变更场地的可比性研究-以注射用重组人生长激素为例

摘要

研究背景：在研发过程中或正式批准后生物制品的生产商经常会发生一些变更。变更的原因为改进生产工艺、增大规模、扩建/新建车间、提高产品稳定性和符合法规规定。当发生这些变更时，生产商通常需要评价产品的相关质量指标，以证明变更没有对药品的安全和有效性产生不利的影响。

研究目的：通过新建车间和老车间生产的注射用重组人生长激素比较研究，分析两个车间注射用重组人生长激素产品质量是否有差异，证明新车间产品是安全性和有效性。

研究方法：1、工艺的研究：根据老车间的历史数据，从被变更的工艺参数和关键质量属性的关系出发，在确定关键工艺参数和关键物料属性的基础上，研究是否由于变更而导致终产品质量的改变。2、所涉及厂房的评估：根据工艺研究结果对涉及到的变更进行风险评估，对变更的潜在影响进行分析。3、产品安全性和有效性研究：用产品放行标准为依据，通过比较两个车间原液、半成品和成品的关键质量属性，评价两个产品的一致性。

研究结果：用产品放行标准为依据，我们以新车间生产的20批原液和老车间原液历史上数据为比较的基础，进行了生物学活性、免疫化学性质，原液纯度、杂质和污染情况比较，证明两个车间的产品没有显著差异。强制降解试验对比表明没有发现两个车间原液的降解产物的降解产物种类和降解速率有显著差异。两个车间3批原液的长期稳定性没有显著差异。结构确证研究表明两个车间的一级和二级没有差异。大鼠体内生物学活性符合要求，没有显著差异。加速和长期稳定性研究表明，两者从杂质分布和降解速率上没有显著差异。

产品质量的相似性主要是由于新车间的在满足产品的工艺要求的基础上，并没有关键工艺参数的变更。发酵和冻干规模的放大没有对关键工艺参数的控制产生影响。这些证据表明新车间厂房和设备的验证表明其达到了设计要求，并可以满足注射用重组人生长激素的工艺要求。

研究结论：由于市场对于产品需求增大经常导致了厂房变更。用生产注射用重组人生长激素厂房变更为案例清楚表明：如果设计合理，在符合cGMP原则的理念的指导下，通过产品质量放行标准进行严格的比较学研究证明了在中国厂房变更的

可实现性。

关键词：重组人生长激素；可比性研究；场地变更，新建车间

Comparability Study of Injectable Recombinant Human Growth Hormone Produced from Original Facility and Newly Built Facility Abstract

Background: Due to market increased demand of biological therapeutics, a new facility is required to meet the market need. A critical systemic evaluation using product quality specification for lot release is designed and implemented for the products produced from both of original facility and newly built facility. This has been demonstrated a very successful approach for the case study of recombinant therapeutic protein human growth hormone in Shanghai, CHINA.

Research Objective: By analysis and comparison of the CQA of the products produced from original facility and newly built facility, we would to convince our self and Chinese drug approval agencies that the facility change not only meet our market demand, but most importantly also meet the requirement of drug quality.

Methods: The methods used were the risk analysis and control for all the possible changes in bio-process due to facility change, and the effects of differences between original facility and new facility on the quality of drug product. Finally, bioassays and regular analytical assays were used to show the quality similarity of Drug Substances and Drug Product.

Results: Our analytical data using 20 lots of drug substances from newly built facility to compare the data generated for the drug substances from the original facility for biological potency, in-vivo activity, immunochemical properties, purity and impurity shows great similarity. Degradation of the products under stress conditions displayed similar profiles for degradation products and degradation rates. In addition, our structural analysis indicated the similarity of primary and secondary structures of the final products from the both facility. All the evidences determined the facility change has NO noticeable or very minimal concerns to manufacture our current product once the correct design and strategy were used.

Conclusions: Our case study using injectable recombinant human growth hormone clearly indicated that, in China, a successful facility change for biological therapeutics with similar drug quality profile in comparison with the original facility can be achieved if a logical design and cGMP concept is correctly implemented.

Keywords:recombinant human growth hormone, comparable research, facility change, new facility