质量控制和保证中英版

Quality Assurance and Control质量保证和质量控制
MICHAEL C. VANDERZWAN
Pharmaceutical Technical, Roche Pharmaceuticals, Basel, Switzerland
I. Introduction介绍. . . . . . . . . . . . . . . . . . . . . . . . . . . 235
II. Defining and Assuring the Quality of the Active Pharmaceutical Ingredient 原料药质量的定义和保证. . . . . . . . . . . . . . . . . . 240
III. The Regulations for Quality 质量监管. . . . . . . . . . . . . . . . . 245
IV. The Quality Control and Quality Assurance Department
质量控制和质量保证. . . . . . . . . . . . . . . . .273
Appendix A附录. . . . . . . . . . . . . . . . . . . . . . . . . . . 280
目录
I. INTRODUCTION介绍 (4)
A. The Product产品 (4)
B. The Process工艺 (5)
C. The Facilities设备 (5)
D. The People人员 (6)
E. The Quality Management Department质量管理部门 (6)
F. The Regulatory Authorities 监管机构 (7)
G. The Regulations法规 (8)
II. DEFINING AND ASSURING THE QUALITY OF THE ACTIVE PHARMACEUTICAL INGREDIENT 原料药质量的定义和质量保证 (9)
A. Defining the API Quality 原料药质量的界定 (10)
B. Testing the API for Its Defined Attributes 原料药定义的属性测试 (11)
C. Designing Quality into the Process 工艺中的质量设计 (12)
D. Validation of the Process 工艺验证 (13)
E. Reality实际 (15)
III. THE REGULATIONS FOR QUALITY质量法规 ................ 错误!未定义书签。

Introduction: The Emergence of Specific Regulations for APIs导言：API具体法规的出现.................................................................................... 错误!未定义书签。

1. ICH Q7A Section I: ‘‘Introduction’’第一部分：简介.......... 错误!未定义书签。

2. ICH Q7A Section 2: ‘‘Quality Management’’第二部分质量管理.错误!未定义书签。

3. ICH Q7A Section 3: ‘‘Personnel’’第三部分人员................... 错误!未定义书签。

4. ICH Q7A Section 4: ‘‘Buildings and Facilities’’第四部分厂房和设施错误!未定义书签。

5. ICH Q7A Section 5: ‘‘Process Equipment’’第五部分工艺设备错误!未定义书签。

6. ICH Q7A Section 6: ‘‘Documents and Records’’第六部分文件和记录.. 错误!未定义书签。

7. ICH Q7A Section 7: ‘‘Materials Management’’第7部分物料管理 (33)
8. ICH Q7A Section 8: ‘‘Production and I n-Process Controls’’第8部分产品和过程控制 (36)
9. ICH Q7A Section 9: ‘‘Packaging and Identification Labeling of APIs and Intermediates’’ 第9部分原料药和中间体的包装和标识标签 (39)
10. ICH Q7A Section 10: ‘‘Storage and Distribution’’储存和发运 (41)
11. ICH Q7A Section 11: ‘‘Laboratory Controls’’ 第11部分实验室控制 (41)
12. ICH Q7A Section 12: ‘‘Validation’’ (42)
13. ICH Q7A Section 13: ‘‘Change Control’’第13部分变更控制 (47)
14. ICH Q7A Section 14: ‘‘Rejection and Re-Use of Materials’’第14部分物料的拒收和再用 (49)
15. ICH Q7A Section 15: ‘‘Complaints and Recalls’’第15部分投诉与召回.52
16. ICH Q7A Section 16: ‘‘Contract Manufacturers (Including Laboratories)’’第16部分协议制造商（包括实验室） (54)
IV. THE QUALITY CONTROL AND QUALITY ASSURANCE DEPARTMENT 质量控制和质量保证部 (54)
I. INTRODUCTION介绍
The quality of active pharmaceutical ingredients (APIs) is defined as meeting the appropriate specifications for the API and being produced in a facility compliant with ICH guidelines ‘‘Q7A’’ and FDA’s current good manufacturing practices (cGMPs) regulations. Most countries regulate the manufacture of APIs. These regulations require a total systems approach to assuring an API has the appropriate level of quality. All components in this system must be properly designed, validated, maintained, and operated to allow the manufacturer to assure the API consistently meets quality requirements. The general components of the system are the process, facilities, and the people. This chapter concerns these components, as well as the product quality itself, the regulations, and the quality management (QM) department. 活性药物成分（APIs）的质量应被定义为符合相应的API规范，并且正在建设中的设施应符合ICH指南'Q7A'和FDA现行的动态药品生产管理规范（cGMP）的规定。

大多数国家对原料药的生产制造都有规定。

这些法规要求有一个总的系统方法来保证API的质量在适当水平。

这个系统中的所有组件必须经过正确的设计，验证，维护和操作，以保证制造商的API始终符合质量要求。

该系统中普遍的组件包含工艺过程、设施和人员。

本章内容包括这些组件，以及产品质量本身，法规条例和质量管理部（QM）。

A. The Product产品
The quality of an API is determined by two factors: its conformance to
pre-established specifications and whether it is produced according to a documented validated process in a cGMP compliant facility. The API must possess appropriate chemical and physical attributes to assure that it delivers the intended pharmacological effect. The chemical attributes describe the appropriate purity and impurity limits. Impurity specifications are established from clinical toxicological studies and are also based on reasonable minimums expected from regulatory authorities and consumers. The physical attributes describe the necessary characteristics for reliable pharmaceutical processing into final dosage forms. These attributes are determined by empirical evidence from formulation trials to produce uniform and stable dosage forms of adequate bioavailability.
API的质量是由两个因素决定：是否与预先建立的标准相一致，是否在符合cGMP 要求的设施内并且根据成文的经验证的工艺过程生产出来的。

API必须具有适当
的化学和物理属性，以确保它提供预期的药理学作用。

化学属性描述了适当的纯度和杂质限度。

杂质规范根据临床毒理学研究建立，同时基于从监管部门和消费者那里得到预期的合理最低值。

物理属性描述了可靠药物加工成最终剂型的必要特征。

这些属性由配方试验的经验证据确定，以生产具有足够生物利用度、均匀且稳定的剂型。

B. The Process工艺
The quality of the API is designed into the molecule through the development of the full manufacturing process, from the laboratory scale synthetic process through to end product.
API的质量通过全面的制造工艺的发展被设计成分子，从实验室规模的合成过程通向最终产品。

The synthetic process must be designed to minimize impurities, especially those that prove difficult to remove in the last step. Thus, through effective process development, yields are maximized, waste is minimized, and impurities are not formed, eliminated, or certainly minimized. The specific controls used by the developmental chemist to produce the high-yield, high-quality product must be documented; this documentation forms the basis for the proof of concept and for the validation report. In nearly all countries today, regulatory authorities require the API to be produced from a documented process that reliably meets all appropriate specifications. This was strengthened by the issuance and adoption of the International Conference on Harmonization Tripartite Guideline of Q7A ‘‘Good Manufacturing Practice Guide for APIs.’’ The European Union, the Japanese Ministry of Health and the United States Food & Drug Administration adopted the guide.
合成方法必须被设计成最小化的杂质，尤其是那些证明在最后一个步骤难以除去的。

因此，通过有效的工艺开发、产量最大化、废弃物最小化、不形成、消除或最小化杂质。

所采用的发展化学家的具体控制来产生高收益、高品质的产品必须被记录;本文档构成了概念证明和验证报告的基础。

在今天几乎所有的国家、监管部门要求API应在符合所有相应规范、有记录的工艺过程来生产。

这方面因为国际会议的三方协调指南Q7A“良好生产实践指南的API”的发行和通过得到了加强。

欧盟，日本监管部门和美国食品药品监督管理局通过了这个指南。

C. The Facilities设施
The facilities in which APIs are produced are also addressed in this chapter because a component of quality of an API is that it be produced in cGMP-compliant facilities. Those components of the facility governed by cGMP are therefore part of this chapter. The essence of cGMP for facilities or, for that matter, any aspect of API manufacture is that the facility performs as designed to assure the quality of the product.
生产API的设施在本章节也进行讨论，因为API的质量的组成部分是通过cGMP的标准设施来生产的。

因此，由cGMP管辖的设施的组成部分是本章节的一部分。

对于这个问题，cGMP的设施或API制造的任何方面的的本质是设施执行的设计，以保证产品的质量。

Further, the performance characteristic must be documented, and management must demonstrate the facility continually performs as designed. Performance control monitoring, preventative maintenance, and carefully controlled and approved repairs or changes to facility components are all considered part of assuring quality of APIs. 此外，性能特点必须记录，管理必须证明该设施持续按设计执行。

性能控制监控、预防性维护、精密控制和批准的设备部件的维修或变更都被认为是保证API质量的一部分。

D. The People人员
The people who produce the API are considered a critical part of the system and, as such, become part of the requirements for quality of APIs. To do their jobs effectively and to assure quality of the API, they must be properly trained and equipped. Qualified personnel must conduct the training; the equipment must be of proper design and function. The supervisors of people manufacturing APIs must also be properly trained to do their jobs. Finally, there must be an adequate number of people to allow sufficient time to perform these responsibilities in a satisfactory manner.
生产API的人员是该系统的一个重要组成部分，因此，成为API的质量要求的一部分。

为了有效地做好本职工作，以确保API的质量，就必须进行适当的培训和装备。

合格人员必须进行培训;设备必须有适当的设计和功能。

人造API的监管人员也必须进行适当的培训来做好本职工作。

最后，必须有适当的人数，以便有充足的时间、以令人满意的方式执行这些职责。

E. The Quality Management Department质量管理部门
As in most any other manufacturing enterprise, there is a quality control and or a
quality assurance department. Today, these departments are usually combined into a QM department.
因为在大多数的任何其他制造企业，有一个质量控制部和/或质量保证部。

如今，这些部门通常被合并成一个质量管理部门。

The role of the QM department has also advanced from ‘‘check-test-decide’’ responsibility to being an equal partner with manufacturing and engineering to manage and improve the quality of the entire process and system.
质量管理部门的角色也从''检查、测试、决定'的职责变为与制造和工程平等的参与者来提高全过程和系统的质量。

For APIs and drug products, the QM department, through its quality assurance arm, still has the responsibility vested in it by regulations to release all products for use and eventually to the market. As a component of the system to produce APIs, the activities and responsibilities of the QM department are also a component of product quality. Most cGMPs require that the QM department is responsible to review and approve production procedures, and any changes to them, most reports, procedures, and controls, deemed necessary to assure the quality of the process and product.
对于原料药和药物产品，质量管理部门，通过其质量保证的手臂，还有赋予的责任，通过法规来释放所有产品中使用，并最终推向市场。

作为该系统的一个组成部分来生产原料药，活动和QM部门的职责是也产品质量的一个组成部分。

大多数的cGMP要求质量管理部门负责审查和批准生产的程序，并且对它们的更改，大多数报告，程序和控制，认为有必要确保过程和产品的质量。

Finally, the QM department must have adequate laboratory facilities and properly trained and experienced people to effectively carry out their responsibilities.
最后，质量管理部门必须有足够的实验室设施和适当的培训，经验丰富的人来有效地履行其职责。

F. The Regulatory Authorities 监管机构
Health authorities in every country regulate drug products. In most countries, these regulations also include APIs. These cGMP regulations require that a drug must meet all predefined quality specifications and be produced from a documented validated process. Further, if the drug, or API, is not produced and controlled according to the established process, then the drug is considered adulterated, and therefore not fit for use or sale. The regulations address every aspect of drug product manufacture, and essentially require that the producer has documented evidence of proof of control over
any aspect that might affect product quality. The regulators were deliberate in their use of the word ‘‘current’’ when the cGMPs were promulgated. This qua lifier enables the agencies to continuously require that manufacturers maintain their facilities and processes at the state of the art, thereby always assuring the public that drug products are as safe and effective as possible.
每一个国家由卫生主管部门管制药品。

在大多数国家，这些法规还包括原料药。

这些的cGMP法规要求药品必须符合所有预定的质量标准，并从记录验证过程中产生的。

此外，没有按已建立的方法制备并控制的药物或API，则该药物被认为是掺假，因此不适合使用或出售。

该法规涉及药品生产每一个环节，而且基本上要求生产者记录控制证明可能影响产品质量的任何方面。

监管机构颁布的法规即cGMP，不断要求制造商维持其设备和工艺的状态，从而保证始终如一的生产安全有效的药品。

G. The Regulations法规
The production of APIs is regulated in most countries. The ICH-harmonized tripartite guideline Q7A entitled as Good Manufacturing Practice Guide for APIs was recommended for adoption at Step 4 of the ICH process on the 10th of November 2000. This document was adopted by the following agencies denoting its widespread acceptance:
原料药的生产在大多数国家是受监管的。

良好生产实践指南API ICH-三方协调指导Q7A（2000年11月10日）被建议使用。

下列机构表示普遍接受：
_ European Union (EU) adopted by CPMP, November 2000, issued as
CPMP/ICH/1935/00 欧盟采用CPMP，2000年11月，以CPMP/ICH/1935/00发行
_ Japanese MHLW adopted November 2nd, 2001 MSB notification NO. 1200
日本MHLW采用2001年11月2日的MSB通知，第1200期
_ United States FDA published in the Federal Register, Vol. 66, No 186, September 25th, 2001, pages 49028–49029.
美国FDA发表在联邦注册，第66卷第186期，2001年9月25日，2001年，第49028-49029页
The production process and all tests and controls must be approved by the regulating government in which APIs will be used, and the facilities and systems in which they are produced must meet the manufacturing standards set down by the governing body. Thus, the quality of APIs is based on two components: meeting final quality
specifications and being produced according to the regulated, approved process in a facility compliant with the appropriate manufacturing standards. It is important to note that both criteria must be met: final specifications and compliance to manufacturing standards. These two components will be dealt with separately in this chapter. It is also important to note that the approach toward quality described in this chapter should apply to any API regardless of the country in which it will be used or sold, or whether or not it will be a regulated item.
生产过程中，所有的测试和控制必须由政府监管包括API，设施和系统，生产必须满足的制造标准。

因此，原料药的质量是基于两部分组成：符合最终质量规范，按规定的已批准的工艺在适合的设施中生产。

注意，两个标准都必须满足。

这两部分将在本章中另行阐述。

同样重要的是要注意，在本章中描述的API质量适用于原料药将在其中使用或出售，不管这个国家是否受法规管制。

The approach to quality, described in this chapter, is based on sound scientific principles, good QM principles, and applies to any API. In fact, these principles apply to the manufacture of any chemical that requires a high assurance of quality.
This chapter will deal with the chemical synthesis of APIs. However, all the principles and regulations also apply to other means of preparation, such as fermentation routes or extraction from natural sources.
质量方针，以本章所述，基于合理的科学原则，良好的质量管理原则，适用于任何API。

事实上，这些原则适用于任何需要高质量的化学品的生产。

本章将涉及原料药的化学合成。

然而，所有的原则规定也适用于其它的制备工艺，如发酵路线或者从天然提取。

Finally, since it is assumed throughout this chapter that the API will be subject to regulatory requirements, reference will be made to the regulations. If the reader is dealing with an unregulated item, such reference may be ignored, but the scientific principles on which the regulation is based should be seriously considered.
II. DEFINING AND ASSURING THE QUALITY OF THE ACTIVE PHARMACEUTICAL INGREDIENT 原料药质量的定义和质量保证
This section of the chapter addresses how to:
_ define the necessary quality attributes
_ test for them,
_ design them into the process, and
_ validate the process to assure consistent production.
As APIs are regulated articles, their quality is determined not only by satisfactory test results, but also the assurance that the process was conducted according to a validated process.
本节解决了如何：
_定义必要的质量属性
_检验
_将设计融入工艺
_验证工艺，以确保生产的一致性。

由于API是受管制物品，其质量不仅取决于令人满意的测试结果，也认为工艺是由验证过程来保证的。

A. Defining the API Quality 原料药质量的定义
The API must have its final chemical purity and impurity and its final physical attributes specified; some articles also require microbiological analyses to be determined, depending on the final dosage form and the manufacturing process involved. These attributes are established to assure an API will perform satisfactorily in the pharmaceutical manufacturing process and will result in a final dosage form; i.e., the drug product that will meet its initial release specifications and final stability requirements. The chemical purity minimum is usually set at 98% to assure proper dosing in the drug product and to assure a minimal amount of impurities. The physical parameters should be established with knowledge of the pharmaceutical process and the ultimate final dosage form. Other attributes usually include color of the solid form and or a solution, melting point, specific rotation if optically active, crystal morphology, and so forth. A list of typical API specifications is provided in Appendix A along with the rationale for each one.
API必须具有其最终的化学纯度和杂质，并规定其最终的物理属性;一些还需要微生物分析，这取决于最终的剂型和所涉及的制造工艺上。

这些属性被建立以保证一个API将在药物制造过程中令人满意地执行，并导致最终剂型即药品将满足其最初版本的规格和最终稳定性的要求。

化学纯度最低通常设定在98％，以保证药品的适当剂量，并且确保最小量的杂质。

物理参数应建立与制药过程和最终剂型的知识基础上。

其他属性通常包括固体形式的颜色和或溶液，熔点，比旋度（如果有光学活性），晶体形态，等等。

附录A提供了典型API的规范列表。

When setting API physical attribute specifications, the most important aspect to
consider is its use in the pharmaceutical process; namely, whether it will be wetted for granulation, dissolved for solution, dry blended, and so on, and the type of drug product to be made: tablets, capsules, solutions, sterile or non sterile, or other. It is also important to know how the drug product will be used by the patient; for example, if it will be used as a powder blended with other excipients, careful consideration should be given to rate of dissolution and the eventual color of solution (for aesthetic reasons) when dissolved by the patient (or healthcare giver) prior to use. For this reason, final API specifications are always defined with the cooperation of the pharmaceutical development area. The quality assurance function approves final API quality standards, taking into consideration all requirements: process related, governmental, and customer.
当建立API的物理属性时，要考虑的最重要的方面是其在制药过程中的使用;如被润湿造粒，溶解于溶液中，干燥混合等，且可以制成的药品类型有：片剂，胶囊剂，溶液剂，无菌或非无菌的，或其他。

同样重要的是要明白药品将用于患者;例如，赋形剂的粉末应考虑到由患者（或保健给予者）溶解的速率和溶液在使用前的最终的颜色（用于美观的原因）。

出于这个原因，最终的API规范始终说明需与药物开发领域的合作。

质量保证职能应在最终批准的API质量标准中同时考虑到所有要求：工艺相关的要求，政府和客户的要求。

B. Testing the API for Its Defined Attributes 原料药质量属性的测试
Each quality attribute required of the API must have a sound and proven test procedure. In regulatory compliance terms, this means the test must be validated; that is, to have documented proof that it performs reliably, is indicative of the attribute under question, and is not biased by interfering components. There are eight specific components of a validated test, and for an excellent treatise on this, the reader is referred to the current USP or the ICH guidance on analytical test validation. Most regulatory authorities require a test for all significant API quality attributes on each lot produced.
API的每个质量属性都必须有一个健全的和可靠的测试程序。

在合规性方面，这意味着必须在试验中验证；也就是说，已经证明程序的执行可靠，而不是由干扰组分造成。

一个验证过程包括8个特定的部分，读者可参考现行USP或ICH分析方法验证的指导。

大多数监管部门都要求每批进行API关键质量属性的测试。

In nearly all cases, the pharmaceutical manufacturer requires a certificate of analysis (C of A) documenting the results obtained on each lot, as well as a statement from the
quality office that the batch met its established quality criteria.
在几乎所有情况下，药品生产商需要COA（分析证书）来记录每批的结果，证明符合质量部分规定的质量标准。

C. Designing Quality into the Process 工艺中的质量设计
As described above, the pharmaceutical manufacturing process and end use of the drug product dosage form are the basis for establishing the limits of chemical purity and physical attributes. Having predefined these attributes, the synthetic chemist and chemical engineer have the task of designing quality into the process; thereby assuring every lot will meet its criteria. This is perhaps the most significant aspect of chemical process validation and a cornerstone of most regulatory requirements for quality assurance. After the chemical process is developed, a technical document, which explains how and why certain reagents, steps, controls, etc. were chosen in order to build quality into the product, should be prepared.
如上所述，药物的制造过程和最终用途的药品剂型受到化学纯度和物理属性的限制。

为达到预定义的属性，合成化学家和化学工程师有将质量设计于工艺的任务，从而确保每一批将符合其标准。

这也许是化学工艺验证最显著的方面和大多数法规要求的质量保证基石。

化学过程开发后，技术文件将解释试剂，步骤，控制等的方式为什么和怎样被选择的将质量设计于产品中。

When the manufacturing team takes on the commercial implementation of the process, and goes through the formal manufacturing validation process, they should rely heavily on this technical document to prove the quality of the final API. As stated in the introduction, quality is designed into the process not for regulatory purposes, but because it makes good manufacturing and business sense to do so. Manufacturers want a process that safely and reliably delivers high yield and quality for economic and environmental reasons.
当制造团队需要对工艺进行商业化生产，并进行正规的生产验证过程，在很大程度上依赖于该技术文件以证明最终API的质量。

正如在简介中说名，质量是设计于过程中，不是出于监管目的，而是因为有良好的生产和经营意识才这样做。

处于经济和环境的原因制造商希望有一个安全，可靠地工艺来达到产品的高产量和高质量。

One should begin the approach to designing quality into the API, with the concept of designing a perfect system. Keep in mind that all the safety, environmental, and economic reasons for developing a perfect chemical synthesis are precisely consistent
with the goal of designing quality into the process, and very well serve all regulatory process validation and control requirements. If one imagines a perfect process, there will be no toxic emissions about which to be concerned, no safety concerns or need for special safety controls, and the yield of each step will be 100% of the desired intermediate, stereo isomer, and end product. Such a process would be free of any impurities and would assay for 100% purity. The next challenge is to design the synthesis so that each step can be precisely controlled to always provide the same end result.
用API质量设计的方法来设计一个完美的系统。

为开发一个完美的化学合成过程，精确符合将质量设计于工艺的目标，需考虑所有的安全、环境和经济原因，还需符合工艺验证的法规和控制要求。

如果想象一个完美的工艺，没有有毒物排放，没有安全问题或需要特殊的安全控制，每一步获得的中间体，立体异构体和最终产品的收率都是100%。

这种工艺将是没有任何杂质，100%纯度，下一个挑战就是设计合成路线精确控制每一步以得到相同结果。

The design work requires a complete understanding of the chemical reactions in the synthetic process under development.
Then a clever design can be developed to eliminate any undesirable side reactions. In some instances, this can be achieved by sophisticated use of functional group protecting agents, and in other instances by changing the sequence of functional group introduction onto the end product building block and sometimes by simple careful control over reaction parameters. Once the process has been perfectly designed, developed, and controlled, the last concern is over the control of quality and reliability of the raw materials, proper functioning of equipment, and error-free operations by personnel. With the vision of a perfect system in mind, one can imagine how the API quality would be perfect and consistent.
设计工作需要对开发中的合成方法的化学反应有一个完整的理解。

然后，一个巧妙的设计可以开发用以消除任何不良副反应。

在一些情况下，这可以通过使用官能团的保护剂来实现，并且在通过改变官能团引入的顺序到最终产品来构建，有时需简单小心地控制反应参数。

一旦过程已经完全设计，开发和控制，最后值得关注的是在质量和原材料，设备的正常运作的可靠性，并通过人员无误差操作的控制。

随着设想的完善制度的实行，可以想见的API质量将是完美的，一贯的。

D. Validation of the Process 工艺验证
This aspect of the regulations is perfectly aligned with business interests. The regulations require that a chemical manufacturing process be validated, which the author personally defines as proof of knowledge of control.
法规这方面是与商业利益完全一致的。

法规要求化学品制造过程必须进行验证，作者个人定义为控制知识的证明。

While the term ‘‘validation’’ has various definitions in several different regulations (cGMPs), all essentially mean or imply ‘‘proof of knowledge of control.’’ In essence, the validation of the process is the description of the process after all development work is completed, with the elaboration of the proof of synthetic pathway, controls over process conditions, and finally, sound analytical proof of quality from samples obtained during actual manufacturing campaigns in the plant. Critical process parameters such as time, temperature, and mixing conditions should be defined, controlled, and monitored. The kinetics of the synthetic pathway is documented in a process manual. The establishment of a process manual for each API is the foundation of process validation. In this manual, one describes proof of the knowledge of the process and the controls necessary for consistent results. Hence, the scientific design process to build the perfect process requires full knowledge of the chemistry of the process. That knowledge is described in the chemical pathway from raw materials to the final API.
术语''验证''有几种不同的规定定义（cGMP），基本意味着或暗示'控制知识的证明''。

在本质上，该方法的验证是开发工作完成后的过程的证明，用拟定合成途径，在控制的工艺条件，实际生产出可获得的样品。

关键的工艺参数，如时间，温度，和混合条件应该被定义，控制和监测。

合成途径的动力学记录在一个工艺手册中。

对于每个API的工艺建立是工艺验证的基础。

在这个手册中，描述了工艺知识和一致的结果对照的证明。

因此，科学的工艺设计的完美过程需要充分了解化学知识。

该知识阐述了从原料到最终API的化学途径。

The scientific evidence, such as intermediate structure elucidation, spectrographic analysis (IR, Near IR, mass spec, UV, NMR, C13NMR, etc.), and the proposed chemical mechanism for each transformation, serves as the proof of that knowledge. Finally, during the course of the process development, full knowledge is gained concerning those parameters and conditions that affect the kinetics, yield, and purity of each step. Experiments to optimize each step for purity and yield lead the process engineer to describe the necessary controls and conditions. These controls are described in a process manual and are used in the scale-up work and ultimate
full-scale operation in the chemical plant.
科学证据，如中间结构解析，光谱分析（红外光谱，近红外光谱，质谱，紫外光谱，核磁共振，C 13 NMR，等等），以及所提出的每个转化的化学机理，都作
为这种知识的证明。

最后，工艺开发过程中应充分了解，获得关于那些影响动力学，产率和纯度的每个步骤的参数和条件的知识。

为优化每一步的纯度和收率所进行的实验，都作为工艺工程师用来描述必要的控制手段和反应条件。

这些控制在流程手册中有描述，并在化工厂进行规模化生产，并最终得到全面运转使用。

E. Reality实际
We realize that the perfect synthetic process will, in all likelihood, be too elusive. Eventually, we must make the decision to focus our resources on the best process available after thorough development work yields a sound and reliable process. Each synthetic challenge represents reality of the business of API manufacturing, and so at some point, the feasibility of further studies vs. commercializing what has been achieved to date must be evaluated on a risk (loosing precious time in the market) to reward (achieving a superior process) basis. It is sufficient to say here that to ensure quality of the final API, the development of the process provides the necessary information to design in-process controls needed to monitor the progress of each step. These controls are the chemical and physical monitors that inform the operator that
the synthesis is proceeding according to the original design. They are used also to inform the operator when the reaction is complete and when the next step may occur.
In many cases, especially when the process is well defined and designed, including
the quality of starting materials and reagents, a good control is simply the use of time, based on a knowledge of the kinetics of the reaction.
我们意识到在所有的可能性中完美的合成过程是很难的。

最后，我们必须集中资源提供最佳的工艺。

每次合成的挑战都代表原料药制造业的现实，因此在某些时候，进一步的研究与商业化风险必须进行评估其可行性（失去宝贵的时间在市场上）去获得（实现一个卓越的技术）。

它足以确保最终的API的质量，该方法的发展提供了必要的信息，设计过程中的控制，以监测每个步骤的进展是需要的。

这些控制是化学和物理监测，即告知操作者该合成是按照原设计跟进。

它们还用来告知操作时反应完全和可能发生的下一个步骤。

在许多情况下，特别是在工艺已被很好定义和设计时，基于化学反应的动力学知识，包括起始物料和试剂的质量，良好的控制能很大的节省时间。