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Harmonizationof best practices and regulatory requirements will enable developersto find the best stability testing approach. 协调最佳指南和法规需求，使研发人员能够找到最佳的稳定性测试方法。 By Felicity Thomas 作者：菲丽希蒂 托马斯 Withinthe bio/pharmaceutical industry, ascertaining drug substance/product stabilityis an integral part of the development process and must be performed accordingto specific regulatory requirements. Rigorous testing methods need to beemployed to determine a product’s stability, safety, integrity, and shelf-lifeunder a variety of stipulated conditions. 在生物/制药行业，确定药物/产品的稳定性是研发过程的一个组成部分，必须根据特定的法规要求来执行。需要使用严格的测试方法来确定产品在各种规定条件下的稳定性、安全性、完整性和货架期。 Rigoroustesting for stability is considered to be a pre-requisite for acceptance orapproval of any bio/pharmaceutical product submission by the relevantregulatory body. “Stability assessment is potentially the most important aspectof drug product development,” says Stuart Kirbyshire, stability manager,Intertek Pharmaceutical Services. “Any regulatory authority will expect you tohave a full and thorough knowledge of your product, and without understandingchanges to chemical and physical stability under variations of temperature,humidity, and light, obtaining approval will prove problematic.” 严格的稳定性测试被认为是相关监管机构接受或批准任何生物/药物产品提交的先决条件。“稳定性评估可能是药物产品研发中最重要的方面，”天祥医药服务公司(Intertek Pharmaceutical Services)稳定性经理StuartKirbyshire表示。“任何监管机构都希望你对自己的产品有全面而彻底的了解，如果不了解在温度、湿度和光线变化下化学和物理稳定性的变化，监管批准方面将会被证明是有问题的。” Guidelines,provided by the International Council for Harmonization (ICH), the World HealthOrganization (WHO), and other agencies, specify that bio/pharmaceuticalproducts need to have an expiration date that has been determined via the mostappropriate stability test protocols (1,2). These guidelines take intoconsideration the climatic zone of the intended market, of which there are fourseparate classifications for worldwide stability testing (3). 由国际协调委员会(ICH)、世界卫生组织(WHO)和其他机构提供的指南规定，生物/制药产品需要有一个通过最适当的稳定性测试方案确定的有效期(1,2)。这些指南考虑了预期市场的气候带，其中有四个单独的分类用于全球稳定性测试(3)。 “It isalso key to assess your product across a broad range of climatic conditions toensure global market reach,” Kirbyshire confers. “Understanding the effects oftransportation and temperature cycling is also desirable to prove there will beno unanticipated events during shipping and storage.” “在广泛的气候条件下评估你的产品也是关键，以确保全球市场的覆盖面，” Kirbyshire承认。“了解运输和温度周期变化的影响也有助于证明在运输和储存期间不会发生意外事件。” Some ofthe guidelines provided for stability testing, however, are only applicable toconventional small-molecule drug products/substances and, as guidelines, do notprovide specific methodologies for the recommended tests. Therefore, analyticalmethods and bioassays need to be developed by analysts, which then must bevalidated. See Table I for an overview of the typical analyticalmethods employed. 然而，为稳定性测试提供的一些指南只适用于传统的小分子药物产品/药物，作为指南，并没有为推荐的测试提供具体的方法。因此，分析方法和生物测定方法需要由分析人员开发，然后必须得到验证。典型分析方法的概述见表一。 Table I:Overview of the typical methodology employed for stability testing in relationto the specific quality attribute to be assessed. 表一: 被评估的相关质量属性稳定性测试所采用的典型方法概述 “Theanalytical techniques employed can vary depending upon the type of molecule,dosage format, and intended therapeutic use,” explains Kirbyshire. “As theprimary purpose for conducting stability studies is to determine shelf life,characterization of degradation products, and potency for any pharmaceuticalproduct.” “使用的分析技术可以根据分子类型、剂型和预期的治疗用途而变化，” Kirbyshire解释说。“进行稳定性研究的主要目的是确定任何药品的货架期、降解产物的特性和药品的效价。” “Forbiologics, driven by their complexity of structure, a more diverse analyticalcapability is required for a stability study. Therefore, it is important todesign stability programmes that incorporate robust analytical approaches,”notes Jordi Trafach, associate director—Biologics, Intertek PharmaceuticalServices. “These analytical approaches should be built on a good scientificunderstanding of degradation pathways and established stability-indicatingmethods, which are sensitive and specific to changes in critical qualityattributes (CQAs).” “对于生物制品，由于其结构的复杂性，稳定性研究需要更多样化的分析能力。因此，设计包含稳健的分析方法的稳定方案非常重要。天祥医药服务公司(Intertek Pharmaceutical Services)生物制品副主任JordiTrafach指出。“这些分析方法应该建立在对降解途径的良好科学理解和建立的稳定性指示方法的基础上，这些方法对关键质量属性(CQAs)的变化是敏感和特定的。” Biologicsare known to be extremely sensitive to environmental factors and susceptible toaggregation and degradation (4). “To reduce the risk of degradation andmaintain the biological activity of the product, suitable conditions forstorage and shelf life must be established,” emphasizes Trafach. “Understandingpotential degradation routes in relation to the storage environment areparamount to establishing which CQAs are more susceptible to change throughoutthe lifetime of the pharmaceutical or biopharmaceutical. Ultimately, thisunderstanding ensures that the optimal quality control strategy is in place tomonitor continued efficacy and safety of a therapeutic.” 众所周知，生物制品对环境因素非常敏感，容易聚集和降解。Trafach强调:“为了降低降解的风险，保持生物制品的生物活性，必须建立合适的储存条件和货架期。”“了解与储存环境相关的潜在降解途径对于确定哪些CQAs在药物或生物制药的整个生命周期中更容易发生变化至关重要。”最终，这种理解确保了最佳的质量控制策略有效性，以监测持续治疗的有效性和安全性。 As aresult of the complex nature of biologics, Trafach states that bespoke,non-compendial methods may be required to monitor all potential and knowndegradants throughout product development. He stresses that it is alsoimportant to consider excipients that are often required in biologicformulations, as these excipients may be susceptible to degradation or may alsoreact with the main biologic product. Trafach指出，由于生物制品的复杂性，在整个产品研发过程中，可能需要使用定制的非药典方法来监测所有潜在的和已知的降解物质。他强调考虑生物制剂中经常需要的辅料也很重要，因为这些辅料可能容易降解，也可能与主要生物制品发生反应。 “Incases where a potential degradant is observed at a later development stage,there may be the requirement to retest, which could lead to delays to the studycompletion, potentially impacting product registration,” Trafach continues.“Stability-indicating methods should be optimized and validated to demonstrateprecision, accuracy, and robustness and that method performance is fit for its intendeduse.” Trafach继续说:“如果在后期的研发阶段观察到潜在的降解物质，可能需要重新测试，这可能导致研究延迟完成，可能影响产品注册。”“应该优化和验证稳定性指示方法，以证明其精密性、准确性和耐受性，并且该方法的性能适合其预期用途。” 强制降解研究 Forced degradation studies are used to determine the degradation products that areformed during accelerated pharmaceutical studies and long-term stabilitystudies (5). These studies are mandated by regulatory bodies for new drug substances and are integral to understanding degradation pathways, and, assuch, gaining a comprehensive assessment of biologic stability, Trafach notes. 在加速药品研究和长期稳定性研究期间，强制降解研究是用来确定形成的降解产物 (5)。这些研究是监管机构强制要求新药物物质必须做的，因此需要完整的理解降解途径,获得生物稳定性的综合评价,Trafach指出。 “Forced degradation studies also drive invaluable information regarding formulation development and process development,” he adds. “A forced degradation study caninclude factors such as temperature, light, pH, oxidizing agents, mechanicalstress, and freeze-thaw cycles. The knowledge from these studies, in conjunction with a detailed understanding of the product and process, help to establish CQAs.” 他补充说:“强制降解研究还推动了有关配方开发和工艺开发的宝贵信息。”“强制降解研究包括诸如温度、光照、pH值、氧化剂、机械应力和冻融循环等因素。从这些研究中获得的知识，结合对产品和流程的详细了解，有助于建立CQAs。” Planning is prudent 合理的计划是明智的 The level of complexity and scientific expertise required to perform stability testing of sufficient quality and efficiency can take a considerable period oftime and incur significant costs (6). However, appropriate procedure planningcan be helpful, according to Kirbyshire. “With good planning of other activities around long-term studies, supported by bracketing and matrixingof batches, pack types, and strengths, as detailed in ICH Q1D, time pressures can be eased,” he says. 进行足够质量和效率的稳定性测试所需的复杂程度和科学专业知识可能需要相当长的时间，并会产生巨大的成本(6)。然而，适当的程序计划是有帮助的，据Kirbyshire说。他还说:“在长期研究的基础上，通过对批次、包装类型和强度(详见ICH Q1D)进行括号法和矩阵化，对其他活动进行良好的规划，时间压力可以得到缓解。” “In addition to planning,” Kirbyshire continues, “testing of a product stored understress conditions can give an early indication of how the long‑term stability may turn out later down the line. So, it’s key to pay particular attention tothe product performance at the early stages of your study at these conditions.” “除了计划之外，”Kirbyshire继续说，“对储存在压力条件下的产品进行测试，可以早期显示出长期的稳定性将会如何发展。”所以，在研究的早期阶段，在这些条件下，特别关注产品性能是非常关键的。” In the future, Kirbyshire believes that there will be increased focus on the benefits of accelerated stability assessment programmes (ASAP) during early stage development, which have the potential to expand into later-stage assessments.“The ASAP strategy is based on the robust methods for forced degradation, wherethe products are submitted to high temperature and humidity conditions, and thetime points reduced to 14 days,” he explains. “This is sufficient enough to cause a suitable increase in degradation, which can be used to predict the potential long-term stability effects.” 在未来，Kirbyshire相信，在早期发展阶段，将更多地关注加速稳定评估方案的好处，这些方案有可能扩大到后期评估。他解释说:“ASAP的策略是基于强降解的稳健的方法，即产品被提交到高温和湿度条件下，时间点减少到14天。”“这足以导致降解的适当增加，这可以用来预测潜在的长期稳定性影响。” Despite some success being witnessed in the small-molecule arena, however, Kirbyshire stresses that suitability for physical stability testing or large-molecule assessment is not currently proven. “With increased use of the technique,further advances will be made establishing ASAP as a reliable andcost-effective method of determining product stability,” he says. 尽管在小分子领域已经取得了一些成功，但是Kirbyshire强调，目前还没有证明适合进行物理稳定性测试或大分子评估。他说:“随着这项技术的使用越来越多，我们将尽快把它确立为确定产品稳定性的可靠而经济的方法，从而取得进一步的进展。” 最终成品的考虑 Stability of a bio/pharmaceutical product will have a dependency upon the dosage form andpackaging-closure system chosen for commercial deployment (7). “The anticipatedshelf life and in-use storage of your product once commercially available willstrongly influence the approach to stability testing during development,”confirms Kirbyshire. (Figure 1) 生物/药物产品的稳定性将取决于用于商业化的剂型和密封包装系统(7)。Kirbyshire证实:“一旦产品上市，预期的货架期和在使用中的存储条件将强烈影响开发过程中稳定性测试的方法。”(图1) Figure1: ICH Stability storage, a broad range of climatic conditions ensure global market reach. 图1:ICH稳定的储存，广泛的气候条件保证了全球市场的覆盖面。 For example, parenteral solutions can have greater susceptibility to extremes of temperature and light, which usually leads to a storage temperature range of 2–8 °C being targeted, he explains. “Therefore, 12 months storage at 2–8 °C and six months accelerated at 25 °C/60% relative humidity (RH) is sufficient to establish shelf life,” he notes. 他解释说，例如，注射的溶液对极端温度和光有更大的敏感性，这通常会导致目标存储温度范围为2-8℃。他指出:“因此，在2-8°C条件下储存12个月，在25°C/60%相对湿度(RH)条件下加速储存6个月，就足以确定有效期。” In the cases of dry powder inhalers (DPIs) and oral solid doses, humidity is the keyattribute to assess, Kirbyshire emphasizes. “Long-term studies at high humidity conditions (e.g., 30 °C/75% RH and 40 °C/75% RH) are required,” he says. “Acritical test at all time points is the assessment of aerodynamic particle size distribution for DPIs and dissolution for oral solid doses, which will confirm continued efficacy. Any reduction in performance may be improved by the use ofeffective packaging and potentially the addition of desiccant materials.Stability studies are key to determining these.” 在干粉吸入剂(DPIs)和口服固体剂的情况下，湿度是要评估的关键属性，Kirbyshire强调。“需要在高湿度条件下进行长期稳定性研究(例如，30°C/75% RH和40°C/75%RH)，”他说。“在所有时间点进行的一项关键试验是评估DPIs的空气动力粒度分布和口服固体剂量的溶出度，这将证实持续有效。任何性能的降低可以通过使用有效的包装和潜在的添加干燥剂来改善。稳定性研究是确定这些的关键。” 外包的稳定性测试 The decision to outsource stability studies can have a significant impact, either positive or negative, on the success of the overall drug development programme. If due diligence is not performed when choosing a partner, thesponsor’s decision could turn out to be costly (8). 将稳定性研究工作外包的决定可能对整个药物研发方案的成功产生重大影响，或积极影响，或消极影响。如果在选择合作伙伴时没有尽职调查，发起人的决定可能代价高昂。 “When assessing any outsourcing stability partner, there are many things toconsider,” reveals Kirbyshire. “They must have an expert understanding of the key regulatory guidance, ICH Q1A R2 but must also show compliance with[International Organization for Standardization] ISO 9001 to give full confidence in the quality systems and data integrity.” “当评估任何外包稳定性试验合作伙伴时，有很多事情需要考虑，”Kirbyshire说。“他们必须对关键的监管指南ICH Q1A R2有专业的理解，但也必须遵守(国际标准化组织)ISO 9001，对质量体系和数据完整性给予充分的信心。” Some other important aspects to consider when choosing an outsourcing partner forstability testing are the qualification and maintenance schedules of thestorage facility and associated monitoring systems, Kirbyshire continues. “The integrity of the study is only as good as the reliability and robustness of the equipment and control strategies utilized by the provider,” he adds.“Excursions from storage conditions can have an unpredictable and severely detrimental effect to any study, be it a short-term assessment of APIstability, through to a full registration stability programme extending up tofive years.” 在选择稳定性测试外包合作伙伴时，还需要考虑其他一些重要方面，如存储设施和相关监控系统的确认和维护计划。他补充说:“研究的完整性只取决于供应商使用的设备和控制策略的可靠性和稳健性。”“从贮藏条件的偏离对任何研究都可能产生不可预测的严重不利影响，无论是对原料药稳定性的短期评估，还是长达5年的全面注册的稳定计划。” Of course, there are noteworthy benefits of partnering with an outsourcing service provider. “As pharmaceutical development has become an increasingly global partnering process, selecting a provider with knowledge and experience ofimport/export requirements is strongly recommended particularly for some of the more challenging markets,” Kirbyshire adds. 当然，与外包服务提供商合作有一些显著的好处。Kirbyshire补充说:“随着制药研发成为一个日益全球化的合作过程，我们强烈建议选择一家具备进出口需求知识和经验的供应商，特别是对一些更具挑战性的市场。” 显著的改善 Over theyears, there have been significant improvements in the reliability of equipmentand monitoring systems, including real-time feedback of potential excursions,according to Kirbyshire. These technological improvements have given rise toaccelerated and efficient decisions to be taken regarding the next stage ofproduct development. Kirbyshire说，这么多年来，设备和监控系统的可靠性有了显著提高，包括对潜在偏离的实时反馈。这些技术上的改进已促使对产品研发的下一阶段作出加速和有效的决定。 “Regulatory decisions are routinely changing based on currently available data andjustified strategies of stability assessment,” he summarizes. “Through harmonization of this information, companies developing medicines can makeinformed decisions on the best approach to adopt for their products.” 他总结道:“监管决策经常根据现有数据和合理的稳定性评估策略而变化。”“通过协调这些信息，研发药物的公司可以就其产品采用的最佳方法做出明智的决定。” References 1.ICH, Q1A–Q1F Stability, ICH Quality Guidelines. 消息来源：制药技术 |
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