Kelley Brian, Kiss Robert, Laird Michael
Vir Biotechnology, Inc., San Francisco, CA, USA.
Sutro Biopharma, Inc., San Francisco, CA, USA.
Adv Biochem Eng Biotechnol. 2018;165:443-462. doi: 10.1007/10_2018_59.
As biopharmaceutical companies have optimized cell line and production culture process development, titers of recombinant antibodies have risen steadily to 3-8 g/L for fed-batch mammalian cultures at production scales of 10 kL or larger. Most new antibody products are produced from Chinese Hamster Ovary (CHO) cell lines, and there are relatively few alternative production hosts under active evaluation. Many companies have adopted a strategy of using the same production cell line for early clinical phases as well as commercial production, which reduces the risk of product comparability issues during the development lifecycle. Product quality and consistency expectations rest on the platform knowledge of the CHO host cell line and processes used for the production of many licensed antibodies. The lack of impact of low-level product variants common to this platform on product safety and efficacy also builds on the established commercial history of recombinant antibodies, which dates back to 1997.Efforts to increase titers further will likely yield diminishing returns. Very few products would benefit significantly from a titer greater than 8 g/L; in many cases, a downstream processing bottleneck would preclude full recovery from production-scale bioreactors for high titer processes. The benefits of a process platform based on standard fed-batch production culture include predictable scale-up, process transfer, and production within a company's manufacturing network or at a contract manufacturing organization. Furthermore, the confidence in an established platform provides key support towards regulatory flexibility (e.g., design space) for license applications following a quality-by-design strategy.These factors suggest that novel technologies for antibody production may not provide a substantial return on investment. What, then, should be the focus of future process development efforts for companies that choose to launch antibody products using their current platform? This review proposes key focus areas in an effort to continually improve process consistency, assure acceptable product quality, and establish appropriate process parameter limits to enable flexible manufacturing options.
随着生物制药公司优化细胞系和生产培养工艺开发，在10 kL或更大生产规模的补料分批哺乳动物培养中，重组抗体的滴度已稳步提高至3 - 8 g/L。大多数新抗体产品由中国仓鼠卵巢（CHO）细胞系生产，目前正在积极评估的替代生产宿主相对较少。许多公司采用了在临床早期阶段和商业化生产中使用相同生产细胞系的策略，这降低了产品在开发生命周期中出现可比性问题的风险。产品质量和一致性期望取决于用于生产许多已获许可抗体的CHO宿主细胞系和工艺的平台知识。该平台常见的低水平产品变体对产品安全性和有效性缺乏影响，这也基于重组抗体自1997年以来已确立的商业历史。进一步提高滴度的努力可能会产生递减的回报。很少有产品会从高于8 g/L的滴度中显著受益；在许多情况下，下游加工瓶颈将妨碍从生产规模的生物反应器中完全回收高滴度工艺的产物。基于标准补料分批生产培养的工艺平台的优势包括可预测的放大、工艺转移以及在公司制造网络内或合同制造组织进行生产。此外，对既定平台的信心为遵循质量源于设计策略的许可申请的监管灵活性（例如，设计空间）提供了关键支持。这些因素表明，抗体生产的新技术可能无法提供可观的投资回报。那么，对于选择使用其当前平台推出抗体产品的公司而言，未来工艺开发努力的重点应该是什么？本综述提出了关键重点领域，以努力持续提高工艺一致性、确保可接受的产品质量，并建立适当的工艺参数限度，以实现灵活的制造选择。
