从BLA缺陷看FDA对生物制品的法规要求

2024-06-06

临床申请临床3期

近年来随着生物制品的快速发展，越来越多的生物制品进入了IND后的临床及BLA阶段，小编本次将对近几年FDA对生物制品BLA阶段所提的缺陷进行汇总，以明确生物制品BLA阶段的法规要求。小编将从以下方面进行生物制品BLA缺陷的汇总及解读： 1 细胞库 FDA Comment 1: Conduct an analysis of the clonality of the master cell bank using a suitable method such as “Next Genetation Sequencing”. FDA Comment 2: Conduct studies to further characterize the master cell bank (MCB) and to support the monoclonality of the MCB. 解读：生物技术药物可保证每批产品都有一个经检定符合限定药物的共同起源细胞。细胞库来源的单克隆性与否对产品生命周期的质量管理非常重要。来源于一个稳定、可持续供应生产用的单克隆细胞系的细胞库能够更好地保持产品批次之间的质量一致性。常规的单克隆化方法如有限稀释法、成像法等对于单克隆性具有一定的概率性，因此BLA前需要通过进一步的检测手段为细胞的单克隆性提供支持性依据。常用的检测手段包括FDA comment中提到的二代测序（NGS，Next Genetation Sequencing）以及荧光原位杂交技术（fluorescence in situ hybridization, FISH）等。 2 HCP FDA Comment 1: Develop and validate a product-specific host cell protein (HCP) assay that has improved sensitivity and capability to detect a greater range of potential HCPs compared to the current assay and to implement this assay for drug substance release. The analytical procedure, validation report, proposed acceptance criterion, and data used to set the proposed acceptance criterion should be submitted. FDA Comment 2: To assess the coverage of the host cell protein (HCP) assay to confirm sensitivity. The assessment should be conducted using 2D SDS-PAGE gels of the range of HCPs detected by a sensitive protein stain, such as silver stain, compared to the range detected by western blot analysis using the antibodies employed in the assays or an assay that is demonstrated to be equally or more sensitive than western blot. The approximate percentage of HCP impurities that are recognized by the HCP antibodies will be provided from an appropriate number of drug substance lots. The validation data and updated to the drug substance control strategy, if applicable, will be provided in the final report to the BLA. 解读：在早期临床阶段，商业化的HCP试剂盒被广泛使用；但临床3期及之后的阶段，根据USP<1132>，建议使用平台型（platform）或上游工艺专属型（upstream process-specific）试剂盒，替换的主要目的正如FDA comment里提到的，“improved sensitivity and capability to detect a greater range of potential HCPs”。当然，试剂盒的替换需要进行桥接试验研究。同时，根据USP<1132>，需要对HCP试剂盒的覆盖率进行评估，评估方法包括两种：2-D SDS-PAGE/Western blot和Immunoaffinity binding/1- or 2-D SDS-PAGE，两种方法的优缺点在USP<1132>中有详细介绍。关于覆盖率的可接受标准，目前国内外法规均未明确，一般业内建议是不低于70%。 3 低内毒素回收（LER） FDA Comment 1: To develop an endotoxin method for the drug product which mitigates the low endotoxin recovery (LER) effect, to submit method qualification results with three lots of drug product and provide results of an LER study performed with the updated method with three lots of drug product. FDA Comment 2: Conduct a low endotoxin recovery (LER) study using an appropriate container (e.g., no endotoxin absorption or interference) to hold spiked drug product with either RSE or CSE (5-10 EU/ml) for 7 days. Samples should be tested using the LAL assay daily during the hold time, and recoveries should be calculated using the nominal spike values or the LRW spiked control at time 0. 解读：低内毒素回收（LER，也叫内毒素掩蔽），是指在使用国际统一的鲎试剂（LAL）药典方法检测细菌内毒素时，无法检测到无菌生物制剂中的加标内毒素的现象。FDA强制要求提供研究数据证明鲎试剂法（USP<85>）在一段时间内从加标样品中回收内毒素的能力，这些研究结果需要包含在生物制品的BLA资料中。参考PDA82，将已知浓度的标准内毒素加到未稀释样品中，随着时间的推移，标准内毒素的回收率无法达到≥50%活性，即为LER现象。LER现象无法通过稀释来避免。样品的贮存和处理方式可能会影响其内毒素含量的可检测性和稳定性。因此，需要对样品进行内毒素加标回收率测试，研究样品从取样至检测的最大允许存放时间。 4 杂质研究 FDA Comment 1: To conduct studies to confirm clearance of process related impurities from the commercial scale drug substance manufacturing process and a risk assessment for the residual levels of impurities on patient safety. The results from these studies and risk assessment will be provided in the final report to the BLA. 解读：在BLA阶段，需要对产品相关杂质和工艺相关杂质进行全面的分析。产品相关杂质包括分子大小变体、电荷变体、疏水性变体、结构变体、翻译后修饰变体等，应对这些杂质进行定性和定量分析，明确降解机制，并评价其对产品安全、有效性的影响；对于工艺相关杂质，需分析生产工艺能否可将相关杂质去除或降低至可接受水平；对于非生物学活性的工艺组分杂质（如甲氨蝶呤、消泡剂等小分子和合成的大分子杂质），可以采用杂质安全因子（impurity safety factor, ISF）或杂质日暴露剂量（permitted daily exposure, PDE）对其进行评估；生物学活性杂质如HCD、Protein A等一般采用缩小规模的加标试验论证工艺的杂质可去除性。 5 质量标准 FDA Comment 1: Implement a drug product release specification for deliverable volume (e.g., according to USP<697>). FDA Comment 2: Implement 100% of the labeled concentration prior to vial fill. Include “gross content of protein content per vial” in the drug product release specification to control the total amount in the final vial. 解读：2022年1月，FDA生效了MAPP 5019.1 Rev 1 Allowable Excess Volume/Content in Injectable Drug and Biological Products，该指南专门针对西林瓶（vial）装制品，包括NDAs、BLAs、ANDAs，也建议IND申办方尽量早的运用该指南，不得晚于Phase 2。该指南的目的是帮助药学质量审评员确认注射剂产品的过量灌装量是否合理，在该指南中明确指出，下表中的项目应该被包含在制剂的质量标准中。 6 参比品 FDA Comment 1: Establish a two-tiered reference material system by qualifying a primary reference standards (PRS) lot against current reference standard batch. The final qualification reports for the PRS will be submitted to the BLA. FDA Comment 2: To establish a working reference standard (WRS) and qualify this WRS against the current primary reference standard (PRS). Once the WRS is established, the qualification data for the first WRS together with a WRS requalification protocol specifying how subsequent working reference standards will be qualified will be submitted. The WRS will be created from a representative DS batch which has passed all release specifications. The WRS will be qualified according to a predefined protocol using a statistically derived replication strategy for key attributes in addition to a panel of extended characterization methods. FDA Comment 3: To scale-up the reference material batch size to generate a sufficient quantity of each reference material lot to prevent frequent replacement of the reference material. 解读：一般情况下，临床早期阶段，建立过渡期参比品；上市申报期间建立两级参比品，一级参比品和工作参比品。一级参比品一般情况下尽量保持不变，除非重大的工艺变更显著影响了产品的关键质量属性，或者一级参比品稳定性不能满足要求需要更换批次，因此一级参比品建立的数量不宜过小。所建立的工作参比品均应采用一级参比品进行标定，以避免因参比品质量属性的变化造成生物学活性的漂移。工作参比品应选择能代表商业化生产工艺的批次进行制备，工作参比品一般情况下建议使用与一级参比品不同批次产品进行制备（首次建立工作参比品可使用与一级参比品相同批次产品进行制备）。 BLA申报资料中关于一级参比品和工作参比品的提交要求，可参考FDA指南 For the submission of chemistry, manufacturing, and controls information for a therapeutic recombinant DNA-derived product or a monoclonal antibody product for in vivo use中的具体资料要求。 7 微生物相关 FDA Comment 1: Submit bioburden method verification data with testing volume of 100 mL for three drug product batches. FDA Comment 2: Conduct the bioburden and endotoxin test method qualification of drug substance using two additional batches. FDA Comment 3: Conduct the sterility and endotoxin test method qualification of drug product using two additional batches. 解读：对于内毒素的方法确认，中美药典中均指明了待确认样品的批次，如中国药典中指出“建立品种的细菌内毒素检查法时，为验证样品和不同生产厂家鲎试剂反应的一致性，应使用两个生产厂家的鲎试剂对至少三批样品进行干扰试验”；而USP<1085>中也提到“Products with greater variability in their starting material, API, and manufacturing process will typically require more than three lots for suitability testing, whereas for products with little or no process or product variability three lots may suffice”. 对于无菌和微生物负载的方法确认，在USP<1227>中，也有“Each validation run should be performed independently at least three times”描述，且结合FDA comments，对于原液和制剂的无菌、微生物负载的方法确认，同样是要求申请人采用3批样品进行。对于制剂除菌过滤前的微生物负载的检验量100ml，中国及欧洲相关指南中均有提到，具体法规截图如下： 8 可见异物 FDA Comment 1: To complete investigations into the root-cause, prevalence and size distribution of the visible particles in your clinical, PPQ, and commercial drug substance lots, and based on these investigations, to propose a control strategy for visible particles in your final drug substance to ensure the drug product will be “free from visible particles”. 解读：可见异物的控制是保证注射剂安全使用的一项重要指标，各国药典对其均有要求。而大多数蛋白都有形成具体的倾向，抗体药物在生产、储存及运输时都会伴随缓慢的聚体形成过程，进而形成可见异物/不溶性微粒。对于可见异物的控制，各国官方均建议在药物开发早期发现并评估形成的风险，如发生概率及严重程度。若在药物开发后期及产品上市后阶段，发现可见异物/不溶性微粒增加，应分析其形成原因及组成，回顾历史批次样品可见异物数据统计情况，并进行充分的安全性评估，明确其是否对药物本身质量、安全性产生影响，形成风险防控手段，采取风险缓解或消除措施，以降低微粒形成的风险因素。 9 包材相容性 FDA Comment 1: Perform a leachable study to evaluate the drug product container closure system through the end of shelf-life when stored under the recommended conditions. Testing will be performed at regular intervals and will include appropriate methods to detect, identify, and quantify organic non-volatile (e.g., HPLC-UV-MS), volatile (e.g., headspace GC-MS) and semi-volatile (e.g., GC-MS) species and metals (e.g., ICP-MS). Study results will be updated annually in the BLA Annual Report. The complete data and risk evaluation for potential impact of leachables on product safety and quality will be submitted to the BLA. FDA Comment 2: To perform extractables/leachables studies and risk assessments to evaluate leachables from the container closure system(s) and manufacturing product conduct surfaces of drug substance and drug product and assess the potential impact of leachables on product quality at the end of the drug product shelf-life. The analyses will be performed using drug substance and drug product lot(s) and/or representative samples analyzed at appropriate time points, including at the end of drug product shelf life. Appropriate methods will be used to detect, identify, and quantify organic non-volatile, volatile and semi-volatile species, and metals. Characterization of the potential impact on product quality will be assessed using adequate analytical methods. Complete data and the risk evaluation for the potential impact of leachables on product safety and quality will be provided in the final report. 解读：包材相容性试验的考察目的是为了确认在拟定的有效期内，药品与内包材的相容性，避免因包装容器可能导致的安全性风险。国内，对于生物制品的包材相容性，可参考化学药品相关指导原则；国外，如USP <1660>、USP <1661>、USP <1663>以及USP <1664>以及EP<3.1.9>等均是包材相容性试验研究的参考（具体指南可参见下表）。完整的包材相容性考察包括可提取物研究、浸出物研究、吸附试验以及安全性评估。提取物和浸出物的考察条件需考虑实际过程中的最极端条件。对于待检测物质，各官方均要求对其中的不挥发物质、半挥发性物质及挥发性物质、小分子挥发物以及元素杂质进行考察，分析方法应适用于检测目的，其灵敏度必须满足分析评价阈值（AET）最终值浓度水平的测定需要。根据试验考察结果进行结果的评估，确定包材的安全性。 10 运输稳定性 FDA Comment 1: To perform a shipping validation study under real time shipping conditions (i.e., temperature, mode of transport, shipping duration, and shipping containers and packing representative of the minimum and maximum load) using a representative commercial drug product lot in the final commercial container closure and packaging systems to evaluate the ability of the shipping containers to maintain the recommended temperature and to evaluate the impact of shipping from the labeling and packaging site to the US Distribution Center on the physical integrity and product quality of drug product. The shipping validation data will be submitted. FDA Comment 2: To perform commercial shipping studies to qualify the actual shipping conditions for the drug product (prefilled pen). The commercial shipping studies will include: a. Product quality assessment on commercial drug product in the commercial container closure system, fully packaged (primary and secondary packaging, etc.) before and after real-time shipping to evaluate the effect of handling and shipping conditions on product quality. b. Analytical testing to evaluate impact on critical quality attributes (CQAs) during shipping. Justification for the selected CQAs will be provided. c. Evaluation of container closure integrity to ensure the maintenance of sterile barrier using an appropriate method (e.g., dye ingress). d. Device functionality tests to demonstrate that the shipping conditions do not adversely impact the integrity and functionality of the device. e. Temperature monitoring of the shipping container (external and internal temperatures) recorded continuously throughout shipping from thermal couple probes placed inside and outside of the shipping container. FDA comment 3: To conduct a study to demonstrate that the pre-filled syringe plunger movement during air transport does not impact product sterility. 解读：生物制品通常要求冷链保存和运输，对产品的运输过程应进行相应的稳定性模拟验证研究。稳定性研究中需充分考虑运输路线、交通工具、距离、时间、条件（温度、湿度、振动情况等）、产品包装情况（外包装、内包装等）、产品放置情况和监控器情况（温度监控器的数量、位置等）等。稳定性研究设计时，应模拟运输时的最差条件，如运输距离、振动频率和幅度及脱冷链等。通过验证研究，应确认产品在运输过程中处于拟定的保存条件下可以保持产品的稳定性，并评估产品在短暂的脱离拟定保存条件下对产品质量的影响。对于需要冷链运输的产品，应对产品脱离冷链的温度、次数、总时间等制定相应的要求。此外，还需要特别关注在运输过程中的包装容器的密封性，以维持产品的无菌性。 11 使用中稳定性 FDA Comment 1: Confirm that there is no significant growth of organisms at 2-8°C in the drug product diluted with 0.9% sodium chloride and 5% dextrose by performing microbiological challenge studies with diverse microorganisms to support the 24-hour storage time. Your study should include Gram-negative microorganisms (such as E. coli and/or E. cloacae) which are known to proliferate in these solutions. The challenge studied should include at a minimum time points at twice the label claim storage time. FDA Comment 2: Provide microbial hold time data in a microbial challenge study to support the total in-use time (storage and infusion time) of diluted drug product in 5% Dextrose Injection beyond 4-hours at ambient temperature. The study should be conducted for twice the worst-case in-use time and bracketing the drug product concentrations that would be administered to patients. The study should also be representative of the in-use conditions; for example, neonates may be kept at temperature above 20-25°C during infusion and the higher temperatures should be simulated in the study supporting in-use conditions. 解读：使用中稳定性（此处特指配伍稳定性）属于稳定性研究的一部分。主要考察药物在临床配制、存放和使用过程中质量随时间的变化情况，为注射剂药品的配制、配制后药液的存放条件和允许时限等提供依据。小编汇总了各申报方向使用中稳定性指南中的技术要求，并对试验批次数量、样品考察时期、试验放置条件、考察指标、考察时长以及对分析方法和方法学的要求做了详细的对比，具体如下：对于微生物挑战，国内和FDA相关法规中均指明，当配伍后药液需在2-8℃下保存超过24小时或25℃保存超过4小时，建议参照相关要求进行微生物挑战试验，微生物增长不超过0.5lg值。微生物挑战试验的试验时长应至少能涵盖说明书中声明的最长储存时间的2倍。 12 容器密封性 FDA Comment 1: Perform the microbial ingress container closure integrity test to validate the maximum and minimum crimping pressures and include a positive control with a breach size of ≤ 20 microns. In addition, monitor the viability of the challenge microorganism at the end of testing. FDA Comment 2: Implement annual container closure integrity testing (CCIT) in lieu of sterility testing in the stability program for drug product and submit the CCIT method validation report. The CCIT method validation should demonstrate that the assay is sensitive enough to detect breaches that could allow microbial ingress. 解读：对于国内，《药品生产质量管理规范》明确规定无菌药品包装容器的密封性应当经过验证，避免产品遭受污染；《化学药品注射剂仿制药质量和疗效一致性评价技术要求》也明确密封性检测方法需经适当的验证；在稳定性考察部分中明确稳定性考察初期和末期进行无菌检查，其他时间点可采用包装系统密封性替代。而FDA指南Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products里也同样阐明了上述观点，且USP<1207>详细的阐述了包装系统密封性的各检查方法的具体验证信息。密封性检查检查方法应结合产品的质量和稳定性要求，优先选择能检测出产品最大允许泄漏限度（MALL）的确定性方法（一般为理化检测方法）。选择保守的产品刚性包装的MALL（0.1~0.3μm的孔）可确保微生物侵入及液体泄漏的风险较低，但大多数情况下，产品的MALL无法确定或者密封性检查方法的灵敏度达不到要求（如0.1~0.3μm孔径的保守值），此时就需要采用2种方法（其中1种推荐微生物挑战法）进行比较研究，为获得有意义的数据，应适当设计和完善测试方案，使用大量不同尺寸孔径的阳性对照样品验证方法灵敏度，确认拟采用的密封性检测方法的灵敏度不低于微生物挑战法的灵敏度。关于皓阳生物杭州皓阳生物技术有限公司成立于2015年，专注于为客户提供抗体、融合蛋白、ADC类产品从早期成药性评估、 IND药学研究到商业化生产的一站式研发、生产服务。服务内容包括：早期成药性评估，稳定细胞株构建，抗体及ADC工艺开发，中试生产和IND申报，临床样品生产，工艺表征、验证和商业化生产，培养基开发定制开发等。公司在上海和杭州两地设有研发、生产基地，上海研发中心依托多种分析手段和瞬时表达平台为客户提供从人源化设计，活性分析到成药性分析多维度的分子设计和评估；杭州研发中心拥有自主开发可授权的高表达稳定细胞株构建平台（皓越）和工艺开发平台；中试生产基地建有完善的250L/500L规模抗体原液和成品GMP生产线和100L规模ADC原液GMP生产线，分别能够在7个月和8个月提供从DNA到毒理批抗体和ADC样品交付。同时公司还在建6*2000L规模抗体商业化生产线和500L规模ADC商业化生产线，将于2024年陆续投入使用。皓阳生物致力于通过帮助新药研发来推动生物医药领域的进步，实现创新为民、科技惠民的目标。公司立足中国，实践 “聆听深耕开拓共赢”的企业精神，努力打造一个行业地位突出，管理先进的现代化企业。更多详情请访问公司官网：www.hs-biopharm.com 关于同写意同写意论坛是中国新药研发行业权威的多元化交流平台，二十年来共举办会议论坛百余期。“同写意新药英才俱乐部”基于同写意论坛而成立，早已成为众多新药英才的精神家园和中国新药思想的重要发源地之一。同写意在北京、苏州、深圳、成都设立多个管理中心负责同写意活动的运营。尊享多重企业/机构会员特权 ● 分享庞大新药生态圈资源库； ● 同写意活动优享折扣； ● 会员专属坐席及专家交流机会； ● 同写意活动优先赞助权； ● 机构品牌活动策划与全方位推广； ● 秘书处一对一贴心服务。入会请联系同写意秘书处同写意创新链盟机构（上下滑动查看更多）立迪生物 | 森西赛智 | 汇芯生物 | 申科生物 | 方拓生物 | 东抗生物 | 科盛达 | 依利特 | 翊曼生物丨锐拓生物丨复百澳生物丨圆因生物丨普洛斯丨华润三九丨皓阳生物丨人福医药丨广生堂药业丨澳宗生物丨妙顺生物 | 荣捷生物丨行诚生物 | 宜联生物 | 生命资本 | 恒诺康丨益诺思 | 深圳细胞谷丨佰诺达生物 | 沃臻生物 | 金仪盛世 | 朗信生物 | 亦笙科技 | 中健云康 | 九州通 | 劲帆医药 | 沙砾生物 | 裕策生物 | 同立海源 | 药明生基 | 奥浦迈 | 原启生物 | 百力司康 | 宁丹新药 | 上海细胞治疗集团 | 滨会生物 | FTA | 派真生物 | 希济生物 | 优睿赛思 | 血霁生物 | 优睿生物 | 邦耀生物 | 华大基因 | 银诺生物 | 百林科医药 | 纳微科技 | 可瑞生物 | 夏尔巴生物 | 金斯瑞蓬勃生物 | 健元医药 | 星眸生物 | 格兰科医药 | 莱羡科学仪器 | 明度智云 | 玮驰仪器 | 康源久远 | 易慕峰 | 茂行生物 | 济民可信 | 欣协生物 | 泰楚生物 | 泰澧生物 | 谱新生物 | 思鹏生物 | 领诺医药 | 宜明生物 | 爱科瑞思 | 阿思科力 | 博格隆生物 | 百吉生物 | 迈邦生物 | 多宁生物 | 万邦医药 | ASCT | 为度生物 | 比邻星创投 | 赛桥生物 | 吉美瑞生 | 荣泽生物 | 科金生物 | 汉超医药 | 康日百奥 | 汉腾生物 | 力品药业 | 安必生 | 博瑞策生物 | 中盛溯源 | 深研生物 | 东方略 | 赛赋医药 | 克睿基因 | 安润医药 | 镁伽科技 | 科锐迈德 | 和元生物 | 申基生物 |楷拓生物| 森松生命科技 | 凯理斯 | 尚德药缘 | 晟国医药 | 健新原力 | 纽福斯 | 华东医药 | 士泽生物 | 影研医疗科技 | 新格元生物 | 依生生物 | 腾迈医药 | 汉欣医药 | 恒驭生物 | 盛诺基 | 序祯达生物 | 乐纯生物 | 速石科技 | 耀海生物 | 新合生物 | 华龛生物 | 恺佧生物 | 成都凡微析 | 正帆科技 | 大橡科技 | 博雅辑因 | 因美纳 | 博雅控股集团 | 近岸蛋白 | 依科赛生物 | 利穗科技 | 东南科仪 | 倍谙基 | 辉诺医药 | 圣诺制药 | 埃格林医药 | 科镁信 | 爱思益普 | 复星医药 | 齐鲁制药 | 捷思英达丨荣昌生物丨泽璟制药丨奕安济世丨礼新医药丨维立志博丨派格生物丨赛生药业丨呈源生物丨启德医药丨双运生物丨宝船生物丨曙方医药丨澳斯康生物丨普莱医药丨维健医药丨海昶生物丨征祥医药丨智核生物丨望石智慧丨博生吉医药丨南京诺丹丨四星玻璃丨艾米能斯丨霁因生物丨普瑞康生物丨映恩生物丨康哲生物丨霍德生物丨海慈药业丨沃生生物丨睿健医药丨矩阵元丨斯微生物丨则正医药丨预立创投丨东立创新丨博安生物丨伟德杰生物丨星奕昂生物丨耀乘健康科技丨琅钰集团丨康德弘翼 | 原力生命科学丨上海科洲丨特瑞思丨药源丨健艾仕生物丨冠科美博丨微境生物丨天境生物丨合源生物丨泛生子丨创胜集团丨加科思药业丨丹诺医药丨凌科药业丨偶领生物丨凯斯艾生物丨成都圣诺丨松禾资本丨清普生物丨和其瑞丨开拓药业丨科兴制药丨玉森新药丨水木未来丨分享投资丨植德律所丨奥来恩丨乐明药业丨东曜药业丨君圣泰丨海创药业丨天汇资本丨再鼎医药丨济煜医药丨百英生物丨基石药业丨君实生物丨Sirnaomics,Inc.丨亦诺微丨博腾股份丨思路迪诊断丨艾博生物丨普瑞金生物丨未知君生物丨尚健生物丨阿诺医药丨有临医药丨赛业生物丨睿智医药丨博济医药丨晶泰科技丨药明康德丨创志科技丨奥星集团丨苏雅医药丨科贝源丨合全药业丨以岭药业丨科睿唯安丨DRG丨博瑞医药丨丽珠医药丨信立泰药业丨步长制药丨华素制药丨众生药业丨上海医药丨高博医疗集团丨药渡丨君联资本丨集萃药康丨诺思格丨精鼎医药丨百利药业丨Pfizer CentreOne丨默克中国创新中心丨奥来恩丨瑞博生物丨新通药物丨广东中润丨医普科诺丨诺唯赞丨康利华丨国信医药丨昆翎丨博纳西亚丨缔脉丨一品红丨和泽医药丨博志研新丨凯莱英医药丨汉佛莱丨英派药业丨京卫制药丨海思科药业丨宏韧医药丨开心生活科技丨哈三联丨Premier Research丨宣泰医药丨先声药业丨海金格丨普瑞盛医药丨Informa丨科特勒丨谋思医药丨HLT丨莱佛士丨辉瑞丨科林利康丨冠科生物丨科文斯丨卫信康丨龙沙（Lonza）丨美迪西丨阳光诺和丨润东医药丨勃林格殷格翰（中国）丨艾苏莱生物丨领晟医疗丨驯鹿医疗丨燃石医学丨中肽生化丨鸿运华宁丨泰格医药丨易迪希丨希麦迪丨百奥赛图丨迪纳利丨青云瑞晶丨鼎丰生科资本丨中源协和丨维亚生物丨青松医药丨中科谱研丨长风药业丨艾欣达伟丨鼎康生物丨中晟全肽丨海步医药丨勤浩医药丨奥萨医药丨太美医疗科技丨生特瑞丨东富龙丨Cytiva丨优辰实验室丨苏桥生物丨君达合创丨澎立生物丨南京澳健丨南京科默丨东阳光丨亚盛医药丨杰克森实验室丨上海科州丨三优生物丨三迭纪丨泰诺麦博丨Cell Signaling Technology丨PPC佳生丨澳斯康丨先为达丨智享生物丨锐得麦丨宜明昂科丨明济生物丨英百瑞丨六合宁远丨天津天诚丨百拓生物丨星药科技丨亓上生物丨真实生物丨引光医药丨方达医药丨高博医疗集团丨赞荣医药丨国投创新丨药明生物丨康哲药业丨高特佳投资丨普瑞基准丨臻格生物丨微谱医药丨和玉资本 | 倚锋资本