《仪器与方法验证专著》（英文版） Analytical Method Validation and Instrument Performance veriticatig

INTRODUCTION undergo extensive testing to obtain initial safety and efficacy data in animal models Upon completion of successful animal safety and efficacy evaluation, submission appropriate regulatory bodies is made to gain approval to administer the first human dose in the clinical phase I trial 1.1.3 Clinical Phases The clinical phase I trial is used to assess the safety and, occasionally, the efficacy f a compound in a few healthy human volunteers. These studies are designed determine the metabolism and pharmacological action of the drug in humans, the side effects associated with increasing doses, and if possible, to gain very early information on the drugs effectiveness. Safety data from these trials will help determine the dosage required for the next phase of drug development. The total number of subjects in phase I studies is generally in the range 20 to 80 Clinical phase Il trials are conducted to evaluate the effectiveness of a drug for particular indication or indications in patients with the targeted disease. These studies also help to determine the common short-term side effects and risks associated with the drug. Phase II studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually no more than several hundred Active Pharmaceutical Ingredient (APl). In this early stage of drug devel opment, only a small quantity of drug substance is needed. As development progresses into later stages, greater quantities of drug substance are needed and will trigger efforts to optimize the synthetic route Formulation Development. The formulation of the new drug product will be designed in conjunction with medical and marketing input. Excipients to be used will be tested for chemical and physical compatibility with the drug substance The preliminary formulation design will be optimized at this stage Analytical Development of API and Drug Products. Early methods to sup- port synthetic and formulation developments are often developed in the form of potency assay, impurities/related substance assay, dissolution, Karl Fischer, iden tity, chiral method, and content uniformity. These analytical methods are devel oped and validated in a fast and timely manner to support all phase Il studies Common Studies Performed on the API and Drug Product. At this stage of the levelopment, it is important to gain preliminary information of the stability of the API and drug product. Therefore, open dish (i.e, nonprotected) stability studies are carried out to understand the chemical and physical stability of both the API and the drug product. Preliminary packaging stability studies are conducted to obtain a preliminary assessment of packaging materials that can be used, nd photostability and thermal studies are conducted to determine the light and thermal stability of the API and drug product

INTRODUCTION 3 undergo extensive testing to obtain initial safety and efficacy data in animal models. Upon completion of successful animal safety and efficacy evaluation, submission to appropriate regulatory bodies is made to gain approval to administer the first human dose in the clinical phase I trial. 1.1.3 Clinical Phases The clinical phase I trial is used to assess the safety and, occasionally, the efficacy of a compound in a few healthy human volunteers. These studies are designed to determine the metabolism and pharmacological action of the drug in humans, the side effects associated with increasing doses, and if possible, to gain very early information on the drug’s effectiveness. Safety data from these trials will help determine the dosage required for the next phase of drug development. The total number of subjects in phase I studies is generally in the range 20 to 80. Clinical phase II trials are conducted to evaluate the effectiveness of a drug for a particular indication or indications in patients with the targeted disease. These studies also help to determine the common short-term side effects and risks associated with the drug. Phase II studies are typically well controlled, closely monitored, and conducted in a relatively small number of patients, usually no more than several hundred. Active Pharmaceutical Ingredient (API). In this early stage of drug devel￾opment, only a small quantity of drug substance is needed. As development progresses into later stages, greater quantities of drug substance are needed and will trigger efforts to optimize the synthetic route. Formulation Development. The formulation of the new drug product will be designed in conjunction with medical and marketing input. Excipients to be used will be tested for chemical and physical compatibility with the drug substance. The preliminary formulation design will be optimized at this stage. Analytical Development of API and Drug Products. Early methods to sup￾port synthetic and formulation developments are often developed in the form of potency assay, impurities/related substance assay, dissolution, Karl Fischer, iden￾tity, chiral method, and content uniformity. These analytical methods are devel￾oped and validated in a fast and timely manner to support all phase II studies. Common Studies Performed on the API and Drug Product. At this stage of the development, it is important to gain preliminary information of the stability of the API and drug product. Therefore, open dish (i.e., nonprotected) stability studies are carried out to understand the chemical and physical stability of both the API and the drug product. Preliminary packaging stability studies are conducted to obtain a preliminary assessment of packaging materials that can be used, and photostability and thermal studies are conducted to determine the light and thermal stability of the API and drug product

PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM Successful efficacy and safety data will guide the decision to proceed to clinical phase Ill in product development. In this stage, the new drug is administered to a larger population of patients using blinded clinical studies. These studies may demonstrate the potential advantages of the new compound compared with similar ompounds already marketed. The data collected from this stage are intended evaluate the overall benefit-risk relationship of the drug and to provide an adequate basis for labeling. Phase Ill studies usually include from several hundred to several thousand subjects and often include single- or double-blind studies designed to eliminate possible bias on the part of both physicians and patients Positive data from this stage will trigger implementation of a global registration and commercialization of the drug product Impurities Level in New Drug Product. As the new drug product formulation progresses to this late stage of development, impurity profiles may differ from those of earlier formulations. The rationale for reporting and control of impurities in the new drug product is often decided at this stage as are recommended storage L. Degradation products and the fro interaction and/or container closure systems will be isolated and identified. The impurity profile of the representative commercial process will be compared with he drug product used in development, and an investigation will be triggered if any difference is observed. Identification of degradation products is required for those that are unusually potent and produce toxic effects at low levels Primary and developmental stability studies help development scientists under- tand the degradation pathways. These studies are developed to get information on the stability of the drug product, expected expiry date, and recommended storage conditions. All specified degradation products, unspecified degradation products, and total degradation products are monitored in these studies Impurities in API. Treatment of the impurities in the API is similar to that for the new drug product. Impurities in the API include organic impurities(process and drug related), inorganic impurities, and residual solvents. Quality control analytical procedures are developed and validated to ensure appropriate detection and quantitation of the impurities. Specification limits for impurities are set based on data from stability studies and chemical development studies. A rationale for he inclusion or exclusion of impurities is set at this stage. The limits set should not be above the safety level or below the limit of the manufacturing proces API Development. The synthetic route will be finalized and a formal primary stability study will be undertaken to assess the stability of the API Formulation Development. The formulation is finalized based on the experience gained in the manufacture of clinical phase I and II trial materials. Scale-up of the nanufacturing process will be completed to qualify the manufacturing capability of the facility. The primary stability study is initiated to assess the stability of the drug product

4 PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM Successful efficacy and safety data will guide the decision to proceed to clinical phase III in product development. In this stage, the new drug is administered to a larger population of patients using blinded clinical studies. These studies may demonstrate the potential advantages of the new compound compared with similar compounds already marketed. The data collected from this stage are intended to evaluate the overall benefit– risk relationship of the drug and to provide an adequate basis for labeling. Phase III studies usually include from several hundred to several thousand subjects and often include single- or double-blind studies designed to eliminate possible bias on the part of both physicians and patients. Positive data from this stage will trigger implementation of a global registration and commercialization of the drug product. Impurities Level in New Drug Product. As the new drug product formulation progresses to this late stage of development, impurity profiles may differ from those of earlier formulations. The rationale for reporting and control of impurities in the new drug product is often decided at this stage as are recommended storage conditions for the product. Degradation products and those arising from excipient interaction and/or container closure systems will be isolated and identified. The impurity profile of the representative commercial process will be compared with the drug product used in development, and an investigation will be triggered if any difference is observed. Identification of degradation products is required for those that are unusually potent and produce toxic effects at low levels. Primary and developmental stability studies help development scientists under￾stand the degradation pathways. These studies are developed to get information on the stability of the drug product, expected expiry date, and recommended storage conditions. All specified degradation products, unspecified degradation products, and total degradation products are monitored in these studies. Impurities in API. Treatment of the impurities in the API is similar to that for the new drug product. Impurities in the API include organic impurities (process and drug related), inorganic impurities, and residual solvents. Quality control analytical procedures are developed and validated to ensure appropriate detection and quantitation of the impurities. Specification limits for impurities are set based on data from stability studies and chemical development studies. A rationale for the inclusion or exclusion of impurities is set at this stage. The limits set should not be above the safety level or below the limit of the manufacturing process and analytical capability. API Development. The synthetic route will be finalized and a formal primary stability study will be undertaken to assess the stability of the API. Formulation Development. The formulation is finalized based on the experience gained in the manufacture of clinical phase I and II trial materials. Scale-up of the manufacturing process will be completed to qualify the manufacturing capability of the facility. The primary stability study is initiated to assess the stability of the drug product

QUALITY SYSTEM FOR THE ANALYTICAL DEVELOPMENT LABORATORY Successful completion of clinical phase I trial is a prerequisite for the final phase of drug development. The complete set of clinical, chemical, and analytical data is documented and submitted for approval by regulatory agencies worldwide Simultaneous activities are initiated to prepare to market the product once reg- ulatory approval is received. As clinical phase Ill is still being conducted on a limited number of patients, postmarketing studies (phase Iv) are often required by regulatory agencies to ensure that clinical data will still be valid. At this point, the company will initiate information and education programs for physi cians, specialists, other health care providers, and patients as to the indications of the new drug 1.2 QUALITY SYSTEM FOR THE ANALYTICAL DEVELOPMENT LABORATORY As global regulatory requirements have become more similar as the result of deliberate harmonization, analytical methods for global products must be able to meet global regulatory requirements. Ideally, a method developed and vali dated in the United States should not need to be revalidated or require patchwork alidation for use in Japan or Europe. The achievement of this objective is the responsibility of senior management and requires participation and commitment by personnel in many different functions at all levels within the establishment and by its suppliers. To achieve this objective reliably, there must be a com- prehensively designed and correctly implemented system of quality standards Icorporating GMPs. It should be fully documented and effectively monitored All parts of the quality systems should be adequately resourced with qualified personnel and suitable premises, equipment, and facilities. It is our intent in the econd part of this chapter to give an overview of the extent and application of analytical quality systems to different stages of the drug development process 1. 2.1 Consideration for Quality Systems in Development An important consideration in the development of quality systems in development is to ask the question: What business does development support? Develop ment does not mean exclusively working to develop formulation or analytical methods; many activities are directly involved in support of clinical material production. Laboratory leadership has the responsibility to consider carefully the customers and functions of an analytical development department. As part of this consideration, several key questions are useful in defining the business and How does the larger organization view development? How close to manufacturing is development?

QUALITY SYSTEM FOR THE ANALYTICAL DEVELOPMENT LABORATORY 5 1.1.4 Regulatory Submission Successful completion of clinical phase III trial is a prerequisite for the final phase of drug development. The complete set of clinical, chemical, and analytical data is documented and submitted for approval by regulatory agencies worldwide. Simultaneous activities are initiated to prepare to market the product once reg￾ulatory approval is received. As clinical phase III is still being conducted on a limited number of patients, postmarketing studies (phase IV) are often required by regulatory agencies to ensure that clinical data will still be valid. At this point, the company will initiate information and education programs for physi￾cians, specialists, other health care providers, and patients as to the indications of the new drug. 1.2 QUALITY SYSTEM FOR THE ANALYTICAL DEVELOPMENT LABORATORY As global regulatory requirements have become more similar as the result of deliberate harmonization, analytical methods for global products must be able to meet global regulatory requirements. Ideally, a method developed and vali￾dated in the United States should not need to be revalidated or require patchwork validation for use in Japan or Europe. The achievement of this objective is the responsibility of senior management and requires participation and commitment by personnel in many different functions at all levels within the establishment and by its suppliers. To achieve this objective reliably, there must be a com￾prehensively designed and correctly implemented system of quality standards incorporating GMPs. It should be fully documented and effectively monitored. All parts of the quality systems should be adequately resourced with qualified personnel and suitable premises, equipment, and facilities. It is our intent in the second part of this chapter to give an overview of the extent and application of analytical quality systems to different stages of the drug development process. 1.2.1 Consideration for Quality Systems in Development An important consideration in the development of quality systems in development is to ask the question: What business does development support? Develop￾ment does not mean exclusively working to develop formulation or analytical methods; many activities are directly involved in support of clinical material production. Laboratory leadership has the responsibility to consider carefully the customers and functions of an analytical development department. As part of this consideration, several key questions are useful in defining the business and quality standards: ž How does the larger organization view development? ž How close to discovery is development? ž How close to manufacturing is development?

PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM Where are there major overlaps in activities and support? What is the desirable quality culture for this organization? Who are the primary customers of development's outputs? When a new molecule enters the development phase, in most cases only the basic information of the new chemical entity is known(e.g, molecular structure and polymorphic and salt forms). However, we do not know what will happen when it is formulated and stored at ordinary environmental conditions. In other words, there is a high degree of variability around what is"about the molecule and its behavior in a variety of systems. The basic task for development is to reduce this high variability by conducting a series of controlled experiments make this information known and thus predictable. In fact, by the time a molecule reaches the significant milestone of launch into commercial activities, most of the behavior and characteristics of the molecule need to be known predictable, and in control There are multiple paths to achieving the state when a product and a pro- cess are"in control. " A pictorial representation of this concept is shown in Figure 1. 2. Simpler molecules may achieve a state of control (predictable state) early in the development process, while more complex molecules may retain a high state of" variability"until late in the process. The goal for development must be a development path that is documented and performed by qualified scientists, equipment, facilities, instruments, etc. Development paths that can be followed are varied, but the final outcome, when a project is transferred to manufacturing, is a product and a process that are in a well-characterized state of control 1.2.2 GMPs Applied to Development The original intent of the Good Manufacturing Practices(GMPs)was to describe standards and activities designed to ensure the strength, identity, safety, purity and quality of pharmaceutical products introduced into commerce. Application of GMPs to development activities has evolved to the state where application of Development 4- Manufacturing sy Launch Figure 1. 2. Variability during the development process

6 PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM ž Where are there major overlaps in activities and support? ž What is the desirable quality culture for this organization? ž Who are the primary customers of development’s outputs? When a new molecule enters the development phase, in most cases only the basic information of the new chemical entity is known (e.g., molecular structure and polymorphic and salt forms). However, we do not know what will happen when it is formulated and stored at ordinary environmental conditions. In other words, there is a high degree of variability around what is “known” about the molecule and its behavior in a variety of systems. The basic task for development is to reduce this high variability by conducting a series of controlled experiments to make this information known and thus predictable. In fact, by the time a molecule reaches the significant milestone of launch into commercial activities, most of the behavior and characteristics of the molecule need to be known, predictable, and in control. There are multiple paths to achieving the state when a product and a pro￾cess are “in control.” A pictorial representation of this concept is shown in Figure 1.2. Simpler molecules may achieve a state of control (predictable state) early in the development process, while more complex molecules may retain a high state of “variability” until late in the process. The goal for development must be a development path that is documented and performed by qualified scientists, equipment, facilities, instruments, etc. Development paths that can be followed are varied, but the final outcome, when a project is transferred to manufacturing, is a product and a process that are in a well-characterized state of control. 1.2.2 GMPs Applied to Development The original intent of the Good Manufacturing Practices (GMPs) was to describe standards and activities designed to ensure the strength, identity, safety, purity, and quality of pharmaceutical products introduced into commerce. Application of GMPs to development activities has evolved to the state where application of Launch Development systems Variability Manufacturing systems Figure 1.2. Variability during the development process

QUALITY SYSTEM FOR THE ANALYTICAL DEVELOPMENT LABORATORY ne basic GMP principles is a common part of business practice for an increasing number of companies. However, the GMPs are silent on explicit guidance for e development phase in several areas. Thus, companies have been left to make their own determinations as to how to apply gMPs prior to commercial introduc- tion of products. More recently, the European Union(EU) and the International Conference on Harmonization(ICh) have offered a variety of guidances in the development of APl. The ICH Q7A GMP Guidance for APIs includes guidance or APls for use in clinical trials. The EU Guideline Annex 13 provides much more specific guidance to the application of GMPs to investigational medicinal products. By extension, one can gain perspective on application of GMPs to the chemistry, manufacturing, and control(CM&c) developmen ely tied to the development, manufacture, and use of investigational medicinal products. Regulatory bodies recognize that knowledge of the drug product and its ana al methods will evolve through the course of development. This is stated explicitly in ICH Q7A: Changes are expected during development, and every change in production, specifications, or test procedures should be recorded ade- quately. The fundamental nature of the development process is one of discovery and making predictable the characteristics of the API or product. It is there fore reasonable to expect that changes in testing, processing, packaging, and so on will occur as more is learned about the molecule. A high-quality sys- tem that supports development must be designed and implemented in a way that does not impede the natural order of development. It must also ensure that the safety of subjects in clinical testing is not compromised. The penultimate anufacturing processes must be supported with sufficient data and results from the development process so that the final processes will be supported in a state of control Processes that are created during development cannot achieve a full state of validation because the processes have not been finalized. Variation is an inheren part of this process, and it allows the development scientists to reach conclusions concerning testing and manufacturing after having examined these processes with rigorous scientific experiments and judgments. The goal for development is to arrive at a state of validation entering manufacturing If one looks at the various clinical stages of development, there is a ques- tion as to what practices should be in place to support phase I, Il, or late hase Ill studies. An all-or-nothing approach to GMPs is not appropriate. There are certain fundamental concepts that must be applied regardless of the clinical hase of development. Examples of these include: (1) documentation, (2)change, ()deviations, (4)equipment and utilities, and (5), training Any high-quality system must be built with an eye to the regulations and expectations of the regulatory agencies that enforce the system. The U.s. Food and Drug Administration(FDA) has recently implemented a systems approach of inspection for ensuring that current GMPs(cGMPs)are followed in the man- ufacturing environment. The FDA will now inspect by systems rather than by

QUALITY SYSTEM FOR THE ANALYTICAL DEVELOPMENT LABORATORY 7 the basic GMP principles is a common part of business practice for an increasing number of companies. However, the GMPs are silent on explicit guidance for the development phase in several areas. Thus, companies have been left to make their own determinations as to how to apply GMPs prior to commercial introduc￾tion of products. More recently, the European Union (EU) and the International Conference on Harmonization (ICH) have offered a variety of guidances in the development of API. The ICH Q7A GMP Guidance for APIs includes guidance for APIs for use in clinical trials. The EU Guideline Annex 13 provides much more specific guidance to the application of GMPs to investigational medicinal products. By extension, one can gain perspective on application of GMPs to the chemistry, manufacturing, and control (CM&C) development process since it is closely tied to the development, manufacture, and use of investigational medicinal products. Regulatory bodies recognize that knowledge of the drug product and its ana￾lytical methods will evolve through the course of development. This is stated explicitly in ICH Q7A: Changes are expected during development, and every change in production, specifications, or test procedures should be recorded ade￾quately. The fundamental nature of the development process is one of discovery and making predictable the characteristics of the API or product. It is there￾fore reasonable to expect that changes in testing, processing, packaging, and so on will occur as more is learned about the molecule. A high-quality sys￾tem that supports development must be designed and implemented in a way that does not impede the natural order of development. It must also ensure that the safety of subjects in clinical testing is not compromised. The penultimate manufacturing processes must be supported with sufficient data and results from the development process so that the final processes will be supported in a state of control. Processes that are created during development cannot achieve a full state of validation because the processes have not been finalized. Variation is an inherent part of this process, and it allows the development scientists to reach conclusions concerning testing and manufacturing after having examined these processes with rigorous scientific experiments and judgments. The goal for development is to arrive at a state of validation entering manufacturing. If one looks at the various clinical stages of development, there is a ques￾tion as to what practices should be in place to support phase I, II, or late phase III studies. An all-or-nothing approach to GMPs is not appropriate. There are certain fundamental concepts that must be applied regardless of the clinical phase of development. Examples of these include: (1) documentation, (2) change, (3) deviations, (4) equipment and utilities, and (5), training. Any high-quality system must be built with an eye to the regulations and expectations of the regulatory agencies that enforce the system. The U.S. Food and Drug Administration (FDA) has recently implemented a systems approach of inspection for ensuring that current GMPs (cGMPs) are followed in the man￾ufacturing environment. The FDA will now inspect by systems rather than by