高效原料药(HPAPI)生产趋势

高效原料药(HPAPI)生产趋势

高效原料药(HPAPI)生产趋势

作者:Maurits Janssen

龙沙(Lonza)制药生物技术商业开发负责人

于2020年5月5日撰稿

如何缩短高效药的生产周期

 

高效原料药(HPAPI)在小分子药物开发过程中所占的比例日趋增大,由于这类药物能在癌症治疗中发挥作用,因此其发展速度要比小分子药物领域的整体发展速度要快。1许多此类药物的审批和商业开发的时间有所缩短,这对需要跟上进度的药品开发商来说是一大挑战。
对药品开发的前端而言,in-silo预测工具等新技术有助于缩短确定候选药品的时间。2与此同时,得益于人工智能AI)技术的发展,首个候选药品已经进入了临床开发阶段。3而对药品开发的后端而言,监管部门审批药品所需的时间正逐渐缩短:根据对2019年药品审批情况的分析,有近四分之三(71%)的药品通过“优先审评”获得了批准。4

 

随着肿瘤领域的竞争日益激烈,目前80%的新药都是由小型、新兴或虚拟的生物技术公司研发的。5这些公司通常缺乏有效开发用于临床试验的高效原料药产品的生产资源、能力和经验。此外,只要这些产品能够研制成功,就会投入商业生产。因此,这些公司倾向于将开发、临床和商业生产外包给资深的合同定制研发生产组织(CDMO合作伙伴。
生物制药公司要确保及时提供足量成品药用于临床试验,才能保证参与临床试验的患者及时取得成品药。否则,患者可能会选择接受其他药品(即竞争药品)的治疗,并导致患者在参与临床试验期间不能使用其他替代产品进行治疗,因为他们一旦接受了其他药品的治疗就无法再参与临床试验。因此,快速生产和扩大生产规模的能力,对于将高效原料药尽快推向临床阶段和市场来说至关重要,而这些能力的差距可能会导致药品开发时间延长。
考虑到这些临床动态,显然,想要从突破性适应证和加速审批途径中获益,必须解决临床供应所面临的挑战。公司领导(尤其是那些小型公司或虚拟公司的领导)应当如何缩短他们高效原料药的生产时间呢?答案在于做出外包决策和选择CDMO合作伙伴,这样才能推动高效原料药化合物快速进入临床阶段或商业开发阶段。就应对缩短后的高效原料药生产时间而言,创新生物技术的领导者可以从与CDMO的合作中受益,CDMO拥有开发原料药和产品方面的专业知识,可作为临床前、临床阶段和商业生产的单一开发合作伙伴。

开发高效原料药的注意事项

 

临床开发的任何阶段,无论是早期还是晚期,所面临的首要问题都是要确保原料药(活性药物成分,API)的数量足以满足未来临床阶段的需求。然而,生产原料药的临床前生产阶段通常与临床后期的生产阶段大不相同。在临床后期,制药商的重点转移到提高产量和加强生产要素上,以此提高成本效率。
很多成熟的制药公司已经学会了如何平衡质量、时间和成本三者的关系。然而,对于在新药临床申报方面占较大份额的小公司而言,上述三者的关系尚不能完美平衡。虽然CDMO可以发挥关键作用,但是在高度分散的外包市场中,难以将经验丰富的和缺乏经验的CDMO区分开来。在选择CDMO合作伙伴以缩短高效原料药的生产时间时,应当考虑以下包括合作伙伴的原料药开发经验和专业水准方面的关键因素:
  • 生产规模:生产规模不仅要考虑到当前的生产需求,还要考虑到未来生产规模扩大后的需求。规模问题可能会引发生产重新验证和相关监管变化的问题,从而推迟项目进入临床阶段和市场的时间,并增加成本。生物技术公司所寻找的CDMO应在临床开发的早期就慎重考虑过并规划出符合各阶段要求的生产规模,以同时满足当前和未来的增长需求。

  • 质量管理体系:质量控制的方法必须适合早期阶段的工作,而且还要能够延用到后期的临床阶段或商业阶段,这些阶段需要验证、记录和保证产品与总体策略一致的能力。CDMO必须在引导客户方面发挥积极作用,为临床应用和市场阶段提供相应的可持续质量控制方法(包括质量源于设计QbD

  • 生产敏锐度:在大多数情况下,低下的生产效率足以支撑早期阶段的工作,但是会延长早期阶段的时间,对开发时间和成本产生负面影响。如果在整个临床开发过程中始终存在生产效率低下的问题,则在未对监管文件进行实质性更改(意味着需要完成相关研究)的情况下,就无法实施工艺化学、工艺参数、中间体或产品规格的变更,推进项目商业化的时间会延长,成本也会相应增加。只要仍然可以在安全和简便的情况下改进工艺,经验丰富的CDMO就会建议继续改进。随着项目进入更大规模的临床研究阶段,这些合作伙伴仍然会对工艺的性能、稳定性和质量持批评态度。

  • 控制措施:对于高效原料药(HPAPI)而言,必须考虑到,控制措施解决方案通常是为生产过程中出现的特定情况而设计的。由于公司需要保证合规以及确保员工的安全,如要改变生产规模、质量控制方法和单元操作(如向反应器中添加起始物料),可能需要改变既定的控制措施解决方案。在一个项目最初的技术转让过程中(如从小型过滤干燥机改为大型离心机),如果对控制措施的经验不足或对控制措施的重视不够,可能会导致单元操作发生变化,从而需要对规章进行更新。许多CDMO加大了对高效原料药性能的投资,并宣称其具有丰富的专业知识;然而,对于生物制药公司而言,更为重要的是,要挑选那些已经实施控制措施原则和安装控制措施硬件的潜在外包合作伙伴,从而确保技术转让和生产实施时间更加高效。

高效原料药的产品类别中有个重要组成部分,即抗体药物偶联物ADC)连接基或有效负载。这一部分的发展十分迅猛,通常与审批程序的加快有关,有时甚至可以直接跨越临床阶段。到2024年5ADC市场预计增长约30%,“速度需求”会更为重要,想要找到一家在高效小分子大分子生物制剂(单克隆抗体和偶联)和最终产品方面真正具有长期经验的CDMO,几乎没有任何难度。6高效处理经验、规模能力、稳定性以及质量和交付的良好记录是CDMO之间的关键差异,与纯小分子导向的化学经验相比,这些关键差异往往能在面向ADC的组合技术中发挥更大的作用。
而缺乏与上述领域相关的专业知识和资源则意味着复杂因素更多、成本更高、质量更低、监管备案更多,总体上而言,药物开发时间也更长,进入市场的时间也会更晚,所有这些都是生物技术创新者不想看到的结果。创新公司在与拥有大量高效原料药处理经验的CDMO合作过程中,不仅仅投资了设备和技术,还可能会缩短生产时间。

有助于成品药开发的CDMO特质

 

高效原料药生产后,在考虑成品药中间体(DPI)和成品药(DP)的开发和生产时,药物开发商很可能从与CDMO的合作中获益,这些CDMO已经展示出其在DPI和DP开发领域具备的专业水准,有助于药物开发商找到以下问题的答案:
  • 制剂技术:有关制剂的问题陈述是否有明确定义?采用哪种制剂方法能够满足产品目标特征?产品的生物利用度是否足够高?如需提高生物利用度,可采用哪些技术以及如何合理选择这些技术?
  • 支持技术:需要哪些支持技术和/或专业工艺?是否拥有符合非cGMP可行性和cGMP临床生产且适应阶段的工艺?是否具有独立商业化生产的能力?
  • 设备:患者需要通过何种特殊设备来使用这些药物?对制剂方法和/或剂型有何影响?
  • 成品药供应:在市场需求迅速增加或减少的情况下(如,获得加速审批、市场推广和获得额外适应证审批),产品供应能否得到支持?
更多成熟的CDMO将有能力在临床开发的较早阶段开展短期的可行性研究(最好在首次人体临床试验之前),在项目早期就能选出上述问题的最佳答案,并可能为长期开发节省时间。例如,通过可行性试验,我们可以判断候选药品临床效果不足到底是由候选药品本身还是由次优或不当制剂造成的。对于本可使用不同制剂方法优化的候选药品,这一过程就可有效避免出现直接放弃该候选药品的情况,从而在决定是否停止、终止或继续开发候选药品时做出更明智的决策。特别是随着从产品概念到投入市场的速度提高,“快速失败”(或适当失败)所带来的压力也相应增加。选择拥有合适成品药中间体(如喷雾干燥分散体)的CDMO,以及成品药相关的专业知识都有助于公司更有效地做出这些决策。

仅与一家综合性的CDMO合作伙伴合作的优势

 

快速开发用于临床试验的高效原料药产品,着眼于未来的商业开发,涉及从原料药到成品药的一系列专业知识。从传统意义上讲,制药领域的许多创新者在开发过程的不同阶段都会选择与不同的CDMO合作,比如,从一家CDMO处接收原料药,进行必要分析后,再交给另一家药品生产商。该价值链中的每位合作伙伴在进一步处理之前(如,为了规避责任问题),都将会再次取样、测试并公开接收到的产品,这样一来就会出现冗余操作,延长开发时间。
然而,在开发过程的不同阶段充斥着各种疑问和问题:
  • 要想将原料药变成制剂,适合采用何种包装和支持技术?
  • 为了避免在价值链的每个阶段对产品进行复验,我们应如何建立一致的质量控制和质量保证机制?
  • 我们如何避免不同阶段的合作伙伴讨论责任问题?
  • 我们如何预测开发进程和开发时间的变化?
  • 我们如何优化整个价值链之间的协作?
解决这些问题最有效的方法可能是采取整体措施,而非在价值链的某一环节上进行解决。因此,为了降低问题的复杂性,节省精力、时间和成本,在价值链中尽量减少合作伙伴的数量可能会更加有利。最好是仅选择一家综合性合作伙伴,将所有活动交由一个整体统一的质量体系进行管理,该系统负责管理厂区之间所有产品的移交;合理安排原料药和成品药之间的包装(可对包装和控制措施联系进行协调);顺利实现不同生产阶段的交接(无需进行多余的测试,在理想情况下,原料药无需按照“分析证书”进行测试即可用于制剂,最终包装后的成品药也是如此);大幅缩短装运时间。同一CDMO也可能在同一厂区开展不同的生产阶段,从而跳过了运输环节,取得了效率上的优势。

挑选正确的合作伙伴

 

高效原料药产品日趋先进,其使用范围也愈发广泛,特别是应用于肿瘤治疗领域。法规流程加快也越来越有助于更好地确保新疗法的迅速发展。制药和生物技术公司的首要任务将仍是正确应对从产品概念到商业化的时间缩短的问题。CDMO在推动这些产品进入临床阶段和市场方面发挥着关键作用,全球各地的患者都能体验到他们所带来的好处。
如要区分不同的协作伙伴,我们应根据具体项目来评估他们的专业水准,并在未来项目开展的设施内对候选CDMO进行实地考察。对于一些较小的CDMO而言,我们可能只需考察一栋建筑,而对于其他CDMO而言,我们可能需要考察同一地点整个厂区内的多个设施,或对范围更广的厂区网络中的不同设施进行考察。对CDMO厂区管理进行充分考察,参观他们的实验室和设施,这些都将有助于确保选择正确的开发和生产合作伙伴。 

作者简介

 

Maurits Janssen博士是龙沙制药与生物技术的商业开发、API开发和生产负责人。他在cGMP定制生产领域拥有从临床阶段到商业阶段的丰富技术开发经验,包括化学(API、高效药、细胞毒性、多肽和生物偶联物)和生物技术(哺乳动物、微生物抗体药物偶联物、细胞疗法病毒疗法)。Janssen博士在位于瑞士巴塞尔的公司总部工作。

关于Lonza龙沙

 

龙沙是全球医药、生命科学及营养保健领域的领先供应商之一。龙沙制药与生物技术业务提供全球化合同定制开发与生产(CDMO)服务,使制药与生物技术公司能为患者带来医学创新。龙沙以高信任度、高质量、全球产能、创新技术平台以及广泛的经验而备受认可。龙沙经营的项目涵盖从前期临床开发到商业化生产的全部过程,涉及哺乳动物和微生物的生物制品、小分子、生物偶联物、细胞和基因疗法等领域。

1897年,龙沙诞生于瑞士的阿尔卑斯山脉地区,迄今拥有 120 个生产基地和办事处,遍布全球超过35个国家。 我们拥有约15,500名全职员工,由他们组成的高效团队及每一名员工都为我们的业务和所在地区及国家做出意义非凡的改变。2019 年,公司销售额达59亿瑞士法郎,核心业务的息税折旧摊销前利润(EBITDA)达16亿瑞士法郎。更多详情,请访问 pharma.lonza.com。

 

Managing accelerated timelines in manufacturing high-potency drugs.

 

Highly potent API (HPAPI) drugs make up a growing percentage of the small molecule drug development pipeline and this group of products is growing faster than the overall small molecule segment,1 largely due to their usefulness in cancer treatments. Many of these drugs have accelerated timelines for approval and commercial development, which can be challenging for drug developers to keep up with.
On the front-end, new technologies such as in-silico prediction tools contribute to shortening candidate selection,2 while Artificial Intelligence (AI) has already brought a first candidate into clinical development.3 On the back-end, regulatory drug approval timelines are being increasingly shortened: when analyzing drug approvals in 2019, almost three-quarters of drugs approved (71%) were approved under Priority Review.4
 
A related trend is increasing competition in the oncology field, with 80% of new IND’s now belonging to small, emerging or virtual biotech companies.5 These firms often lack the manufacturing resources, capabilities and experience to effectively develop a HPAPI product for clinical trials and, if successful, on to commercial production. As such, these companies tend to outsource development, clinical and commercial manufacturing to established contract development & manufacturing organization (CDMO) partners.
 
It is critical that biopharma companies ensure timely availability of sufficient drug product for clinical trials, so that clinical products are available in time for patients as soon as they are identified. If not, a patient may be treated with a different (i.e., competing) product, thus excluding that patient from the trial since patients cannot be treated with alternative products during their involvement in an ongoing clinical trial. Thus, the ability to rapidly manufacture and scale up are critical for bringing HPAPI drugs to clinic and to market at the most optimal timeline possible, while gaps in those capabilities may lead to lengthened development timelines.
 
Taking these clinical dynamics into account, it becomes immediately clear that to benefit from a breakthrough indication or accelerated approval pathway, the clinical supply challenge must be addressed. What can company leaders—especially those of small or virtual companies—do to manage shortened timelines for their HPAPI products? One answer lies in the outsourcing decision and choosing a CDMO partner that can help rapidly progress HPAPI compounds to clinical or commercial development. When it comes to managing accelerated timelines for HPAPI products, innovator biotech leaders can benefit from working with CDMOs that have expertise in developing both drug substance and product and can be a single development partner across pre-clinical, clinical and commercial production.

Considerations for Developing HPAPI Drug Substance

 

In any clinical development, whether early or late phase, the first challenge is to ensure sufficient quantity of the drug substance (active pharmaceutical ingredient; API) to cover future clinical phases. However, a pre-clinical manufacturing process to make drug substances is often quite different from what is used in later clinical phases, where the drug maker’s focus shifts to yield improvement and robust manufacturing elements to drive cost efficiencies.
 
More mature pharmaceutical companies have learned how to balance the elements of quality, time and cost. However, for the smaller companies that hold a large part of all INDs, such balance may be under-developed. CDMOs can play a pivotal role, but the highly fragmented outsourcing market can make it difficult to differentiate the experienced from the less experienced. The following critical parameters covering drug substance development experience and expertise should be considered when choosing a CDMO partner to manage shortened development timelines for HPAPI products:
 
  • Manufacturing scale: Manufacturing scale should factor in not only immediate needs, but also what will be needed in the future when production scales up. Scale issues can lead to manufacturing re-validation and related regulatory changes, thereby delaying the programs into clinic and market and also adding costs. Biotech companies should look for a CDMO that will, early on during clinical development, consider and propose phase-appropriate manufacturing scales that reflect both current needs and future growth.

  • Quality regime: The approach to quality control must be suitable for early-phase work, as well as continued into later clinical or commercial phases—requiring the ability to validate, document, and stay in compliance with overall policies. The CDMO must be in a position to play an active role in guiding their customer and provide a sustainable phase-appropriate quality approach to the clinic and to the market (including Quality by Design).

  • Manufacturing acumen: In many cases, manufacturing inefficiencies are adequate for early stage work but are carried forward too long and negatively impact timelines and costs. If manufacturing inefficiencies are carried throughout clinical development, changes in process chemistry, process parameters, intermediate or product specifications can no longer be implemented without substantial change to regulatory documentation (meaning that related studies that need to be completed), resulting in longer timelines and higher costs upon progressing the program to commercialization. Well-seasoned, experienced CDMOs recommend process improvements when these can still be implemented safely and easily.  Such partners remain critical of the process performance, robustness and quality as the program progresses into larger clinical studies.

  • Containment: When considering Highly Potent APIs (HPAPIs), it must be taken into account that containment solutions are often designed for specific situations in the manufacturing process. As companies need to remain compliant and ensure the safety of their employees, a change in scale, approach or unit operations (e.g., adding starting materials to the reactors) may require a change in the required containment solution. Insufficient experience with containment or insufficient attention to containment requirements during initial technical transfer of a program (e.g., change from small filter dryer to a larger centrifuge) may result in changes to unit operations, necessitating a regulatory update. Many CDMOs have increased investments in HPAPI capabilities and claim extensive expertise; however, it is important for biopharma companies to identify potential outsourcing partners that have implemented containment principles and hardware appropriately to ensure efficient technical transfer and manufacturing implementation timelines.

When looking at the HPAPI product category, a key component is the drug linkers or payloads for antibody drug conjugates (ADCs). This component is growing particularly fast and is often associated with accelerated pathways, sometimes even jumping clinical phases. With the ADC market expected to grow around 30% until 2024,5 the “need for speed” is even more crucial and the challenge of finding a CDMO with the real long-term experience across high potency small molecules, large-molecule biologics (monoclonal antibody and conjugation) and the final product are scarce.6 Experience with high-potency handling, scale-ability, robustness and a track record of quality and delivery are key differentiators that tend to play an even more pronounced role in the combined technologies for ADCs than when a purely small molecule-oriented chemical experience is required.
 
Lacking expertise and resources related to the areas above may mean more complications, higher costs, lower quality, additional regulatory filings and result in overall a longer drug development timeline overall and slower time to market entry—all outcomes that biotech innovators want to avoid. When innovator companies partner with CDMOs that have substantial experience in the HPAPI environment—not just investments in equipment and technology—they may stand to achieve shorter production timelines.

CDMO Qualities to Aid Drug Product Development

 

Following HPAPI drug substance production, when considering the development and manufacturing of drug product intermediates (DPI) and drug products (DP), drug developers stand to gain from working with CDMOs that have demonstrated expertise in DPI and DP development and can help find answers to the following questions:
  • Formulation technology: Has the formulation problem statement been adequately defined? What formulation approach is best to meet the target product profile? Is the product’s bioavailability sufficient? If bioavailability enhancement is required what technologies are available and how can they be rationally chosen?

  • Enabling technology: What enabling technology and/or specialized processing is required? Is phase-appropriate processing in place for non-cGMP feasibility and cGMP clinical manufacture? Is there a line-of-sight to commercial manufacture?

  • Devices: What special devices are required for patients to use the drugs? What is the impact on the formulation approach and/or dosage form?

  • Drug product supply: Can product supply be supported in situations where market demand increases or decreases rapidly (e.g. obtaining accelerated approval, market introduction and approval for additional indications)?

More mature CDMOs will have capabilities to run short feasibility studies relatively early in clinical development (preferably before First-in-Human testing), selecting the best answers to the questions above early in the program and potentially saving time in the long run. For example, with feasibility testing one can tell whether a candidate’s insufficient clinical effect is caused by the candidate itself or by a sub-optimal or inappropriate formulation. This process can help avoid abandoning candidates that could have been optimized with a different formulation approach, allowing for more informed decision on whether to halt, terminate or progress candidates through the pipeline. Especially with increasing speed from concept to the market, the pressure to “Fail Fast” (or fail appropriately) has increased. Choosing a CDMO with the proper drug product intermediate, e.g. a spray dried dispersion, and drug product expertise can help companies make those decisions more effectively.

Benefits of Working with a Single Integrated CDMO Partner

 

Rapidly developing a HPAPI product for clinical trials – with an eye to commercial development in the future – involves expertise across the drug substance-drug product spectrum. Traditionally, many pharmaceutical innovators have worked with various CDMOs for different parts of the development process, receiving the drug substance from one and running the required analyses before handing off to a different drug product manufacturer. Each partner in this value chain will again sample, test and release the incoming product before further processing (e.g., to avoid liability issues), thus creating redundant activities that lengthen development timelines.
But many questions and issues cross between different stages of the process:
  • What packaging and enabling technologies are best to move the drug substance to formulation?

  • How can we organize a consistent quality control and quality assurance mechanism to avoid full retesting at each step of the value chain?

  • How do we avoid liability discussions between different stages?

  • How do we anticipate changes in schedules and timelines?

  • How do we optimize the ease of collaboration over the entire value chain?

The most effective way to address these questions may be holistically, rather than at any one point in the value chain. As such, it may be beneficial to work with as few partners as possible across the value chain, in order to save complexity, effort, time and costs. The ideal situation may be one integrated partner, with all activities managed by one overall harmonized quality system governing all product transfers between sites, idealized packaging arrangements between drug substance and drug product (allowing coordination in packaging and containment connections), smooth handovers between production stages (no excess testing required and ideally drug substance can be used for formulation without testing based on its Certificate of Analysis, and similar for drug product towards final packing), and substantial reduction of shipping timelines. A single CDMO may also have different production stages housed at a single site, removing the need for shipping and creating further advantages in terms of efficiency.

Selecting the Right Partner

 

HPAPI products continue to become more advanced and widely used, especially in oncology treatments. Accelerated regulatory pathways are also increasingly utilized to better ensure that new therapies are rapidly advanced. Managing shortened timelines from concept to commercialization will continue to be a top priority for pharma and biotech players. CDMOs can play a pivotal role bringing these products to clinic and to market so patients around the world can experience their benefits.
When differentiating between collaboration partners, one should evaluate technical expertise based on specific programs and visit the candidate CDMO organization at the facility where the program will be performed. For some smaller CDMOs that means visiting one building, while for others it will mean visiting an entire site with several facilities in one location, or facilities within a broader site network. Extensive interviews with CDMO site management and tours of their laboratories and facilities will help ensure that the right development and manufacturing partner is chosen. 
 

About the author

 

Dr. Maurits Janssen is Head of Commercial Development, API Development & Manufacturing at Lonza Pharma & Biotech. He has experience progressing a broad portfolio of technologies in cGMP custom manufacturing from clinical into commercial phase, including chemistry (APIs, highly potent, cytotoxic, peptides and bioconjugates) and biotechnology (mammalian, microbial, antibody drug conjugates, cell therapy and viral therapeutics). Dr. Janssen is based in the company’s headquarters in Basel, Switzerland.

参考文献

1、Citeline and internal Lonza Market Analysis

2、 The Drugmaker’s Guide to the GalaxyA. Mullard, Nature, 2017, 549, 445-447.

3、AI-designed drugs to enter human clinical trials for the first time, M. Murgia, Financial Times, January 31, 2020

4、 CDER New Drugs Program: 2019 Update. K. Sharma (FDA), FDA/CMS Summit, December 3 , 2019

5、Citeline and internal Lonza Market Analysis.

6、Lonza has more than 20 years of experience in handling high potency programs and a proven track record of over 11 years in Antibody Drug Conjugate programs. Lonza has supported over 30% of all accelerated programs in the past 5 years and Lonza is the selected manufacturing partner for the majority of approved ADCs: See video on youtube: https://www.youtube.com/watch?v=KkAKgU2A6qo

 

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