Supplier Qualification Program for Key Raw Materials
实际上，药品生产过程中大多数关键物料可能都没有建立行业标准。此外，国内外，目前并没有专门针对供应商资质确认的指南文件，特别是对于关键物料，这使得建立供应商资质确认流程更具挑战性，对于供应商的资质认定以及管理，往往依赖于每个公司的内部要求。大多数物料相关指南文件都仅仅适用于药品及其相关起始原料。部分直接与药液接触的关键物料可能超出这些文件的范围。
本文作者是来自J&J的QA 验证专家，其在验证和供应商管理拥有丰富经验。
With the publication of recent guidance, specifically the US FDA Quality Systems Approach to Pharmaceutical cGMP Regulations1 and the PIC/S guide on Good Manufacturing Practice for Medicinal Products,2 the pharmaceutical industry has been scrutinizing raw material suppliers with more rigorous qualification programs to determine if they can provide the necessary goods and services to the standards required by companies meeting GMP.随着最新指南的发布，特别是美国FDA质量体系对药物cGMP法规的方法和《药品良好生产规范PIC/S指南》，制药行业一直在审查具有更严格的资质确认计划的原材料供应商，以确定他们是否能够提供必要的商品和服务，以达到符合GMP的公司要求的标准。
The supplier qualification program is an evaluation of raw material suppliers. The requirements for supplier qualification are wide-ranging and complex, and a qualification process should identify and mitigate the associated supply risks of raw materials and services. Different regulations and guidance for medicinal drug products for human or veterinary use and investigational medicinal drug products must be followed, and various European directives and GMP guidelines also define requirements and expectations.3 , 4 For this article, “raw material” is considered any material that is somehow employed in a GMP-regulated process, and “supplier” is used in this discussion as a general term to encompass source manufacturers, vendors, re-packagers, and distributors.供应商资质确认流程是对物料供应商的一个整体评估。对供应商资质确认资质确认过程应识别和减轻物料&服务相关的供应风险。对于人类或兽医用药产品以及研究性药物产品，必须遵守不同的法规和指南，各种欧洲指令和GMP指南也定义了要求和期望。在本文中，“物料”被认为是在GMP监管过程中以某种方式使用的任何材料，并且“供应商”在本讨论中用作包含制造商，供应商，重新包装商和分销商的通用术语。
Supplier qualification can also be considered a risk assessment tool because it produces an acceptable level of assurance that suppliers, vendors, and contractors can supply consistent quality of raw materials and services in compliance with applicable requirements. The quality system approach calls for periodic auditing of suppliers either by paper or on-site, and the approval process may include proof or completion of some activities and documentation.资质确认也可以被视为一种风险评估工具，因为它提供了一个被认可的保证，即供应商，销售商和承包商，可以提供符合要求的物料和服务。质量体系方法要求通过纸质或现场对供应商进行定期审计，审评过程可能包括证明或完成某些活动和文件。
Auditing suppliers is an expensive task that requires a serious commitment of time and resources. However, from a business perspective, it makes good sense to evaluate suppliers at a frequency and level of requirements appropriate to their impact on the final drug product. Several papers have been published about supplier qualification strategies for active pharmaceutical ingredients (APIs), excipients, and primary packaging components.5 , 6 , 7 , 8 , 9 This article focuses on non-GMP-regulated raw materials such as detergents, disinfectants, gowning, and other consumables for life sciences applications.供应商审计是一项繁重的任务，需要投入大量时间和资源。然而，从商业化角度来看，以适合供应商对最终药物产品影响的频率和要求水平来评估供应商是很有意义的。已经发表了几篇关于活性药物成分（API）、辅料和初级包装组件的供应商资质确认策略的论文，详见索引5 , 6 , 7 , 8 , 9。本文重点介绍非GMP监管的原材料，如洗涤剂、消毒剂、防护服和其他生命科学应用的消耗品。
RISK-BASED MATERIAL EVALUATION 基于风险的物料评估
A wide range of raw materials can affect product quality or process performance. Raw materials include APIs, process aids, materials, contacting process fluids, excipients, devices, and primary and secondary packaging. Raw materials may be further classified by their use in the manufacturing process and their subsequent effect on quality.种类繁多的物料会影响产品质量或工艺性能。原料包括原料药、工艺助剂、物料、接触工艺流体、辅料、设备以及一次和二次包装。原材料可以根据它们在制造过程中的用途及其对质量的后续影响进一步分类。
For simplification purposes, in this article, the categories are defined as follows:为简化起见，本文中的类别定义如下：
Starting raw materials: These materials are known to significantly affect product quality, with them. Examples include APIs, excipients, USP-grade reagents, and primary packaging起始物料：已知这些物料与它们直接接触。示例包括 API、辅料、USP 级试剂和一级包装成分。
Key raw materials: These materials impact process consistency, but do not significantly Some examples are detergents, disinfectants, and food-grade lubricants. Also, they components, and other processing aids.关键物料：这些材料会影响工艺的一致性，但不会显著影响产品质量。它们可以根据需要根据风险商品化学品，二次包装成分和其他加工辅助工具。
Non-starting or non-key raw materials: These materials do not meet the other categories.非起始或非关键物料：这些材料不符合其他类别。
Regulatory guidelines focus on manufacturing practices for the starting raw materials intended to be parts of the medicinal product, such as APIs, excipients, and primary packaging components. The guidelines for starting raw materials define similar GMP requirements for drug products,10 , 11 , 12 which is reasonable because APIs and excipients are recognized as primary materials for medicinal products, and are therefore a potentially higher risk to final product quality.监管指南侧重于作为医药产品一部分的起始物料（如原料药、辅料和初级包装成分）的生产实践。起始物料指南对药品定义了类似的GMP要求，这是合理的，因为原料药和辅料被认为是医药产品的主要材料，因此对最终产品质量的潜在风险更高。
Key raw materials used in the facility are considered important due to their role in a validated process (e.g., cleaning validation, sterilization processes, and disinfectant qualification), but they are not regulated by the FDA or any other GMP authorities. Virtually no industry standards have been established for most key raw materials. Further, guidance that specifically addresses supplier qualification has not been formally established, especially for key raw materials, which makes establishing supplier qualification processes even more challenging and reliant upon each company’s requirements.设施中使用的关键物料由于其在验证过程（例如，清洁验证，灭菌过程和消毒剂认证）中的作用而被认为是重要的，但它们不受FDA或任何其他GMP当局的监管。实际上，大多数关键物料都没有建立行业标准。此外，专门针对供应商资质的指南尚未正式建立，特别是对于关键原物料，这使得建立供应商资质确认流程更具挑战性，并且依赖于每个公司的要求。
The supplier auditing program should be based on the risk associated with the material being provided.13 Raw materials should be classified as high, medium, or low risk depending on the criticality of the medicinal product or process. If the pharmaceutical manufacturer has many suppliers, then these suppliers should also be assessed by classifying them into different levels based on their impact on the medicinal product.供应商审计计划应基于与所提供物料相关的风险。根据药品或工艺的临界程度，应将物料原材料分为高、中或低风险。如果药品制造商有许多供应商，那么这些供应商也应该通过根据他们对药品的影响将其分类到不同的级别来评估。
The ICH Q9 Quality Risk Management guidelines offers principles and tools applicable to different aspects of pharmaceutical quality.14 As shown in Figure 1, risk assessment becomes a critical aspect in the qualification and management of raw material suppliers. Therefore, the ICH Q9 guideline can be a useful reference when creating a supplier qualification program. The example in Figure 1 relates to cleaning agents used for cleaning validation of processing equipment. The risk management process could be implemented retrospectively for currently used cleaning agents and prospectively during cleaning process development.ICH Q9质量风险管理指南提供了适用于药品质量不同方面的原则和工具。如图1所示，风险评估成为物料供应商资质确认和管理的关键方面。因此，在创建供应商资质确认流程时，ICH Q9 指南可以作为有用的参考。图1中的示例涉及用于加工设备清洁验证的清洁剂。风险管理过程可以追溯实施当前使用的清洁剂，也可以在清洁过程开发过程中进行预期实施。
The following questions may be used to guide the risk assessment process:以下问题可用于指导风险评估过程：
In what part of the product manufacturing process is the material used?在产品制造过程的哪个部分使用了该物料？
What role does the supplier play in the supply chain?供应商在供应链中扮演什么角色？
Has the validation or product development team determined the classification of this raw 验证或研发团队是否确定了这种物料的分类？为什么或为什么不呢？
Is this supplier the sole source of the raw material?这个供应商是该物料的唯一来源吗？
To what industries does the supplier provide materials?供应商向哪些行业提供材料？
The need for supplier qualification may be misinterpreted during the early stages of product or process development, such as clinical trials and revalidation work.15 For example, it is expected that the raw material used in the development phase, not the supplier, will be qualified during stage 1 of the life cycle model, as discussed in the FDA Process Validation Guidance.16 Raw material qualification differs in that the focus is on demonstrating that the material is adequate for the process (e.g., manufacturing, cleaning, and sterilization). However, the raw material supplier will subsequently be qualified should the development or validation groups determine that the material or components will be used in the commercial-scale process. Table 1 is a good example of how the ICH Q9–recommended risk assessment tools can be valuable when evaluating multiple suppliers of the same raw material type.在产品或工艺开发的早期阶段，例如临床试验和再验证工作，对供应商资质确认的需求可能会被误解。例如，正如FDA工艺验证指南中所讨论的那样，预计在开发阶段使用的物料，而不是供应商，将在生命周期模型的第1阶段获得资质。物料物料足以用于该工艺（例如，制造，清洁和灭菌）。但是，如果研发或验证小组确定该材料或组件将在商业规模的过程中使用，则物料供应商随后将获得资质。表1是一个很好的例子，说明在评估相同原材料类型的多个供应商时，ICH Q9推荐的风险评估工具如何具有价值。
Table 1 depicts the foundations of such a risk assessment to determine the appropriate level of quality and technical requirements by including the two primary principles issued by ICH Q9 : (a) that the evaluation of the risk to quality could be based on scientific knowledge and ultimately link to the protection of the patient, and (b) that the level of effort, formality, and documentation of the quality risk management process could be commensurate with the level of risk.14
表1描述了这种风险评估的基础，通过包括ICH Q9发布的两项主要原则来确定适当的质量和技术要求水平：（a）质量风险的评估应基于科学知识，并最终与保护患者有关，以及（b） 质量风险管理过程的形式和文档记录应与风险等级对等。
INDUSTRY TRENDS 行业动态
Supplier qualification should be completed before the pharmaceutical manufacturer reviews. The qualification relies on approval of the test results reported on the certificate of analysis or conformance and on at least one on-site identity test.供应商资质确认应在药品制造商审查之前完成。该资质确认依赖于对COA或COC的测试结果的获批，以及至少一次现场鉴别测试。
The general supplier approval procedure for key raw materials starts with the buyer, purchasing, or procurement department contacting the preselected supplier. An internal specification sheet is created and sent to the supplier for review and approval. Supplier assessment surveys, also known as paper audits, may also be sent to the supplier at this point. The supplier-completed questionnaire is then received by the company’s procurement and then quality departments. Suppliers may be required to provide samples (if first qualified), and the quality control lab tests those samples. The samples provided will be analyzed by quality control (QC) and reported to quality assurance (QA). If the results comply with the established specification, then QA may plan for an on-site supplier audit. An on-site supplier audit is planned and scheduled. If the on-site audit results are satisfactory, then the supplier is considered approved.关键原材料的一般供应商批准程序从买方、采购或采购部门联系预选供应商开始。创建内部规格表并将其发送给供应商进行审查和批准。供应商评估调查，也称为纸质审核，也可以在此时发送给供应商。供应商完成的问卷由公司的采购部门收到，然后是质量部门。供应商可能需要提供样品（如果首先合格），质量控制实验室会测试这些样品。所提供的样品将通过质量控制（QC）进行分析，并报告给质量保证（QA）。如果结果符合既定规范，则QA可能会计划进行现场供应商审核。计划和安排现场供应商审计。如果现场审核结果令人满意，则认为供应商已获得批准。
It is important to note that all steps mentioned may not apply to all key raw materials and may vary per company. As previously mentioned, the supplier qualification requirement should consider the risk classification of the material. Over the years, global companies have established minimum sup-plier qualification requirements including quality surveys, quality agreements, on-site audits, and technical support.重要的是要注意，提到的所有步骤可能不适用于所有关键物料，因公司而异。如前所述，供应商资质要求应考虑物料的风险分类。多年来，全球公司已经建立了最低要求，包括质量调查，质量协议，现场审计和技术支持。
Quality Surveys 质量调查
To determine if a supplier can meet expected quality requirements when supplying raw materials, a questionnaire may be used to gain information about the quality standards, regulations, certifications, or best practices applicable to the type of key raw material being supplied. Surveys should contain questions applicable to the approval of a particular supplier. While it is important to know that a supplier of key raw materials has appropriate quality systems and best practices while manufacturing key raw materials, the materials are not GMP regulated, and full adherence to the GMP regulations established for drugs, medical devices, or other GMP-regulated materials is not realistic. The best that can be expected is a key raw material being manufactured “at an FDA registered site” or “manufactured under a quality system that models a GMP-compliant quality system.”为了确定供应商在供应原材料时是否能够满足预期的质量要求，可以使用调查问卷来获取有关适用于所供应的关键原材料类型的质量标准，法规，认证或最佳实践的信息。调查应包含适用于特定供应商批准的问题。虽然重要的是要知道关键原材料的供应商在制造关键原材料时具有适当的质量体系和最佳实践，但这些物料不受GMP监管，并且要求其完全遵守为药品，医疗器械或其他GMP监管材料制定的GMP法规，是不现实的。可以预期的最好结果是，物料“在FDA注册工厂”或“在类似GMP的质量体系的质量体系下”被生产。
Quality surveys are intended to provide a basic understanding of the supplier’s quality management system. Questions should be straight to the point and clear, and companies should be cautious about including questions unrelated to quality systems such as pricing, environmental health and safety practices, or product technical questions. Instead, other survey forms that focus on those business aspects can be sent separately. Because of proprietary and company confidential restrictions, many key raw suppliers may omit details when responding to survey questions that ask to “describe,” “explain,” or “attach a copy.” For the same reasons, a supplier may deny some information (e.g., highest education level achieved by an individual in a certain position) if irrelevant to quality systems.质量调查旨在提供对供应商质量管理体系的基本了解。问题应该直截了当，清晰明了，公司应该谨慎对待与质量体系无关的问题，如定价、环境健康和安全实践或产品技术问题。相反，其他关注这些业务方面的调查表单可以单独发送。由于专有和公司机密的限制，许多关键的供应商在回答要求“描述”、“解释”或“附上副本”的调查问题时可能会省略详细信息。出于同样的原因，如果与质量体系无关，供应商可以拒绝某些信息（例如，某个职位的个人达到的最高教育水平）。
Quality Agreements 质量协议
In November 2016, the FDA published the guidance Contract Manufacturing Arrangements for Drugs: Quality Agreements, which describes the agency’s current expectations for firms that outsource the production of drugs subject to current GMP regulations. 17 This guidance has been the basis for quality agreements in the industry, even though it is focused on contract manufacturers instead of raw material suppliers. Nevertheless, the concepts in the guidance document could be applied in the quality agreement to establish the expectations between the contract giver (company) and contract acceptor (supplier). Several important aspects for quality agreements are discussed or recommended in the literature.18 , 19 , 20 , 212016年11月，FDA发布了指导性药物合同生产安排：质量协议，其中描述了该机构目前对外包受当前GMP法规约束的药物生产公司的期望。该指南一直是该行业质量协议的基础，尽管它侧重于合同制造商而不是原材料供应商。然而，指导文件中的概念可以应用于质量协议，以确定合同给予者（公司）和合同接受者（供应商）之间的期望。文献中讨论或推荐了质量协议的几个重要方面。
The following aspects must be clearly stated and agreed upon:必须明确说明和商定以下几个方面：
The roles and responsibilities of the company and the supplier公司和供应商的角色和责任
How deviations and out-of-specification results will be investigated, documented, and 如何调查、记录和解决偏差和超标的结果
How changes that may need to be made to the manufacturing process, equipment, 如何管理和传达可能需要对生产工艺、设备、分析方法或规格进行的变更
How complaints are handled and resolved如何处理和解决投诉
What rights the company has for on-site audits and management of audit observations公司对现场审计和审计意见管理有哪些权利
Common issues with quality agreements about key raw materials are that they often prohibit all changes without first obtaining the company’s consent. First, this type of broad prohibition exceeds the legal requirements applicable to medicinal drugs, which permit routine, non-major changes to be made without first notifying the FDA. By unduly restricting non-major process improvements, companies may substantially undermine the suppliers’ ability to implement quality-improving, efficiency-generating, and cost-saving measures that, in the long run, benefit both parties.关于关键物料的质量协议的常见问题是，它们通常要求所有变更需事先获得甲方公司的同意。首先，这种类型的广泛禁令超出了适用于药物的法律要求，这些要求允许在不事先通知FDA的情况下进行常规的非重大更改。通过不适当地限制非重大工艺改进，甲方公司可能会严重损害供应商实施质量改进，提高效率和节省成本的措施的能力，但是，从长远来看，这些措施对双方都有利。
Additionally, it is not logistically possible for suppliers of non-customized globally available key raw materials to contact every end user and request consent to proceed with a change. For example, if a key raw material supplier accepts a contract with excessive change notification requirements without review, this could eventually compromise the supplier’s ability to maintain compliance with the established quality agreement between both parties. On the other hand, suppliers must acknowledge the needs of GMP-regulated companies and avoid significant changes that affect product quality, fit, form, and function, which may impact the use of the key raw material by companies in validated manufacturing. When unavoidable, all efforts should be made to ensure that the company is notified in a timely fashion and provided sufficient information and product supply to address their validation concerns.此外，非定制的全球可用关键物料供应商，在物流上不可能联系每个最终用户，并请求同意进行变更。例如，如果关键物料供应商未经审查，就接受了具有过多变更通知要求的合同，这最终可能会损害供应商保持遵守双方之间既定质量协议的能力。另一方面，供应商必须承认受GMP监管的公司的需求，并避免影响产品质量，适用性，形式和功能的重大变化，这可能会影响公司在经过验证的已被使用的关键物料。在不可避免的情况下，应尽一切努力确保及时通知公司，并提供足够的信息和产品供应，以解决其验证问题。
Quality agreements vary in their level of procedural specificity, and often the requirements are inconsistent with the supplier’s standard procedures. Some quality agreements may merely state that the supplier “has procedures” governing a particular area. Other companies may set forth detailed procedures that the supplier must implement for a particular area and these detailed requirements may create issues for key raw material suppliers. For example, the quality agreement may provide a three-year retention period for batch records, but the supplier’s normal procedure may call for a two-year retention period. In this example, although there may be nothing inherently unreasonable about retaining batch records for an additional year, the supplier may want to follow current policies instead of assuming the long-term cost of tailoring its procedures to accommodate a single customer.质量协议在程序特异性方面各不相同，并且要求通常与供应商的标准程序不一致。有些质量协议可能只是说供应商“有管理某一特定领域的程序”。其他公司可能会规定供应商必须针对特定领域实施的详细程序，这些详细要求可能会给关键原材料供应商带来问题。例如，质量协议可能为批次记录规定三年的保留期，但供应商的正常程序可能要求两年的保留期。在此示例中，尽管将批次记录再保留一年可能没有什么内在的不合理之处，但供应商可能希望遵循当前政策，而不是承担调整其程序以适应单个客户的长期成本。
On-Site Audits 现场审计
Pharmaceutical manufacturers are responsible for auditing high- and moderate-risk suppliers, and these audits should be determined on a case-by-case basis. Where an audit is not deemed necessary, this should be justified appropriately, including with a formal risk assessment. When a supplier audit is indicated, it should be conducted by staff with adequate knowledge and training. A written plan for the audit should be prepared before the audit. After the audit, an audit report should record what was reviewed and any observations identified. The supplier should be expected to deliver a written response to any deficiencies, and these responses should be reviewed before the audit is closed. The resulting audit report can form the basis for the approval of the supplier.制药商负责审核高风险和中等风险的供应商，这些审核应根据具体情况确定。如果认为没有必要进行审计，则应适当说明理由，包括进行正式的风险评估。当需要供应商审核时，应由具有足够知识和培训的员工进行。在审计之前，应制定审计的书面计划。审计后，审计报告应记录所审查的内容和确定的任何意见。应期望供应商对任何缺陷作出书面答复，并应在审计结束之前审查这些答复。由此产生的审核报告可以构成供应商批准的基础。
The supplier should be re-audited at a specified frequency to verify ongoing performance. A rationale for the minimum audit frequencies for each supplier should be documented. The standard industry practice is every 3–5 years for non-GMP-regulated key raw materials. Even if the initial audit was on site, a desktop and/or questionnaire audit might be acceptable for re-audits if there have been no quality issues and the supplier has a good quality and compliance history.应以指定的频率对供应商进行重新审核，以确认物料的持续性能。应记录每个供应商的最低审核频率的理由。非GMP监管的关键物料的标准行业惯例是每3-5年一次。即使初始审计是在现场进行的，如果没有质量问题并且供应商具有良好的质量和合规性历史记录，桌面和/或问卷审核也可能被接受用于重新审核。
The COVID-19 pandemic resulted in governments imposing temporary measures such as confinement, quarantine orders, and travel restrictions that are impacting GMP manufacturers in their capacities to perform on-site supplier inspections. Consequently, many drug manufacturers have adopted temporary measures such as performing virtual supplier audits to maintain compliance and supply of medicines to patients. The term “virtual audit” applies to inspections performed off-site using enhanced communication and information technology to fulfill a legal requirement of an on-site inspection. The only difference is that the inspector is not physically present. These audits may also be described as “remote” or as “distant inspections.”COVID-19大流行导致政府实施临时措施，如禁闭，检疫令和旅行限制，这些措施影响了GMP制造商进行现场供应商检查的能力。因此，许多药品制造商采取了临时措施，例如进行远程供应商审核，以保持合规性并向患者供应药品。“虚拟审计”一词适用于使用增强的通信和信息技术在场外进行的视察，以满足现场视察的法律要求。唯一的区别是检查员不在场。这些审计也可以被描述为“远程”或“远程审计”。
Technical Support 技术支持
The supplier’s ability to provide technical support is critical for the design, qualification, and monitoring stages of the process life cycle approach. For example, for cleaning agents used in validated cleaning applications, technical support could include laboratory testing for selecting the best cleaning agent and cleaning parameters, which saves time and resources during start-up or when trouble-shooting existing cleaning issues. Technical support should be available via phone calls, emails, teleconferences, webinars, and on-site support if needed. Technical literature may include the following, as applicable: material safety data sheet, certificate of manufacture/analysis, technical data sheets, technical tips, and laboratory reports.供应商提供技术支持的能力对于过程生命周期方法的设计、资质确认和监控阶段至关重要。例如，对于经过验证的清洁应用中使用的清洁剂，技术支持可能包括实验室测试，以选择最佳的清洁剂和清洁参数，从而在启动或对现有清洁问题进行故障排除时节省时间和资源。如果需要，应通过电话，电子邮件，电话会议，网络研讨会和现场支持提供技术支持。技术文献可能包括以下内容（如适用）：材料安全数据表、制造/分析证书、技术数据表、技术提示和实验室报告。
COMMON ISSUES WITH GUIDANCE DOCUMENTS
指南文件的常见问题
A series of supply chain disasters—such as heparin, melamine, and nitrosamines contamination—has resulted in more pressure than ever for pharmaceutical manufacturers to develop better supplier qualification practices.22 Material management and supplier evaluation are key processes to avoid batch failures and adverse effects on patients. As a result, pharmaceutical manufacturers are demanding quality system compliance with adequate standards and increased information transparency from their suppliers.23 Some raw material suppliers require more provenance information from their suppliers, such as source, origin, and other essential information for traceability purposes.一系列供应链灾难（如肝素、三聚氰胺和亚硝胺污染）给制药商带来了前所未有的压力，要求他们制定更好的供应商资质确认实践。物料管理和供应商评估是避免批次故障和对患者产生不利影响的关键流程。因此，制药商要求质量体系符合适当的标准，并提高供应商的信息透明度。一些物料供应商要求其供应商提供更多的来源信息，例如来源，原产地和其他基本信息，以便于可追溯性。
Most FDA (or equivalent agency) guidance documents related to the subjects mentioned previously are applicable to medicinal products and their starting raw materials. However, key raw materials that are not purposely added to or in direct contact with the medicinal product may be beyond the scope of those documents. For that reason, requesting suppliers of key raw materials to make the product fully compliant with such guidance documents is not realistic. In some cases, compliance may not even be feasible due to the type of material.针对大多数与前面提的相关主题，在FDA（或同等机构）指南文件都只适用于医药产品及其起始原料。但是，未有意添加到药品中或与药品直接接触的关键物料，可能超出这些文件的范围。因此，要求关键物料的供应商使产品完全符合此类指导文件是不现实的。在某些情况下，由于物料的类型，合规性甚至可能不可行。
The USP <467> Residual Solvents and USP <232> Elemental Impurities guidances are good examples to illustrate this issue. The first is a standard for the testing and potential reporting of residual solvents in pharmaceutical products. Residual solvent is defined as organic volatile chemicals that are used or produced in the manufacture of drug substances, excipients, or in the preparation of drug products.24 Similarly, elemental impurities specify limits for the number of elemental impurities in drug products.25 , 26 These impurities include catalysts and environmental contaminants that may be present in drug substances, excipients, or drug products. These impurities may occur naturally, be added intentionally, or be introduced inadvertently.USP <467> 残留溶剂和 USP <232> 元素杂质指南就是说明此问题的很好的例子。第一个是药品中残留溶剂的测试和潜在报告的标准。残留溶剂被定义为在制造药物物质，辅料或制备药物产品时使用或生产的有机挥发性化学品。同样，元素杂质规定了药物产品中元素杂质数量的限制。这些杂质包括可能存在于药物物质、辅料或药物产品中的催化剂和环境污染物。这些杂质可能是自然发生的，有意添加的，或者无意中引入的。
These USP documents do not apply to key raw materials such as cleaning and germicidal agents used in drug manufacturing facilities because these types of items are intended to clean and disinfect surfaces. Some surfaces on which these cleaning agents are applied may also be in direct contact with drug products; however, residues are generally removed before the equipment is used. An effective and validated cleaning procedure will ensure that any potential for residuals from cleaning agents is not transferred over from the cleaning process into the next batch of drug product.这些 USP 文件，不适用于关键物料，例如药品生产设施中使用的清洁剂和杀菌剂，因为这些类型的物品旨在清洁和消毒表面。施加这些清洁剂的某些表面也可能与药物产品直接接触;但是，残留物通常在使用设备之前被去除。有效且经过验证的清洁程序，将确保清洁剂残留不会从清洁过程中转移到下一批药物产品中。
Even though key raw materials may be excluded from USP <467>, USP <232>, and other similar guidance documents, assessing the risk for potential contamination into the manufacturing process is still recommended. A better approach is to ask suppliers more pertinent questions as applicable to the material instead of requesting a declaration of compliance with these standards or guidance documents. Table 2 provides a list of common compliance topics and reference guidance documents with a suggested question for non-GMP-regulated key raw material suppliers.这些 USP 文件不适用于关键物料，例如药品生产设施中使用的清洁剂和杀菌剂，因为这些类型的物品旨在清洁和消毒表面。施加这些清洁剂的某些表面也可能与药物产品直接接触;但是，残留物通常在使用设备之前被去除。有效且经过验证的清洁程序将确保清洁剂残留的任何潜在不会从清洁过程中转移到下一批药物产品中。
CONCLUSION 结论
Considering the regulatory challenges, it is important to have a deep understanding of key raw material suppliers when sourcing materials worldwide. Suppliers must be willing to provide the information needed for regulatory filings or other regulatory requirements, including materials not governed by GMP regulations. Favoring suppliers that can supply reliable and high-quality products ensures safe and effective drugs and makes good business sense.
考虑到监管挑战，在全球采购物料时，深入了解关键物料供应商非常重要。供应商必须愿意提供监管备案或其他监管要求所需的信息，包括不受GMP法规约束的材料。首选提供可靠和高质量产品的供应商，可以确保药企生产安全有效的药物，并具有良好的商业意义。
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