為什么需要凍融工藝的步驟

Regulations mandate that biopharmaceutical product quality be controlled throughout manufacturing, storage, transportation, and delivery to patients (1). Operations often include freezing and thawing of a bulk drug substance, dilution of that purified substance to a target concentration, filtration, filling into a selected container–closure system, additional processing (e.g., lyophilization), inspection, packaging, storage, transport, and delivery (2).

法規(guī)要求在制造，儲(chǔ)存，運(yùn)輸和交付給患者的過(guò)程中控制生物制藥產(chǎn)品的質(zhì)量（1）。 操作通常包括將原液冷凍和解凍，將純化后原液稀釋至目標(biāo)濃度，過(guò)濾，灌裝到選定的封閉容器系統(tǒng)，額外工藝（例如，凍干），檢查，包裝，儲(chǔ)存，運(yùn)輸和交付（2）

Freezing is a common processing step used to maintain stability and quality of a drug substance during development and production of biopharmaceutical products. It is generally agreed upon that freezing drug substance maximizes productivity and reduces overall production costs by decoupling bulk solution manufacture and storage steps from final product manufacture.

冷凍是用于在生物制藥產(chǎn)品的開(kāi)發(fā)和生產(chǎn)期間維持藥物的穩(wěn)定性和質(zhì)量的常見(jiàn)工藝步驟。 人們普遍認(rèn)為，通過(guò)將散裝原液生產(chǎn)和儲(chǔ)存步驟與終成品過(guò)程分離，冷凍藥物大限度地提高了生產(chǎn)率并降低了總體生產(chǎn)成本。

Freezing provides flexibility and cost savings by enabling batch processing: Large volumes of an expensive biological drug substance can be frozen in batches to allow the drug product to be manufactured based on real-time commercial or clinical demands. Freezing a drug substance before drug product manufacture also reduces microbial growth risk and eliminates mechanical (agitation) stresses during transportation.

通過(guò)批量處理，冷凍提供了靈活性、節(jié)約成本：可以批量冷凍大體積昂貴的原液，以允許基于實(shí)時(shí)商業(yè)或臨床需求來(lái)制造藥物產(chǎn)品。 在藥品生產(chǎn)之前冷凍藥物也降低了微生物生長(zhǎng)風(fēng)險(xiǎn)并消除了運(yùn)輸過(guò)程中的機(jī)械（攪動(dòng)）壓力。

Most important, this allows for a longer shelf life. Freezing decelerates chemical degradation (because reaction kinetics depend directly on temperature) and physical degradation (immobilizing drug substance in a frozen matrix limits protein–protein interactions) (3–13). Furthermore, application of freeze–thaw processes extends to storage of process intermediates, allowing for longer hold steps between manufacturing operations. Although freezing is considered to be a conservative approach, frozen storage is one of the most efficient and reliable methods to minimize protein interactions with container–closures and extend the shelf life of biological products in solution-based formulations (13).

重要的是，這可以延長(zhǎng)保質(zhì)期。 冷凍減緩化學(xué)降解（因?yàn)榉磻?yīng)動(dòng)力學(xué)直接取決于溫度）和物理降解（固定藥物在冷凍基質(zhì)中限制蛋白質(zhì)間相互作用）（3-13）。 此外，凍融工藝的應(yīng)用延伸到工藝中間體的存儲(chǔ)，允許制造操作之間更長(zhǎng)的保持步驟。 雖然冷凍被認(rèn)為是一種保守的方法，但冷凍儲(chǔ)存是有效和可靠的方法之一，可以大限度地減少蛋白質(zhì)與容器封閉物的相互作用，并延長(zhǎng)生物制品在溶液型配方中的保質(zhì)期（13）。