2018年2月2日
苏珊.J .施妮波
<<制药技术>>
第42卷第2期，第61-62页
Regardless of the phase of development and the level ofGMPs being applied, there should be adequate controls and knowledge to assure patient safety, according to Susan Schniepp, fellow at Regulatory Compliance Associates.
无论处在药品开发的哪个阶段，无论运用的GMP的水平如何，都应该要有充分的控制和知识以保障患者的安全。
-苏珊.J.施妮波
药政合规协会成员
《制药技术》杂志社编辑顾问委员会成员
Q. I work in the quality and regulatory departments of a contract manufacturer. We have clients with products in various stages of development that are using multiple contracts with multiple services providers for various stages of the manufacturing process. I always struggle with knowing which level of current good manufacturing practices (cGMPs) apply to different development stages. Can you provide some guidance on this point?
问：我在合同生产商的质量和合规部门工作，我们客户的产品处于研发各个阶段，有多种服务提供商涉及不同生产步骤。我经常感到困惑，对于不同研发阶段采取什么水平的cGMP管理。请提供一些相关指导。
A. In today’s pharmaceutical environment, it is not uncommon for more than one company to be involved in the development of a product. Virtual companies may use the services of a contract laboratory, a contract manufacturer, a contract research organization (CRO), etc., to develop their products from conception to market approval. Some of these relationships can be complex, so it is important for every organization involved in the drug development process to be familiar with what the applicable GMPs are and at which stage of the development process they apply (1-4).
答：在现今的制药环境，公司产品涉及研发阶段已很普遍。一些虚拟公司可能会利用合同实验室，合同生产以及合同研发公司（CRO）等对产品进行从概念到上市批准的研发活动。这其中的关系会很复杂，故对每个涉及研发阶段的组织来说，熟悉什么样的GMP合适以及在哪个阶段使用，就变得非常重要。
Areas to be reviewed to determine the appropriate level of control needed in concert with the phase development stage include: level of validation of test methods, level of detail needed in batch records, level of control needed on incoming materials, and facility and equipment controls. An example is qualifying raw materials. In Phase I/II of the development process, you may only decide to document the source and quality of the material used to produce the product;when you enter into Phase III you will want to qualify your supplier and establish a quality agreement in addition to the material qualification.
为确保有恰当的控制水准而需要评估的内容应与研发阶段相适应，包括测试方法的验证水平，批记录详细程度，来料的控制水平，以及厂房设备的控制。比如原料的资质确认，研发I、II期仅需记录使用物料的来源和品质，当进入III期时，将需要对供应商确认并附质量协议。
Although not all GMP requirements apply to products in the early stages of development, the requirements for change control and deviation investigation should be robust and utilized at all stages of product development. The information documented in change control and as part of an investigation helps ensure that process improvements are efficient and do not repeat strategies that were discounted during earlier stages in the development process. It also helps to capture the product and process history needed in the later phases of development for the process validation activities.
虽然不是所有GMP要求均适用于研发早期阶段，但是变更控制和偏差调查的要求在研发所有阶段必须是稳健（Robust) 的。变更控制记录下的信息以及部分调查内容将有助于提高工艺研发的效率，避免重复研发早期阶段已忽视的内容。也有助于获得用于研发后期工艺验证活动的产品和工艺历史。
To determine the impact of the deviation on the product quality, it is important to determine the ‘root cause’ of the deviation. The process used in the industry to determine root cause is, of course, the investigation procedure. This procedure, regardless of whether the product you are investigating is biotech or traditional, or new or old, should require the investigator to review various systems and determine whether they were the cause of the deviation being investigated. This concept is important because of the aforementioned possibility that more than one company is involved in the product development. When more than one company is involved, there is a necessity for technology transfer (5,6). Without a robust and transparent exchange of information, the technology-transfer activity has the potential to be frustrating and delayed while people try to find a common understanding and locate necessary information crucial to the success of the drug development process. It is important to keep in mind that change control and deviations are critical elements for ensuring product quality and patient safety regardless of the stage of development a product is at in the product lifecycle.
The criticality of an efficient change-control system that can track and ensure proper evaluation and implementation of changes should be obvious at all stages of product development. As a change becomes more complex (e.g., a change that involves multiple products and country registrations), it becomes harder to implement. Complex changes are difficult enough for a single company with multiple sites, but they are even more exaggerated for virtual companies. For the latter, multiple contract service providers are often involved and each one has its own processes and procedures for managing a requested change.
为确认偏差对产品质量的影响，确定偏差的根本原因很重要。确定根本原因的过程即为调查程序。不论调查的产品是生物制品、传统产品，或是新的还是老产品，均要求调查人员确认各种系统，并确哪些系统是正在调查偏差的原因。这个概念很重要，因为上面提到可能有不止一家公司参与产品研发。当不止一家公司涉及产品研发时，有必要进行技术转移。若没有一个稳健和透明的信息交换，技术转移活动将产生令人沮丧并延期的结果，因为研发人员会花费大量时间查询一个共性的理解以及查找对产品研发成功至关重要的必要信息。记住这一点很重要，不论处于哪个研发阶段，处于产品生命周期哪个时期，变更控制和偏差是确保产品质量和患者安全的关键因素。在产品开发的各个阶段，有效的变更控制的关键在于能够跟踪并确保正确评估和实施变更。当变更很复杂时（例如，变更涉及多个产品和多国注册），实施变更会很困难。复杂的变更对于一家有多个厂址的公司很困难，对于虚拟公司来说，这个过程的复杂程度更夸张。对于后者，虚拟公司有多个合同服务供应商，每家供应商均有其自身流程和规定处理要求的变更。
The time required to transfer, validate, train, and obtain regulatory approval for multiple products requires enormous coordination. It is important to keep in mind that as the complexity of the change increases, the need for additional resources can also increase. The complexity of the change can impact the strategies for implementation, the tactics needed to effectively implement the change, and the time it takes for a change to be approved. At the same time, drug license holders will need to establish consistency in their regulatory filings without affecting product quality. When dealing with this change, focus on the steps needed to effectively implement the change. Working closely with your CMO/CRO to identify an accurate timeline for completion, including the necessary training required for employees, can help expedite the time it takes to complete the change request. Coordinating these activities with regulatory requirements also will help ensure necessary changes are implemented globally in an efficient and effective manner throughout the product lifecycle.
对于大多数产品的转移、验证、培训以及获得官方批准需要大量协调工作。要谨记，随着变更复杂性增大，额外需要的资料将随之增加。变更复杂性将影响变更实施策略，应批准实施变更的策略以及变更需要的时长。同时，证书持有人需要保证与注册资料的一致性，并且不影响产品质量。当处理这些变更时，应重点关注保证有效实施的步骤。与CMO/CRO加强合作，确认准确的完成时限，包括员工培训，这些将有助于加快完成变更。变更也要与药政要求相协调，保证变更在产品整个生命周期内全面高效实施。
Applying the correct level of cGMPs to the product development stage is really a matter of common sense. The earlier the product phase is, the more flexible your requirements. As the product approaches Phase III, the board requirements should mimic commercialization requirements. The concept is the GMPs applied should be appropriate to the stage of development and that ‘full GMPs’ should be in place during the later stages of clinical development where the final safety and efficacy of a product are being established. Keep in mind that regardless of the phase of development and the level of GMPs being applied, the first and foremost thought when releasing product at any stage for human consumption is: are there adequate controls and knowledge to assure patient safety?
产品研发阶段实施正确水准的cGMP是广泛共识。产品处于研发阶段越早，要求越灵活。当产品研发处于III阶段，要求要仿照商业化生产要求。这一概念就是GMP必须与研发的不同阶段相适应，当产品安全性和有效性被确定时，依照完整的GMP管理。无论处于研发哪个阶段以及采取什么水准的GMP管理，首要考虑的是当产品放行用于人用时，是否有足够的控制和知识能够保证患者安全？
参考文献
1. FDA,INDs for Phase 1 Studies of Drugs & Biotech Products,November 1995.
2. FDA,Draft Guidance:INDs-Approaches to Complying with CGMP’s for Phase 1 Drugs(CDER, CBER, Jan. 6, 2012)
3. FDA,INDs for Phase 2 and Phase 3 Studies: Chemistry, Manufacturing and Controls Information(May 2003).
4. European Commission,EU GMPs, EudraLex, Volume 4 Annex 13.
5. EC,EudraLex, The Rules Governing Medicinal Products in the European Union, Volume 4, EU Guidelines to Good Manufacturing Practice, Medicinal Products for Human and Veterinary Use.
6. FDA,Guidance for Industry, Contract Manufacturing Arrangements for Drugs: Quality Agreements(CDER, CBER, CVM, May 2013).