Process Validation: General Principles and Practices" Industrial Guidelines

"Process Validation: General Principles and Practices" Industrial Guide - Philosophy of Quality System Based on Science and Risk

Xu Hefeng

       The FDA released its final version of the industrial guide entitled "Process Validation: General Principles and Practices" on January 24 (the draft version of this guide was issued at the FDA in November 2008 Released on the official website). As soon as this guide was released, there has been a strong reaction among the pharmaceutical industry and enterprises in the United States and many other countries. The pharmaceutical industry in the world is actively discussing the content of this guideline and preparing for the corresponding work. This newspaper has been the first time the industry experts on the outline of the translation and analysis, is now published here, with  readers.　　■ 　　■ 　　"Process Validation: General Principles and Practices" Industrial Guidelines ("Guidelines") In more than two years of solicitation, a number of international organizations, such as the ISPE, the American Association of Injectors (PDAs) And some large pharmaceutical companies, have all expressed their opinions on the draft Guide, which shows the world pharmaceutical industry's concern about this document. 　　On May 11, 1987, the FDA issued a circular announcing the advent of the 1987 Guide to the "General Principles of Process Validation." The recently released Guide, the first revision of the 1987 version, expresses the FDA's current thinking on validation of pharmaceutical processes and is consistent with the basic principles first introduced in the 1987 guide. 　　The Guide also provides advice on some of the goals of the 21st century pharmaceutical cGMP-risk-based approach that reflects the FDA initiative, in particular the recommendations on the use of advanced technologies in the manufacture of pharmaceuticals and the implementation of modern risk management and Quality management system tools and concepts. Throughout the Guide, it is clear that the concept is the internationally based science-based, risk-based quality system that has been internationally recommended. However, this document does not stipulate the number of verifications necessary for process validation in process validation. Therefore, other relevant documents should be consulted for specific operations. 　　Guide outline 

　　The body of the Guide contains seven chapters. In addition to the main body of the text there are "terms" and "reference documents" two chapters. Generally speaking, the Guide and the Guide to the draft version have little difference but are more rigorous in their basic concepts and basic elements.From the document, we can see that it integrates the basic concepts of ICH-Q8, Q9 and Q10. The author is now briefly described as follows: 

　　Chapter I: Introduction 

　　Introduction pointed out that process validation and product life cycle are linked. This view is one of the pillars of the Guide, which runs through the paper. This chapter sets forth the scope of application of the Guide, including: pharmaceuticals for humans, animals, biologics, pharmaceutical ingredients and drug substances in composite products (pharmaceuticals and medical devices).Excludes Type A dosing products and medicated feeds, medical devices, dietary supplements, and human tissue for transplantation under section 361 of the United States Public Health Services Act.The guidelines are not regulated for the validation of automated process control systems that are in widespread use today. 

　　In particular, it is important to note that "commercial manufacturing" in this chapter replaces "commercial production" in the draft guide. In our paper, however, there is no distinction between the notion of "manufacturing" and "production" (in fact, the two are different). 

　　Chapter 2: Background 

　　This chapter reviews the history of process validation guides. The process validation is based on the recommendations of some of the goals of the 21st century pharmaceutical cGMP-risk-based approach proposed by the FDA in 2002, with particular reference to the use of advanced technologies in the manufacture of pharmaceuticals and the implementation of modern risk management And quality management system tools and concepts. 

　　In this chapter is divided into two sections: process validation and drug quality; process validation methods. 

　　Process Validation and Quality of Pharmaceuticals section describes the significance of validating process validation and emphasizes the concept of quality from design (QbD), which states that quality can not be adequately assured simply by monitoring or testing the manufacturing process and finished product. At the same time pointed out the purpose of each step of the production process control.

　　Process Validation is defined in the subsection on Process Validation Methods: "This guide defines process validation as collecting and evaluating data from the process design stage up to commercial production, using the data to establish scientific evidence that the process is consistent Produce qualified products Process validation involves a series of activities that take place in the product life cycle and production. " 

　　In this section, process validation activities are described as three phases. Stage 1 - Process Design: During this stage, the commercial production process is determined based on knowledge gained from the development and magnification test activities. Stage 2 - Process Validation: At this stage, the process that has been designed is evaluated to determine if it is capable of repeated commercial 

　　production. The third phase - continuous process verification: the controlled status of the process in daily production has been continuously guaranteed. The three stages of process qualification are in full agreement with the ICH-Q10's product lifecycle philosophy. 

　　One of the highlights of this section is the emphasis on the four areas that companies need to be clear about process validation: understanding the source of variation, detecting the presence and extent of variation, understanding the effects of variation on processes and ultimately on product attributes, Process and product risk approach to control variation. 

　　This subsection adds a clause not found in the draft guide, which may be relevant to most pharmaceutical companies in our country. The article states, "For older products, companies can continually improve their processes by leveraging knowledge gained from original process development and validation efforts and manufacturing experience." It addresses the issue of not validating products and processes with modern methods in the past. 

　　Chapter 3: Legal and Regulatory Requirements for Process Validation 

　　This chapter mainly describes the legal and regulatory foundations of the Guide, which is based on the US Federal Regulations (CFR) and cGMP. 

　　Chapter 4: Recommendations 

　　This chapter is the center of the Guide, giving a detailed description of modern process validation.The chapter consists of four subsections: General Ideas for Process Validation, Phase I - Process Design, Phase II - Process Validation, Phase III - Continuous Process Validation, detailing the process at each stage The goal of process validation.

　　Chapter 5: Process Performance Confirmation Batch Synchronization Release Synchronization is 

　　only possible in rare cases where the entire process performance plan for the product has been completed before the product is released. Possible conditions include rare drugs (products in limited need) and radiopharmaceuticals. However, the Guide advises manufacturers to contact the FDA prior to the simultaneous release. The simultaneous release of products for sale on the market should be closely tracked so that immediate action can be taken in the event of a complaint (root cause). In addition, each batch of product manufactured under simultaneous release should be placed immediately into the stability program. 

　　Chapter 6: Document 

　　Files are very important for every stage of the validation life cycle. The Guide describes the documentation required to validate the life cycle. Since the cGMP required for verifying the degree and type of documentation during the lifecycle is different, the files required are different. 

　　Chapter VII: Analysis Methods 

　　This chapter points out that in the development stage, does not require validated analytical methods, but it must be scientific and reasonable. In clinical stages 2 and 3, the analytical method should meet the cGMP requirements. 


　　The far-reaching impact 

　　of the release of the Guide is not only about process validation but also having or will have a significant impact on work related to process validation. To sum up, there are three points: 

　　1. To strengthen the link between research and development and quality management The 

　　"Guide" made clear the concept that the traditional GMP does not include research and development, and research and development included in the quality system is now management system basic requirements.

　　In terms of process validation itself, when process validation begins, what parameters process validation needs to verify, and the tasks and goals at each stage are issues that must be addressed in process validation. The release of the Guide has fundamentally solved the problem. The purpose of the first phase of process validation in this guide has also been described. At the same time, the publication of the Guide will have a significant impact on drug research and development. After the release of ICH-Q8, the idea of ​​quality stemming from design came into the field of pharmaceuticals, however, except for the documents required by the new drug declaration, the quality involved in the site inspection and audits of GMP compliance did not come from the concept of design. In addition, since many developments, especially in the early stages of development, are not under the control of quality management, the links between research and development and quality management are not very close. The "Guide" for the development of new products after the project, enlarge, and commercialization of the manufacturing process at all stages of the task and purpose are standardized, which strengthened the relationship between research and development and quality management, thus regulating the research and development work. 

　　2. To become the basis for on-site inspection 

　　FDA released the revised draft process validation guide, many regulatory and auditors will use their ideas for on-site inspection or audit, but because the document is still in the draft stage, many terms have not yet fixed, In the field inspection or audit is only as an exploration. After the publication of the Guidelines, it has become the standard for modern process verification. It can be expected that in the near future, this standard will be used by both the FDA and other relevant international on-site inspections or audits. Our relevant on-site inspections, especially the approval It is also possible to use this concept before the inspection. 

　　3. Extensive Impact on Implementation Process Validation The impact of the 

　　Guide on process validation may be the most direct. It not only challenges today's process validation methods, but more importantly has a significant impact from the quality system level to the concrete implementation level. At the quality management system level, in addition to the scope of the quality system previously mentioned, we must make changes to the current general principles of verification, process development and general requirements for amplification in order to meet the requirements of the Guide. From the implementation level may be more extensive, for example, process validation program, process validation reports, and process validation approval. 

　　The challenge is coming

　　China is a big country producing bulk pharmaceuticals. The implementation of GMP is far behind that of Europe and the United States. There are also differences in the level of GMP implementation. In addition, the related process development in our country is still relatively backward in comparison with that in Europe and the United States, mainly in generic drugs, with independent intellectual property rights Sparse variety of drugs. Through the analysis of some audit data released after the draft guideline mentioned above, the author finds that there are major problems in the development of China's pharmaceutical industry, including the following aspects: 

　　First, the key parameters and scope of the process are not identified. R & D is not in full accordance with the requirements of the international GMP. In many cases, the process is only going through the process. There are still a lot of elements lacking in commercial manufacturing (especially the elements required in the Guide). Now some enterprises in order to make up for such a problem, had to carry out secondary development. 

　　Second, the transfer of technology in the process of transfer is only the process, but not in the corresponding development process to transfer all the knowledge, in many cases just transfer the final result of the development process. 

　　Another thing that needs our special attention is that our country's "knowledge management" has not yet been carried out, and some are just some simple rules within the enterprise. In ICH-Q8, Q9, Q10 requires the establishment of "knowledge management" system. Imperfections in "knowledge management" can have a significant impact on our process validation. 

　　To sum up, in the future, we should standardize the quality management system in accordance with the requirements of the internationally accepted quality system, incorporate research and development into the quality system, and integrate quality risk management into the quality system.In actual work, we should make full use of the two tools of quality risk management and knowledge management to form a quality manual, management standards and corresponding operating procedures in line with the above Guide as soon as possible. 

　　(Department of International Trade, Tohoku Pharmaceutical Co., Ltd., Senior Document Manager)