zhàn)。
References
生物制劑的冷凍和冷鏈解決方案——最佳實(shí)踐
Alexander Fuchs
May 6, 2024
Freezing biologics is an almost unavoidable step in the process of preserving and storing them for an extended period of time. After all, biologics encompass a diverse range of therapeutic products derived from living organisms. They include monoclonal antibodies, protein solutions, and other biotherapeutics – complex formulations engineered to treat various diseases and medical conditions. The freeze-thaw process requires close attention to formulation, cooling rates, and cryoprotective strategies to maintain the stability and efficacy of the drug product.
冷凍是生物制劑長期保存和儲存過程中幾乎不可避免的步驟。畢竟，生物制劑涵蓋了多種源自活體生物的治療產(chǎn)品，包括單克隆抗體、蛋白質(zhì)溶液和其他生物治療藥物——這些復(fù)雜的制劑旨在治療各種疾病和病癥。凍融過程需要密切關(guān)注制劑配方、冷卻速率和冷凍保護(hù)策略，以維持藥物產(chǎn)品的穩(wěn)定性和療效。
Safe cold storage of biologics is key in ensuring the efficacy and safety of pharmaceutical products throughout their lifecycle. As the demand for biopharmaceuticals continues to rise, so does the need for efficient and reliable storage solutions that maintain the integrity of the cold chain. Biologics are often highly temperature-sensitive, requiring precise control to prevent degradation and ensure potency.
生物制劑的安全冷藏是確保藥物產(chǎn)品在其整個(gè)生命周期內(nèi)療效和安全性的關(guān)鍵。隨著對生物制藥的需求持續(xù)增長，對能夠維持冷鏈完整性的高效可靠儲存解決方案的需求也日益增加。生物制劑通常對溫度高度敏感，需要精確控制溫度以防止降解并確保其效力。
In this article, we will discuss essential requirements and innovative solutions for freezing and storing biologics along the cold chain – from ultracold and cryogenic freezers to solutions for safe packaging of biologics.
本文將探討生物制劑在冷鏈中冷凍和儲存的基本要求和創(chuàng)新解決方案——從超低溫和低溫冷凍機(jī)到生物制劑的安全包裝方案。
Biologics early considerations 生物制劑早期考量
Freezing biologics demands the consideration of various critical factors to uphold their integrity and efficacy throughout the process. Some of these considerations include:
生物制劑的冷凍保存需要考慮多種關(guān)鍵因素，以確保其在整個(gè)過程中保持完整性和有效性。這些因素包括：
Container selection: Vials, cryovessels, or single-use bags – there are numerous types of containers to choose from when freezing biologics. It is important for manufacturers to consider the thermodynamic characteristics of the materials they are made of to ensure that they can endure the stress that may come with extreme temperature gradients while protecting valuable therapies, such as mAbs or mRNA vaccines.
容器選擇：冷凍保存生物制劑時(shí)，可選擇的容器類型多種多樣，例如小瓶、冷凍容器或一次性冷凍袋。生產(chǎn)商必須考慮容器材料的熱力學(xué)特性，以確保其能夠承受極端溫度梯度帶來的壓力，同時(shí)保護(hù)重要的治療藥物，例如單克隆抗體或mRNA疫苗。
However, container options do not only differ in terms of built materials, but also in regard to their size: The volume of individual units significantly impacts their freezing behavior, thus also the risk for detrimental effects of freezing like unwanted ice crystal formation or protein concentration.
然而，容器的選擇不僅體現(xiàn)在材料上，還體現(xiàn)在其尺寸上：單個(gè)容器的體積會顯著影響其冷凍性能，進(jìn)而影響冷凍過程中可能產(chǎn)生的有害影響，例如形成不必要的冰晶或蛋白質(zhì)濃縮。
Formulation and cryoprotective agents: Biologics themselves are already highly complex structures, but they are often not frozen alone, but in combination with other substances, such as cryoprotective agents (CPAs or cryoprotectants). Excipients like glycerol and glycol in formulation development play vital roles in mitigating cryoconcentration effects and sustaining the stability of proteins during freezing and thawing cycles.
制劑和冷凍保護(hù)劑：生物制劑本身就是高度復(fù)雜的結(jié)構(gòu)，但它們通常并非單獨(dú)冷凍，而是與其他物質(zhì)（例如冷凍保護(hù)劑）混合使用。在制劑研發(fā)中，甘油和乙二醇等輔料在減輕冷凍濃縮效應(yīng)和維持蛋白質(zhì)在凍融循環(huán)中的穩(wěn)定性方面發(fā)揮著至關(guān)重要的作用。
Freezing and thawing protocols: Cooling rates are a fundamental aspect in achieving desired freeze-thaw profiles and preserving protein stability. It is one of the most decisive steps in unit operation of pharmaceutical freezers, which is why the next chapter will discuss this facet in more detail. 1
凍融方案：冷卻速率是實(shí)現(xiàn)理想凍融曲線和保持蛋白質(zhì)穩(wěn)定性的關(guān)鍵因素。它是制藥冷凍機(jī)單元操作中最關(guān)鍵的步驟之一，因此下一章將更詳細(xì)地討論這一方面。
Hitting the right cooling rate and speed for biological drug substances
生物藥物的冷卻速率和速度要合適。
Hitting the optimal cooling rate is crucial when freezing biological drug substances. This rate directly impacts various aspects of the process, including ice formation, protein denaturation, and overall product stability.
在冷凍生物藥物時(shí)，達(dá)到最佳冷卻速率至關(guān)重要。該速率直接影響工藝的各個(gè)方面，包括冰的形成、蛋白質(zhì)變性和產(chǎn)品的整體穩(wěn)定性。
Since there is no cooling and thawing rate that is considered to be universally ideal, it has to be individualized for each product. This requires thorough stability studies, including characterization of all its components and the kinetics occurring during freezing.
由于不存在普遍適用的理想冷卻和解凍速率，因此必須針對每種產(chǎn)品進(jìn)行個(gè)性化設(shè)置。這需要進(jìn)行全面的穩(wěn)定性研究，包括對所有成分的表征以及冷凍過程中發(fā)生的動力學(xué)變化。
Linked to freezing rates is the time for phase transition as an even more crucial factor for protein stability: It refers to the amount of time it takes for the product to transition from the liquid to the frozen state, and determines effects like cryoconcentration, pH changes, and glass formation. 2
與冷凍速率密切相關(guān)的是相變時(shí)間，它是影響蛋白質(zhì)穩(wěn)定性的一個(gè)更為關(guān)鍵的因素：相變時(shí)間是指產(chǎn)品從液態(tài)轉(zhuǎn)變?yōu)楣虘B(tài)所需的時(shí)間，它決定了諸如冷凍濃縮、pH 值變化和玻璃態(tài)形成等效應(yīng)。
Freezing strategies for biologics 生物制劑的冷凍策略
Biotechnology knows several freezing strategies for biologics, with some of them being more eligible than others. However, it always depends on the very scope that a pharmaceutical company or CDMO has when subjecting their products to a distinct freezing method, as well as the individual product characteristics.
生物技術(shù)領(lǐng)域針對生物制劑開發(fā)了多種冷凍策略，其中一些策略比其他策略更適用。然而，最終選擇哪種冷凍方法，始終取決于制藥公司或合同研發(fā)生產(chǎn)機(jī)構(gòu)（CDMO）的具體業(yè)務(wù)范圍以及產(chǎn)品的特性。
In the following sections, we will discuss four methods to freeze biologics and biosimilars.
在接下來的章節(jié)中，我們將討論四種生物制劑和生物類似藥的冷凍方法。
Slow uncontrolled freezing 緩慢不受控制的冷凍
Slow uncontrolled freezing, characterized by gradual cooling rates and minimal control over ice crystal formation, may appear as a simple approach, but poses significant risks to protein solutions. This method often results in the formation of unwanted ice crystals, inducing denaturation and compromising product stability.
緩慢且不受控的冷凍方法，其特點(diǎn)是冷卻速率緩慢，且對冰晶形成控制甚微，看似簡單，但卻對蛋白質(zhì)溶液構(gòu)成重大風(fēng)險(xiǎn)。該方法通常會導(dǎo)致形成不必要的冰晶，從而誘發(fā)蛋白質(zhì)變性并損害產(chǎn)品穩(wěn)定性。
Furthermore, slow freezing brings an increased risk for cryoconcentration, describing an inhomogeneous distribution of protein mass within the sample. 3
此外，緩慢冷凍還會增加冷凍濃縮的風(fēng)險(xiǎn)，冷凍濃縮是指樣品中蛋白質(zhì)質(zhì)量分布不均勻。³
Lyophilization of biologics 生物制劑的凍干
Lyophilization, or freeze-drying, stands as a popular method for preserving biologics, involving freezing the product followed by ice removal under vacuum for extended frozen storage. This process utilizes buffer solutions like sucrose to minimize ice nucleation and stabilize protein formulations.
凍干，也稱冷凍干燥，是一種常用的生物制劑保存方法，其原理是將產(chǎn)品冷凍，然后在真空條件下去除冰層，從而實(shí)現(xiàn)長期冷凍保存。該過程利用蔗糖等緩沖溶液來減少冰核的形成并穩(wěn)定蛋白質(zhì)制劑。
While lyophilization offers advantages in the preservation of biopharmaceuticals, it also presents disadvantages. These may include high operational costs, longer processing times, and product loss as a result of protein denaturation. Therefore, products like pharmaceuticals based on LNPs are usually not freeze-dried. 4
雖然凍干在生物制藥的保存方面具有優(yōu)勢，但也存在一些缺點(diǎn)。這些缺點(diǎn)包括較高的操作成本、較長的處理時(shí)間以及因蛋白質(zhì)變性造成的產(chǎn)品損失。因此，像基于脂質(zhì)納米顆粒（LNP）的藥物這類產(chǎn)品通常不采用凍干工藝。
Controlled plate freezing 受控平板冷凍
Controlled plate freezing is a methodical approach to freezing biologics that involves precise regulation of freezing rates and temperature gradients. This technique is not only valuable during process development and small-scale production: With innovative plate freezing and thawing systems like RoSS.pFTU, both small and large-scale freezing of biologics is possible.
可控平板冷凍是一種系統(tǒng)化的生物制劑冷凍方法，它涉及對冷凍速率和溫度梯度的精確控制。這項(xiàng)技術(shù)不僅在工藝開發(fā)和小規(guī)模生產(chǎn)中具有價(jià)值，而且借助RoSS.pFTU等創(chuàng)新型平板冷凍和解凍系統(tǒng)，生物制劑的小規(guī)模和大規(guī)模冷凍均可實(shí)現(xiàn)。
By optimizing heat transfer and freezing time, controlled plate freezing ensures the preservation of protein stability throughout the freezing process, with a decreased risk for protein aggregation and other unwanted freezing effects.
通過優(yōu)化傳熱和冷凍時(shí)間，可控平板冷凍能夠確保蛋白質(zhì)在整個(gè)冷凍過程中保持穩(wěn)定性，并降低蛋白質(zhì)聚集和其他不良冷凍效應(yīng)的風(fēng)險(xiǎn)。
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Freeze & Thaw platform 冷凍和解凍平臺 The Single Use Support freeze-thaw platforms provide insular solutions for the freeze/thaw processes of each clinical phase. Our new freeze-thaw units are fully scalable and compatible with all batch sizes and bags from all established manufacturers – you will only require one single system from the lab to blockbuster production. 一次性使用的凍融平臺為每個(gè)臨床階段的凍融流程提供獨(dú)立的解決方案。我們?nèi)碌膬鋈谘b置具有完全可擴(kuò)展性，并兼容所有知名制造商的所有批次規(guī)格和包裝袋——您只需一套系統(tǒng)即可完成從實(shí)驗(yàn)室到重磅藥物生產(chǎn)的整個(gè)流程。 |
Cryogenic freezing and cryopreservation 低溫冷凍和冷凍保存
Cryogenic freezing involves the use of extremely low temperatures (down to around -180°C) for the preservation of biologics, ensuring long-term stability and viability. This method, integral to cryopreservation, safeguards the integrity of biotherapeutics over extended periods.
低溫冷凍是指利用極低溫度（低至約-180°C）保存生物制品，以確保其長期穩(wěn)定性和活性。該方法是冷凍保存不可或缺的一部分，能夠長期保障生物治療藥物的完整性。
Cryobiology plays an important role in individualizing the ideal process parameters and storage temperatures for, e.g., cell therapies, which are typically stored at around -150°C. It represents an essential preservation method in bioprocessing, when ultra-low temperatures (around -80°C) are not sufficient to preserve product quality.
低溫生物學(xué)在確定理想的工藝參數(shù)和儲存溫度方面發(fā)揮著重要作用，例如，細(xì)胞療法通常儲存在約-150°C的溫度下。當(dāng)超低溫（約-80°C）不足以保證產(chǎn)品質(zhì)量時(shí)，低溫冷凍便成為生物加工過程中必不可少的保存方法。
Control over freezing rates, though, has long been a major challenge during cryogenic freezing, due to the use of liquid nitrogen as cooling means. Single Use Support has therefore developed the first truly controlled cryogenic freezer, the RoSS.LN2F, which protects biologics from full exposure to LN2 while following adjustable freezing profiles. 5
然而，由于使用液氮作為冷卻手段，控制冷凍速率一直是低溫冷凍過程中的一大挑戰(zhàn)。因此，Single Use Support公司開發(fā)了首款真正可控的低溫冷凍機(jī)RoSS.LN2F，該設(shè)備能夠根據(jù)可調(diào)節(jié)的冷凍曲線，在避免生物制品完全暴露于液氮的情況下，保護(hù)其免受液氮的直接影響。
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RoSS.LN2F | Cryogenic Freezer低溫冷凍機(jī) RoSS.LN2F is a powerful cryogenic controlled rate freezer for temperatures down to -170°C. An enclosed LN2 system and our innovative direct injection system ensure no direct exposure and no mechanical compressors are needed. This ensures a safe, low-maintenance and energy-saving handling. RoSS.LN2F 是一款功能強(qiáng)大的低溫可控速冷凍機(jī)，可實(shí)現(xiàn)低至 -170°C 的溫度。其封閉式液氮系統(tǒng)和我們創(chuàng)新的直接噴射系統(tǒng)確保了無直接接觸，無需機(jī)械壓縮機(jī)。這保證了安全、低維護(hù)和節(jié)能的操作。 |
Freezing biologics and the advances with single-use technologies
生物制劑的冷凍保存及一次性使用技術(shù)的進(jìn)步
For cryopreservation of sensitive biologics Single Use Support is convinced of plate freezing and cryogenic freezing as two extremely favorable approaches to control the cooling and thawing process. They can ideally cater to individual product requirements in terms of cooling rates and target temperature, ensuring ideal results upon thawing.
對于敏感生物制劑的冷凍保存，Single Use Support 堅(jiān)信平板冷凍和低溫冷凍是控制冷卻和解凍過程的兩種極其理想的方法。它們能夠完美滿足不同產(chǎn)品在冷卻速率和目標(biāo)溫度方面的個(gè)性化需求，確保解凍后達(dá)到理想效果。
This is why Single Use Support offers innovative solutions for both methods, providing reliable and scalable options for controlled freezing and thawing. The plate-based freeze and thaw technology of the RoSS.pFTU platform ensures homogeneous processing with full control over the process, minimizing the formation of ice crystals and maintaining the stability of biologic substances.
因此，Single Use Support 為這兩種方法提供了創(chuàng)新解決方案，為可控的冷凍和解凍提供了可靠且可擴(kuò)展的選擇。RoSS.pFTU 平臺的平板式凍融技術(shù)可確保處理過程的均勻性，并實(shí)現(xiàn)對整個(gè)過程的完全控制，最大限度地減少冰晶的形成，從而維持生物物質(zhì)的穩(wěn)定性。
The cryogenic freezer RoSS.LN2F, on the other hand, enables pharmaceutical manufacturers to ensure long-term storage at even lower temperatures, ensuring the viability of biotherapeutics like certain cell-based products – for small and large volumes.
另一方面，低溫冷凍機(jī) RoSS.LN2F 使制藥企業(yè)能夠在更低的溫度下進(jìn)行長期儲存，從而確保某些細(xì)胞療法等生物治療藥物（無論小批量還是大批量）的活性。
Both systems work with high-quality single-use bags covered in the RoSS® Shell as protective packaging solution. And being based on a modular and vendor-agnostic setup, the solutions by Single Use Support are fully scalable, catering to both small and large scale demands when processing bulk drug substances.
這兩個(gè)系統(tǒng)均采用高品質(zhì)的一次性包裝袋，并以 RoSS® Shell 作為保護(hù)性包裝解決方案。 Single Use Support 的解決方案基于模塊化和供應(yīng)商無關(guān)的架構(gòu)，具有完全可擴(kuò)展性，能夠滿足原料藥加工過程中從小規(guī)模到大規(guī)模的各種需求。
Single Use Support couples the individual strengths of plate and cryogenic freezing with the overall advantages of single-use technologies: They allow for safe and efficient bioprocessing, with elevated flexibility, cost-effectiveness, and sustainability due to a reduction of resource consumption for manual cleaning and sterilization.
Single Use Support 將平板冷凍和低溫冷凍各自的優(yōu)勢與一次性技術(shù)的整體優(yōu)勢相結(jié)合：由于減少了人工清潔和滅菌所需的資源消耗，該方案能夠?qū)崿F(xiàn)安全高效的生物加工，并具有更高的靈活性、成本效益和可持續(xù)性。
What’s needed along the cold chain of biologics?
生物制劑冷鏈需要哪些環(huán)節(jié)？
The safe storage of biologics along the cold chain requires meticulous attention to several critical factors to ensure product integrity and efficacy. From temperature control to protection from contamination, various elements must be carefully managed to maintain the quality of biologic products throughout biomanufacturing – all in regard to regulatory compliance.
生物制劑在冷鏈中的安全儲存需要對多個(gè)關(guān)鍵因素進(jìn)行細(xì)致關(guān)注，以確保產(chǎn)品的完整性和有效性。從溫度控制到防止污染，必須精心管理各種要素，以在整個(gè)生物制藥過程中維持生物制品的質(zhì)量——所有這些都必須符合監(jiān)管要求。
What makes cold chain management of biologics and biosimilars even more complex is the need for individualized approaches, depending on the very product or intermediate that is currently being processed. Different types of biologics have unique requirements and vulnerabilities – e.g. physical stress, light or oxygen exposure. One of the most common aspects to be considered is temperature, along with bringing efficiency and safety into harmony.
生物制劑和生物類似藥的冷鏈管理之所以更加復(fù)雜，是因?yàn)樾枰鶕?jù)當(dāng)前正在加工的具體產(chǎn)品或中間體采取個(gè)性化的方法。不同類型的生物制劑具有獨(dú)特的要求和脆弱性——例如，物理應(yīng)力、光照或氧氣暴露。需要考慮的最常見因素之一是溫度，以及如何在效率和安全性之間取得平衡。
Best choice for cold storage of Biopharmaceuticals - A Comparison
生物制藥冷藏的最佳選擇——比較
Temperature control in cold storage 冷庫的溫度控制
Temperature control plays a pivotal role in the storage of biologics due to the inherent sensitivity of these products to temperature fluctuations. Biologics, such as mRNA vaccines or allogeneic stem cell therapies, often contain delicate molecular structures that can be easily compromised by exposure to inappropriate temperatures.
由于生物制品本身對溫度波動非常敏感，溫度控制在生物制品的儲存中起著至關(guān)重要的作用。例如，mRNA疫苗或異體干細(xì)胞療法等生物制品通常含有精細(xì)的分子結(jié)構(gòu)，暴露于不適宜的溫度下很容易受到破壞。
Maintaining the prescribed temperature range is critical to preserving the stability and efficacy of biologic products. Deviations from the recommended storage conditions can lead to irreversible damage, including denaturation of proteins, loss of biological activity, protein stability, and degradation of nucleic acids. These alterations can not only render the product ineffective, but also pose potential safety risks to patients.
維持規(guī)定的溫度范圍對于保持生物制品的穩(wěn)定性和有效性至關(guān)重要。偏離推薦的儲存條件會導(dǎo)致不可逆的損害，包括蛋白質(zhì)變性、生物活性喪失、蛋白質(zhì)穩(wěn)定性下降以及核酸降解。這些改變不僅會使產(chǎn)品失效，還會對患者構(gòu)成潛在的安全風(fēng)險(xiǎn)。
It is the recommended storage temperature that, being specific for each product type, makes cold chain management so complex for pharmaceutical companies and CDMOs. For instance, Fc-fusion proteins have been found to aggregate during long-term storage at -30°C; samples stored at both -70°C and -20°C, on the other hand, remained stable.
正是由于每種產(chǎn)品類型的推薦儲存溫度各不相同，才使得制藥公司和合同研發(fā)生產(chǎn)機(jī)構(gòu)（CDMO）的冷鏈管理如此復(fù)雜。例如，研究發(fā)現(xiàn)Fc融合蛋白在-30°C長期儲存期間會發(fā)生聚集；而儲存在-70°C和-20°C的樣品則保持穩(wěn)定。
Nevertheless, there are some rules of thumb regarding typical storage temperatures for biologics:
不過，關(guān)于生物制劑的典型儲存溫度，有一些經(jīng)驗(yàn)法則：
- monoclonal antibodies: -80°C單克隆抗體：-80°C
- mRNA: -80°C
- gene therapies: -80°C 基因療法：-80°C
- cell therapies: -130°C and lower 細(xì)胞療法：-130°C 及以下
- gene-modified cell therapies: lower than -150°C 基因修飾細(xì)胞療法：低于 -150°C
此外，生物制品的溫度敏感性不僅限于儲存，還體現(xiàn)在運(yùn)輸和處理過程中。運(yùn)輸過程中的溫度波動會對產(chǎn)品質(zhì)量產(chǎn)生不利影響，尤其是在溫度波動超出可接受范圍的情況下。
Combining efficiency and safety 兼顧效率與安全性
Achieving the delicate equilibrium between efficiency and safety is a balancing act in the storage of biologics. While optimizing storage processes for efficiency is essential to meet production demands and minimize costs, it must not compromise the safety and integrity of biologic products.
在生物制品的儲存過程中，如何在效率和安全性之間取得微妙的平衡至關(guān)重要。優(yōu)化儲存流程以提高效率對于滿足生產(chǎn)需求和降低成本至關(guān)重要，但絕不能以犧牲生物制品的安全性和完整性為代價(jià)。
Efficiency in storage entails streamlining workflows, maximizing storage capacity, and minimizing downtime. However, these optimizations must not compromise safety measures, such as temperature control, contamination prevention, and product traceability.
提高儲存效率意味著簡化工作流程、最大化儲存容量和最小化停機(jī)時(shí)間。然而，這些優(yōu)化措施絕不能影響安全措施，例如溫度控制、污染預(yù)防和產(chǎn)品可追溯性。
By integrating efficient storage practices with advanced systems and robust safety protocols, biopharmaceutical companies can ensure that biologic products are stored in optimal conditions while reducing the risk of product loss or compromise. This holistic approach to storage management not only optimizes efficiency in biomanufacturing, but also safeguards product quality and patient safety throughout the cold chain. 6 7
通過將高效的儲存實(shí)踐與先進(jìn)的系統(tǒng)和完善的安全規(guī)程相結(jié)合，生物制藥公司可以確保生物制品在最佳條件下儲存，同時(shí)降低產(chǎn)品損失或受損的風(fēng)險(xiǎn)。這種全面的儲存管理方法不僅優(yōu)化了生物制藥的效率，而且在整個(gè)冷鏈過程中保障了產(chǎn)品質(zhì)量和患者安全。
窗體底端
Managing the cold chain: The potential of single-use technologies
冷鏈管理：一次性技術(shù)的潛力
Effectively managing the cold chain presents significant challenges in the storage and transportation of biologics or biosimilars. However, single-use technologies offer immense potential in addressing these challenges and optimizing cold chain management processes.
有效管理生物制劑或生物類似藥的冷鏈在儲存和運(yùn)輸方面面臨著諸多挑戰(zhàn)。然而，一次性技術(shù)在應(yīng)對這些挑戰(zhàn)和優(yōu)化冷鏈管理流程方面展現(xiàn)出巨大的潛力。
In contrast to walk-in freezers and cold rooms, upright ultra-cold storage freezers with a customized inner shelving system allow maximized storage density and space efficiency. Combined with advanced temperature control including digital alarming management as well as long temperature holding in the case of failure, these freezers offer an elevated level of reliability and safety while being energy-effective and user-friendly.
與步入式冷凍庫和冷藏室相比，配備定制內(nèi)部擱架系統(tǒng)的立式超低溫冷凍庫能夠最大限度地提高存儲密度和空間利用率。結(jié)合先進(jìn)的溫度控制技術(shù)（包括數(shù)字報(bào)警管理）以及故障時(shí)的長時(shí)間溫度保持功能，這些冷凍庫在提供更高可靠性和安全性的同時(shí)，還兼具節(jié)能和易用性。
As not only the number of individual freezers, but also their interior can be customized according to specific needs, they are prepared to be used at different scales, making production lines ready for future changes in capacity needs.
由于不僅冷凍庫的數(shù)量，而且其內(nèi)部結(jié)構(gòu)也可以根據(jù)具體需求進(jìn)行定制，因此它們可以適應(yīng)不同規(guī)模的應(yīng)用，使生產(chǎn)線能夠應(yīng)對未來產(chǎn)能需求的變化。
Ultra-cold storage for biologics – when refrigeration is not enough
生物制劑的超低溫儲存——當(dāng)普通冷藏不足以滿足需求時(shí)
Ultra-cold storage involves temperatures around -80°C, and is crucial for preserving the efficacy and stability of biologics, such as vaccines, cell therapies, and mRNA-based drugs. These delicate biopharmaceuticals often require storage at ultra-low temperatures to prevent degradation and maintain protein stability along with therapeutic properties.
超低溫儲存是指在約-80°C的溫度下進(jìn)行儲存，對于保持生物制劑（例如疫苗、細(xì)胞療法和mRNA藥物）的療效和穩(wěn)定性至關(guān)重要。這些敏感的生物制藥產(chǎn)品通常需要在超低溫下儲存，以防止降解并維持蛋白質(zhì)穩(wěn)定性及其治療特性。
Ultra-low temperature storage can either be necessary超低溫儲存可能是必要的。
- right after freezing for shipping and long term storage,冷凍后立即進(jìn)行運(yùn)輸和長期儲存；
- upon arrival at the drug product manufacturing site prior to fill/finish,
- or when buffer, media or intermediate drug substances need to be short- or midterm stored during bioprocessing.
However, achieving and maintaining such extreme temperatures presents several challenges:
然而，實(shí)現(xiàn)并維持如此極端的溫度面臨著諸多挑戰(zhàn)：
- Infrastructure requirements: Ultra-cold storage necessitates specialized freezers with precise temperature control capabilities, which can be expensive to purchase and maintain. Additionally, facilities must have adequate space, power supply, and backup systems to support these freezers – and to scale up capacities if need be. Here, storage density is an essential criterion, as e.g. walk-in freezers come with a large footprint, need specialized infrastructure, and require a considerable amount of energy, while upright storage freezers may be more resource effective.
- Temperature control: Maintaining consistent temperatures throughout the storage period is paramount for ensuring the integrity of biologics. Fluctuations or deviations from the desired temperature range can compromise product quality and efficacy, leading to potential safety concerns.
- Logistical concerns: Transporting biologics to and from ultra-cold storage facilities requires careful planning and coordination to prevent temperature excursions. Any deviation from the recommended temperature range during transit can result in product degradation and loss of potency.
Single Use Support's ultra cold storage RoSS.ULTF addresses these challenges by offering precise temperature control down to -75°C (-103°F), ensuring the integrity of stored biologics. Its modularity allows for tailored shelving systems to accommodate various sizes of bioprocess containers, maximizing storage density and providing efficient storage solutions.
Single Use Support 的超低溫存儲系統(tǒng) RoSS.ULTF 通過提供低至 -75°C (-103°F) 的精確溫度控制，有效應(yīng)對了這些挑戰(zhàn)，確保儲存的生物制品的完整性。其模塊化設(shè)計(jì)允許定制貨架系統(tǒng)，以適應(yīng)各種尺寸的生物工藝容器，從而最大限度地提高存儲密度并提供高效的存儲解決方案。
Moreover, its modularity enables easy integration into existing facilities, offering flexibility in storage location and setup. Being compatible not only with RoSS® Shells as a dedicated protective packaging solution further discussed below, but also with all other primary packagings, the RoSS.ULTF provides additional protection for single-use bioprocess containers during storage and transport.
此外，其模塊化設(shè)計(jì)使其能夠輕松集成到現(xiàn)有設(shè)施中，從而在存儲位置和設(shè)置方面提供更大的靈活性。RoSS.ULTF 不僅與下文將詳細(xì)介紹的專用保護(hù)性包裝解決方案 RoSS® Shells 兼容，而且與所有其他初級包裝兼容，可在存儲和運(yùn)輸過程中為一次性生物工藝容器提供額外的保護(hù)。
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RoSS.ULTF | Ultra-low Temperature Storage 超低溫儲藏冷凍柜 RoSS.ULTF is an ultra-low temperature storage fridge for frozen drug substances in different sizes. The ULT storage freezer keeps the desired set point temperature down to -80°C. RoSS.ULTF offers highest storage density, is fully movable and can be modularly adapted to your individual needs. RoSS.ULTF 是一款超低溫冷凍藥品存儲冰箱，適用于不同規(guī)格的冷凍藥品。該超低溫存儲冰箱可將設(shè)定溫度維持在 -80°C 以下。RoSS.ULTF 具有極高的存儲密度，可完全移動，并可根據(jù)您的具體需求進(jìn)行模塊化定制。 |
Enhanced protection during cold storage and logistics of biologics
加強(qiáng)生物制品冷藏和物流過程中的保護(hù)
Effective protection during biologic storage is crucial for maintaining potency and safety. Temperature fluctuations and environmental factors can compromise their integrity, leading to reduced efficacy or complete loss. Robust protection measures are thus essential.
在生物制劑儲存過程中，有效的保護(hù)對于維持其效力和安全性至關(guān)重要。溫度波動和環(huán)境因素會損害其完整性，導(dǎo)致效力降低甚至完全喪失。因此，強(qiáng)有力的保護(hù)措施必不可少。
The RoSS® Shell offers a solution by providing a secure enclosure for single-use bags, shielding biologics during transportation, freeze-thaw cycles, and storage. Its versatility and compatibility with various bag sizes and manufacturers ensure consistent protection from physical stress, which might lead to bag ruptures and product loss.
RoSS® Shell 提供了一種解決方案，它為一次性包裝袋提供安全的封閉空間，在運(yùn)輸、凍融循環(huán)和儲存過程中保護(hù)生物制劑。其通用性以及與各種尺寸和制造商的包裝袋的兼容性，確保了對可能導(dǎo)致包裝袋破裂和產(chǎn)品損失的物理應(yīng)力的持續(xù)保護(hù)。
Moreover, the RoSS® Shell's stackable design optimizes storage space, making it ideal for streamlining cold chain logistics. It represents a significant advancement in biologic protection, offering reliability and efficiency throughout the supply chain.
此外，RoSS® Shell 的可堆疊設(shè)計(jì)優(yōu)化了存儲空間，使其成為簡化冷鏈物流的理想之選。它代表了生物保護(hù)領(lǐng)域的一項(xiàng)重大進(jìn)步，為整個(gè)供應(yīng)鏈提供了可靠性和效率。
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RoSS® Shell | Protecting single-use bags一次性袋子保護(hù)殼 The safest transport solution for all available single-use bioprocess containers. Robust. Scalable. Single-use bag independent. 適用于所有一次性生物工藝容器的最安全運(yùn)輸解決方案。堅(jiān)固耐用、可擴(kuò)展、無需使用一次性包裝袋。 |
Putting the puzzle together – platform solutions by Single Use Support
拼圖游戲——Single Use Support 的平臺解決方案
Single Use Support integrates a suite of platform solutions tailored to the various demands of biopharmaceutical production. One of the key elements in the product portfolio is the RoSS.pFTU platform for freeze/thaw processes in the production of biologics, featuring scalable units adaptable to diverse batch sizes and bag types. This system based on plate freezing ensures meticulous control over the process of freezing biologics, safeguarding the integrity of valuable biopharmaceuticals.
Single Use Support 整合了一系列平臺解決方案，旨在滿足生物制藥生產(chǎn)的各種需求。其產(chǎn)品組合中的關(guān)鍵要素之一是 RoSS.pFTU 平臺，該平臺用于生物制劑生產(chǎn)中的凍融工藝，配備可擴(kuò)展單元，能夠適應(yīng)不同的批次大小和包裝袋類型。該系統(tǒng)基于平板凍融技術(shù)，可確保對生物制劑凍融過程進(jìn)行精確控制，從而保障珍貴生物制藥的完整性。
Should even lower temperatures be required, Single Use Support also offers RoSS.LN2F – a cryogenic freezer that is able to reach temperatures as low as -170°C in a controlled manner.
如果需要更低的溫度，Single Use Support 還提供 RoSS.LN2F——一款能夠以可控方式達(dá)到低至 -170°C 的低溫冷凍機(jī)。
Moreover, fluid management solutions for biosimilars and biologics offer unmatched versatility and efficacy, seamlessly fitting into existing manufacturing workflows. With a focus on quality, safety, and scalability, the RoSS.FILL solutions are designed for the fluid transfer of delicate substances.
此外，用于生物類似藥和生物制劑的流體管理解決方案具有無與倫比的多功能性和高效性，可無縫集成到現(xiàn)有的生產(chǎn)流程中。RoSS.FILL 解決方案專注于質(zhì)量、安全性和可擴(kuò)展性，專為易損物質(zhì)的流體轉(zhuǎn)移而設(shè)計(jì)。
In order to provide a safe and resource effective storage solution for biologics and biosimilars, Single Use Support has developed the ultra-low temperature freezer RoSS.ULTF, with customizable inner shelving and elevated temperature monitoring. It provides stable temperatures down to -75°C, protecting valuable biopharmaceuticals in different primary packaging solutions and sizes.
為了給生物制劑和生物類似藥提供安全高效的存儲方案，Single Use Support 開發(fā)了超低溫冷凍柜 RoSS.ULTF，該冷凍柜配備可定制的內(nèi)部擱架和先進(jìn)的溫度監(jiān)控系統(tǒng)。它能提供低至 -75°C 的穩(wěn)定溫度，保護(hù)采用不同初級包裝和規(guī)格的珍貴生物制藥產(chǎn)品。
With the advanced platform solutions by Single Use Support, pharmaceutical manufacturers can rely on future-proof systems that aid in mastering the complexities in storing valuable biologics safely and with precision.
憑借 Single Use Support 的先進(jìn)平臺解決方案，制藥企業(yè)可以信賴面向未來的系統(tǒng)，從而安全、精準(zhǔn)地應(yīng)對存儲珍貴生物制劑的復(fù)雜挑戰(zhàn)。
References
- Winter is coming: the future of cryopreservation, http://dx.doi.org/10.1186/s12915-021-00976-8, Published 2021-03-24
- Large-Scale Freezing of Biologics: Understanding Protein and Solute Concentration Changes in a Cryovessel-PartI., https://www.biopharminternational.com/view/large-scale-freezing-biologics-understanding-protein-and-solute-concentration-changes-cryovessel-par , Published 06/2010
- Shedding light on optimal freezing results for drug substance., https://www.susupport.com/knowledge/freeze-thaw/shedding-light-optimal-freezing-results-drug-substance , Published 05/2021
- Lyophilization considerations: Comparing freeze-drying to freezing for biopharmaceutical products. , https://www.susupport.com/knowledge/freeze-thaw/lyophilization-considerations-comparing-freeze-drying-freezing-biopharmaceutical-products, Published 07/2023
- l Cryogenic Freezing: All you need to know., https://www.susupport.com/knowledge/freeze-thaw/cryogenic-freezing-process-biopharma?rel=search, Published 08/2022
- Freezing of Biologicals Revisited: Scale, Stability, Excipients, and Degradation Stresses, http://dx.doi.org/10.1016/j.xphs.2019.10.062, Published 2019-11-07
- Pharmaceutical cold chain management, https://www.susupport.com/knowledge/freeze-thaw/pharmaceutical-cold-chain-management-overview-freezing-ranges, Published 25.07.2022
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