PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM specific facility or product. The premise in this system is that activities in a phar- maceutical company can be organized into systems that are sets of operations and related activities. Control of all systems helps to ensure that the firm will produce drugs that are safe and that have the identity and strength and meet the quality and purity characteristics that are intended. The goal of this programs activities is to minimize consumers exposure to adulterated drug products. A company is out of control if any of its systems is out of control The following six systems are identified to be audited in the FDA systems (GMP subparts are shown in parentheses): Quality system(B, E, F, G,I,J, K) Facilities and equipment systems(B, C, D, Materials system(B, E,H,) Packaging and labeling systems(B, G, J) Production system(B, F,J) Laboratory and control systems(B, I,J,K) An analysis of the citations of each cGMP system reveals that two subparts are included in all the citations: Organization and Personnel(subpart B)and Records and Reports(subpart J). This analysis points to a fundamental precept in the systems guidance. Having the right number of appropriately qualified personnel in place along with a strong documentation, records, and reports system are the foundation of success in implementation of cGMPs in a manufacturing operation It therefore follows that the same principles apply to the development processes that lead to the successful implementation of manufacturing operations During the development process, it is important to control variables that affect he quality of the data that are generated and the ability to recreate the work. It is important to recognize that by its nature, the development process does not achieve a complete success rate. That is, many more molecules enter drug development than transit successfully to the market. Thus, it is reasonable to evelop guidance and practices as to how much control and effort are put into key activities depending on the phase of development. For example, analytical methods used to determine purity and potency of an experimental API that is very early in development will need a less rigorous method validation exercise than would be required for a quality control laboratory method used in manufacturing n early phase project may have only a limited number of lots to be tested; the testing may be performed in only one laboratory by a limited number of analysts. The ability of the laboratory to"control"the method and its use is relatively high, particularly if laboratory leadership is clear in its expectations for the performance of the work e environment in which this method is used changes significantly wher the method is transferred to a quality control laboratory. The method may be replicated in several laboratories, multiple analysts may use it, the method may be one of many methods used in the laboratory, and the technical depth of the analysts may be less deep than those in the development laboratory. Thus, it is incumbent on the development laboratory to recognize when projects move to later phases of development. The developing laboratory must be aware of the needs of the receiving laboratories as well as regulatory expectations for
8 PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM specific facility or product. The premise in this system is that activities in a pharmaceutical company can be organized into systems that are sets of operations and related activities. Control of all systems helps to ensure that the firm will produce drugs that are safe and that have the identity and strength and meet the quality and purity characteristics that are intended. The goal of this program’s activities is to minimize consumers exposure to adulterated drug products. A company is out of control if any of its systems is out of control. The following six systems are identified to be audited in the FDA systems (GMP subparts are shown in parentheses): Quality system (B, E, F, G, I, J, K) Facilities and equipment systems (B, C, D, J) Materials system (B, E, H, J) Packaging and labeling systems (B, G, J) Production system (B, F, J) Laboratory and control systems (B, I, J, K) An analysis of the citations of each cGMP system reveals that two subparts are included in all the citations: Organization and Personnel (subpart B) and Records and Reports (subpart J). This analysis points to a fundamental precept in the systems guidance. Having the right number of appropriately qualified personnel in place along with a strong documentation, records, and reports system are the foundation of success in implementation of cGMPs in a manufacturing operation. It therefore follows that the same principles apply to the development processes that lead to the successful implementation of manufacturing operations. During the development process, it is important to control variables that affect the quality of the data that are generated and the ability to recreate the work. It is important to recognize that by its nature, the development process does not achieve a complete success rate. That is, many more molecules enter drug development than transit successfully to the market. Thus, it is reasonable to develop guidance and practices as to how much control and effort are put into key activities depending on the phase of development. For example, analytical methods used to determine purity and potency of an experimental API that is very early in development will need a less rigorous method validation exercise than would be required for a quality control laboratory method used in manufacturing. An early phase project may have only a limited number of lots to be tested; the testing may be performed in only one laboratory by a limited number of analysts. The ability of the laboratory to “control” the method and its use is relatively high, particularly if laboratory leadership is clear in its expectations for the performance of the work. The environment in which this method is used changes significantly when the method is transferred to a quality control laboratory. The method may be replicated in several laboratories, multiple analysts may use it, the method may be one of many methods used in the laboratory, and the technical depth of the analysts may be less deep than those in the development laboratory. Thus, it is incumbent on the development laboratory to recognize when projects move to later phases of development. The developing laboratory must be aware of the needs of the receiving laboratories as well as regulatory expectations for
CONCLUSIONS successful validation of a method to be used in support of a commercial product The validation exercise becomes larger; more detailed, and collects a larger bod of data to ensure that the method is robust and appropriate for use Similar examples apply to the development of synthetic and biochemical pro- cess for generation of API as well as experimental pharmaceutical products These examples are familiar to scientists who work in the drug development business. Unexpected findings are often part of the development process. A suc cessful quality system that supports this work will aid in the creation of an environment that ensures that this work is performed in an environment where the quality of the data and results are well controlled. Thus, one would expect strong emphasis on documentation systems and standards, employee training and qualification, equipment and instrument qualification, and utilities qualification Controlling these variables provides a higher degree of assurance in the results and interpretation of results of me development business will make or break ality within the success of the quality system of the business. It is important that the opment process be described and mapped. The process should be docum and the process understood. The path that the development area will be taking begins with the decision to develop the molecule. Actions are needed to ensure that an appropriate quality system will be implemented and maintained. Financ ing for the quality system should be given appropriate financial backup to ensure functional system and not a minimal budget. The culture of the development area in the company should understand the full value of quality. It is wrong to focus solely on speed of development and work with the attitude of fixing quality as the process is developed while hoping that any problems that occur will never be found. Quality must include the willingness of development leadership to invest in systems and processes so that development can go rapidly. It is important to recognize signs in the development laboratory which indicate that the quality system has been implemented successfully. The following list includes some of the observations that can be made easily if the quality system is functioning as intended 1. Expectations are high for documentation and reports. This observation demonstrates the maturity of the scientists in the laboratory to think and practice good quality principles 2. Processes for planning and conducting work are robust 3. Project planning includes quality objectives 4. The system is able to accommodate all types of molecules 5. The development process is mapped and followed. 6. Leadership is actively involved 1.3 CONCLUSIONS This introductory chapter gave a quick overview of the drug discovery process Normal activities required from molecule discovery to launch of the product are
CONCLUSIONS 9 successful validation of a method to be used in support of a commercial product. The validation exercise becomes larger; more detailed, and collects a larger body of data to ensure that the method is robust and appropriate for use. Similar examples apply to the development of synthetic and biochemical process for generation of API as well as experimental pharmaceutical products. These examples are familiar to scientists who work in the drug development business. Unexpected findings are often part of the development process. A successful quality system that supports this work will aid in the creation of an environment that ensures that this work is performed in an environment where the quality of the data and results are well controlled. Thus, one would expect strong emphasis on documentation systems and standards, employee training and qualification, equipment and instrument qualification, and utilities qualification. Controlling these variables provides a higher degree of assurance in the results and interpretation of results. The culture around quality within the development business will make or break the success of the quality system of the business. It is important that the development process be described and mapped. The process should be documented and the process understood. The path that the development area will be taking begins with the decision to develop the molecule. Actions are needed to ensure that an appropriate quality system will be implemented and maintained. Financing for the quality system should be given appropriate financial backup to ensure a functional system and not a minimal budget. The culture of the development area in the company should understand the full value of quality. It is wrong to focus solely on speed of development and work with the attitude of fixing quality issues as the process is developed while hoping that any problems that occur will never be found. Quality must include the willingness of development leadership to invest in systems and processes so that development can go rapidly. It is important to recognize signs in the development laboratory which indicate that the quality system has been implemented successfully. The following list includes some of the observations that can be made easily if the quality system is functioning as intended. 1. Expectations are high for documentation and reports. This observation demonstrates the maturity of the scientists in the laboratory to think and practice good quality principles. 2. Processes for planning and conducting work are robust. 3. Project planning includes quality objectives. 4. The system is able to accommodate all types of molecules. 5. The development process is mapped and followed. 6. Leadership is actively involved. 1.3 CONCLUSIONS This introductory chapter gave a quick overview of the drug discovery process. Normal activities required from molecule discovery to launch of the product are
10 PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM described Quality systems for drug development must be built with an eye to the fundamental aspects of the discovery and development processes. There must be recognition that there is evolution on some standards during development. The business must have clarity about its purpose and the processes used to run the business. Quality expectations must be part of the development culture to ensure compliance with cGMP requirements. Quality and business leadership must provide a capable environment in which discovery and development occur
10 PHARMACEUTICAL PRODUCT DEVELOPMENT AND QUALITY SYSTEM described. Quality systems for drug development must be built with an eye to the fundamental aspects of the discovery and development processes. There must be recognition that there is evolution on some standards during development. The business must have clarity about its purpose and the processes used to run the business. Quality expectations must be part of the development culture to ensure compliance with cGMP requirements. Quality and business leadership must provide a capable environment in which discovery and development occur
POTENCY METHOD VALIDATION CHUNG CHOW CHAN PH.D Eli Lilly Canada. In 2.1 INTRODUCTION Assay as defined by the Japanese Pharmacopoeia is a test to determine the omposition, the content of the ingredients, and the potency unit of medicine by physical, chemical, or biological procedures. This chapter focuses on validation of the potency assay by high-performance liquid chromatography(HPLC). Ana- lytical method development and validation involve a series of activities that are ongoing during the life cycle of a drug product and drug substance. Figure 2.1 summarizes the life cycle of an analytical method Analytical potency method development should be performed to the extent that it is sufficient for its intended purpose. It is important to understand and know the molecular structure of the analyte during the method development process, as this will facilitate the identification of potential degradation impurities. For example, an impurity of M+ 16 in the mass spectrum of a sample may indicate the probability of a nitrogen oxide formation. Upon successful completion of method development, the potency method will then be validated to show proof that it is suitable for its intended purpose. Finally, the method validated will be transferred to the quality control laboratory in preparation for the launch of the drug substance or drug product The method will be used in the manufacturing facility for the release of both drug substance and drug product. However, if there are any changes in the manufacturing process that have the potential to change the degradation pattern Analytical Method Validation and Instrument Performance Verification, Edited by Chung Chow IsBN 0-471-25953.5 Copyright o 2004 John Wiley Sons, Inc
2 POTENCY METHOD VALIDATION CHUNG CHOW CHAN, PH.D. Eli Lilly Canada, Inc. 2.1 INTRODUCTION Assay as defined by the Japanese Pharmacopoeia is a test to determine the composition, the content of the ingredients, and the potency unit of medicine by physical, chemical, or biological procedures. This chapter focuses on validation of the potency assay by high-performance liquid chromatography (HPLC). Analytical method development and validation involve a series of activities that are ongoing during the life cycle of a drug product and drug substance. Figure 2.1 summarizes the life cycle of an analytical method. Analytical potency method development should be performed to the extent that it is sufficient for its intended purpose. It is important to understand and know the molecular structure of the analyte during the method development process, as this will facilitate the identification of potential degradation impurities. For example, an impurity of M + 16 in the mass spectrum of a sample may indicate the probability of a nitrogen oxide formation. Upon successful completion of method development, the potency method will then be validated to show proof that it is suitable for its intended purpose. Finally, the method validated will be transferred to the quality control laboratory in preparation for the launch of the drug substance or drug product. The method will be used in the manufacturing facility for the release of both drug substance and drug product. However, if there are any changes in the manufacturing process that have the potential to change the degradation pattern Analytical Method Validation and Instrument Performance Verification, Edited by Chung Chow Chan, Herman Lam, Y. C. Lee, and Xue-Ming Zhang ISBN 0-471-25953-5 Copyright 2004 John Wiley & Sons, Inc. 11
POTENCY METHOD VALIDATION Method development Method validation/revalidation QC laboratory Figure 2.1. Life cycle of an analytical method f the drug substance and drug product, this validated method may need to be revalidated. This process of revalidation is described in more detail later in the chapter. Whether it is a drug substance or a drug product, the final product will need to be analyzed to assess its potency or strength. The potency of a drug substance is typically reported as a percentage value(e. g,98.0%), whereas a drug product is reported in terms of its intended concentration or label claim 2.2 SCOPE OF CHAPTER In this chapter we outline the general requirements for the hPlC potency method validation in pharmaceutical products. The discussion is based on method valida- tion for small-molecule pharmaceutical products of synthetic origin. Even though most of quirements are similar for a drug substance, method validation for a drug substance is not discussed in detail in this chapter. The discussion focuses on current regulatory requirements in the pharmaceutical industry. Since the expectations for method validation are different at different stages of the product development process, the information given in this chapter is most suit able for the final method validation according to International Conference on Harmonization (ICH) requirements to prepare for regulatory submissions [e.g New Drug Application(NDA)]. Even though the method validation is related to HPLC analysis, most of the principles are also applicable to other analytical techniques [e.g, thin-layer chromatography (TLC), ultraviolet analysis (UV) ICH Q2A [1] proposed the guidelines shown in Table 2. 1 for the validation of a potency assay for a drug substance or drug product In this chapter we discuss the following topics regarding validation practices 1. Types of quantitation technique 2. System suitability requirements ability indicating potency assay 4. Strategies and validation characteristics 5. Revalidation
12 POTENCY METHOD VALIDATION Method development Method validation/revalidation QC laboratory Figure 2.1. Life cycle of an analytical method. of the drug substance and drug product, this validated method may need to be revalidated. This process of revalidation is described in more detail later in the chapter. Whether it is a drug substance or a drug product, the final product will need to be analyzed to assess its potency or strength. The potency of a drug substance is typically reported as a percentage value (e.g., 98.0%), whereas a drug product is reported in terms of its intended concentration or label claim. 2.2 SCOPE OF CHAPTER In this chapter we outline the general requirements for the HPLC potency method validation in pharmaceutical products. The discussion is based on method validation for small-molecule pharmaceutical products of synthetic origin. Even though most of the requirements are similar for a drug substance, method validation for a drug substance is not discussed in detail in this chapter. The discussion focuses on current regulatory requirements in the pharmaceutical industry. Since the expectations for method validation are different at different stages of the product development process, the information given in this chapter is most suitable for the final method validation according to International Conference on Harmonization (ICH) requirements to prepare for regulatory submissions [e.g., New Drug Application (NDA)]. Even though the method validation is related to HPLC analysis, most of the principles are also applicable to other analytical techniques [e.g., thin-layer chromatography (TLC), ultraviolet analysis (UV)]. ICH Q2A [1] proposed the guidelines shown in Table 2.1 for the validation of a potency assay for a drug substance or drug product. In this chapter we discuss the following topics regarding validation practices: 1. Types of quantitation technique 2. System suitability requirements 3. Stability indicating potency assay 4. Strategies and validation characteristics 5. Revalidation