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The Risk Knowledge Infinity (RKI) Cycle Framework was featured as part of the ICH-sanctioned training materials supporting the recent issuance of ICH Q9(R1) Quality Risk Management To support ICH Q9(R1) understanding and adoption, this paper presents a case study on the application of the RKI Cycle, based on an underlying out-of-specification investigation. This case study provides a stepwise walk-through of the cycle to illustrate how key concepts within the ICH Q9(R1) revision can be achieved through better connecting quality risk management and knowledge management with a framework such as the RKI Cycle.

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In the past few years, there have been several instances of illicit pharmaceutical manufacturing in Japan, and there is a growing awareness of the importance of corporate compliance and pharmaceutical manufacturing and quality controls. One cause of illicit manufacturing is the inadequate development of quality culture. This study focuses on the degree of quality culture development in Japanese pharmaceutical companies manufacturing generic drugs. Because no evaluation index for Japan can visualize the degree of quality culture development in each company, this study sought to establish this index to utilize it as a tool for evaluating the degree of quality culture development that would enable each company to continuously monitor and improve its own. We conducted a questionnaire survey among Japan Generic Medicines Association members to evaluate the degree of their quality culture development. The questionnaire contained 28 questions in five evaluation categories. Potential indicators of quality culture development included "Employee growth and satisfaction"; "Management commitment"; "Improvement activities"; "Communication"; and "Environment, health, and safety." We obtained 294 responses from 37 Marketing Authorization Holder (MAH) and 61 manufacturing sites. Respondents were classified by roles of management, manager, and nonmanager. The results confirmed the current status of quality culture development efforts, showing that important messages such as the corporate philosophy as communicated by the management is well known, awareness of quality culture development level differs by role, and appropriate resources are not adequately allocated to employees or facilities. Based on the results, use of the index of quality culture development helped to make relative comparisons and visualize the areas to be addressed for quality culture development. This study established and visualized the index for the degree of quality culture development in domestic generic drug manufacturing companies and we hope this indicator becomes a useful tool for evaluating a company's quality culture development level.

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In the past few years, there have been several instances of illicit pharmaceutical manufacturing in Japan. Insufficient good manufacturing practice compliance and lack of quality culture in some pharmaceutical companies have been suggested as the underlying reasons for such cases. We aimed to focus on knowledge management and fostering of quality culture in pharmaceutical companies in Japan to understand their current situation and find a strategy for the availability of high-quality reliable pharmaceutical products. A wide-ranging questionnaire survey was conducted to understand the issues related to knowledge management and fostering of quality culture across pharmaceutical companies in Japan. A published investigation report on an illicit manufacturing case was closely examined by organizing the available facts using the diagram. Based on 395 responses to the questionnaire survey, we found that although pharmaceutical companies understand the importance of knowledge management and quality culture, issues exist in their operational methods. A total of 94% of the respondents agreed that they mentioned "knowledge management" as an enabler of the Pharmaceutical Quality System of ICH Q10, and 98% of the respondents accepted that insufficient fostering of quality culture leads to corporate risk. However, the survey revealed that many companies are struggling with this approach. Based on a report on an illicit manufacturing case, we analyzed the direct causes of misconduct and prepared a systematic summary that can be easily comprehended. Comparison of the illicit manufacturing case report with our questionnaire results suggests that many pharmaceutical companies do not regard the misconduct case as a situation that could occur in their company. With the revision of the Pharmaceuticals and Medical Devices Act and good manufacturing practice Ministerial Ordinance, we advocate the need for all employees of pharmaceutical companies to reconsider the priorities of their companies from the patient perspective.

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The pharmacy compounding of personalized preparations has evolved a great deal, and with it, the way of working and the legal requirements have also evolved. An adequate pharmaceutical quality system for personalized preparations presents fundamental differences with respect to the system designed for industrial medicines since the size, complexity, and characteristics of the activity of the manufacturing laboratory and the applications and uses of the manufactured medicines must be taken into account. Legislation must advance and adapt to the needs of personalized preparations, filling the deficiencies currently found in this field. The limitations of personalized preparation in its pharmaceutical quality system are analysed and a method based on a proficiency testing program specially designed to overcome these limitations is proposed: the Personalized Preparation Quality Assurance Program (PACMI). This method makes it possible to expand the samples and destructive tests, and dedicate more resources, facilities, and equipment. It allows for more in-depth knowledge of the product and the processes used, and for proposed improvements that increase the overall quality for improved patient health. PACMI introduces tools used in risk management in order to guarantee the quality of an essentially heterogeneous service: personalized preparation.

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Post-approval changes (PACs) are inevitable and necessary throughout the life of a drug product. Because many PACs require prior approval by individual regulatory agencies each having their own reporting requirements and approval timelines, this results in companies having to manage several versions of a manufacturing process at the same time. The global regulatory complexity increases risk of drug shortages. Chief quality officers and heads of quality from more than 20 global pharmaceutical companies have come together to speak with One-Voice-of-Quality (1VQ) and develop solutions to this problem by developing a science and risk-based approach to manage more PACs in the pharmaceutical quality system (PQS) rather than submitting these as prior approval supplements. Pharmaceutical companies already conduct management review (MR) according to the International Conference on Harmonization (ICH) Q10. This One-Voice-Of-Quality paper is a practical guide on how companies can expand the MR to also evaluate and demonstrate the effectiveness of their PQS in specifically managing PACs to achieve regulatory flexibility as stated in ICH Q10, Annex 1. Examples of PQS key performance indicators (KPIs) that may be used to assess, plan, implement, and monitor PACs are described. The intent is to provide assurance through MR that PACs can be managed effectively in the PQS, thereby resulting in a reduced need for regulatory prior approval of certain low risk changes that enhance product availability, reduce the risk of drug shortages, and/or facilitate timely innovation and continual improvement in the pharmaceutical industry. This document is endorsed by 1VQ chief quality officers and heads of quality.

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Do the changes to ISO 9001 from the 2008 version to the 2015 version warrant revision of ICH Q10? Or does ICH Q10 still meet the ISO 9001 principles? In 2008, the International Conference on Harmonisation (ICH) issued guideline ICH Q10, describing a model for a pharmaceutical quality system (PQS) that can be implemented throughout the different stages of a product life cycle. Explicitly, the guideline was not intended to create any new expectations beyond the existing regulatory requirements. ICH Q10 was founded on principles established by the International Organization for Standardization (ISO) describing a model for the structure of a quality management system (QMS). Since 1987, these principles were codified in the ISO 9000 series of quality standards, for example, as revised in ISO 9001:2008. ICH Q10 also incorporated applicable good manufacturing practice (GMP) regulations and complemented the existing ICH Q8 (R2) "Pharmaceutical Development" and ICH Q9 "Quality Risk Management" guidelines. ICH Q10 represents a harmonized model for a PQS that can be implemented throughout the different stages of a product life cycle. In 2015, ISO published ISO 9001:2015, a significant revision to the ISO 9001 QMS standard. This 2015 version contained extensive changes and a new structure. This revision to ISO 9001 raised the question of whether ICH Q10 should be reviewed and potentially revised, and whether ICH Q10 continues to meet the ISO 9000 principles. This article assessed whether the changes to the ISO 9001:2015 standard could make a revision of the ICH Q10 guideline necessary and whether ICH Q10 still represents a current model of a pharmaceutical quality management system.

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Post-approval changes are inevitable and necessary throughout the life of a drug product-to implement new knowledge, maintain a state of control, and drive continual improvement. Many post-approval changes require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual post-approval changes usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods. This global complexity slows down continual improvement and innovation and can cause drug shortages and current good manufacturing practices compliance issues. Manufacturers that market products globally experience the greatest challenge and risks in their daily operations because of this post-approval change complexity. A global problem needs a global solution. This paper has been sponsored and endorsed by senior quality leaders (Chief Quality Officers/Heads of Quality) from >20 global pharmaceutical companies who have collaborated to speak with "One-Voice-Of-Quality" (1VQ). The paper provides two specific solutions that lay the foundation for an aligned and standardized industry position on the topic of effective management of post-approval changes in the pharmaceutical quality system (PQS). This document represents the 1VQ standard approach for the steps necessary to establish and demonstrate an effective quality system to fully leverage a risk-based approach to post-approval changes as laid out by ICH Q10 Annex 1. Implementation of the solutions presented in this paper can help achieve a transformational shift with faster implementation of new knowledge, continual improvement, and innovation through post-approval changes. The Chief Quality Officers/Heads of Quality are inviting other companies to join the 1VQ (contact either Emma Ramnarine or Anders Vinther) and other stakeholders to join the dialog.

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It is important to identify, assess, and address current barriers to implementation of post-approval changes that are intended to ensure continued (uninterrupted) operations and drive innovation and continual improvement in a maximally efficient, agile, and flexible pharmaceutical manufacturing sector. Leveraging the International Conference for Harmonisation Quality Guideline Q10 provides regulatory relief when it comes to addressing changes related to excipients, specifically excipient supplier's name and address changes, which will ensure a sustainable, reliable global supply and the availability of high quality product to patients through the entire commercial lifecycle of a product without extensive regulatory oversight.

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Post-approval changes are inevitable and necessary throughout the life of a drug product-to implement new knowledge, maintain a state of control, and drive continual improvement. Many of these post-approval changes require regulatory agency approval by individual countries before implementation. Because of the global regulatory complexity, individual post-approval changes usually take years for full worldwide approval even when they reduce patient risk, improve compliance, or enhance the manufacturing process or test methods. This global complexity slows down continual improvement and innovation and can cause drug shortages and current good manufacturing practices compliance issues. Manufacturers that market products globally experience the greatest challenge and risks in their daily operations because of this post-approval change complexity. A global problem needs a global solution. Quality leaders speaking globally with "One Voice of Quality" are essential for solving this difficult problem. This concept paper has been developed under the sponsorship of a group of Chief Quality Officers (Heads of Quality) from >25 global pharmaceutical companies and has been endorsed by the Parenteral Drug Association. The intent of this concept paper is to develop and implement aligned, standard solutions within the industry, leveraging the core foundation of the pharmaceutical quality system, such that a transformational shift can be achieved with faster implementation of new knowledge, continual improvement, and innovation through post-approval changes.LAY ABSTRACT: Pharmaceutical manufacturers must make changes to their products and manufacturing processes over time as they incorporate new technology and new information. Because drug products are highly regulated in every country, the manufacturer must often contact national drug regulators before making these changes, even if the manufacturer is confident, based on testing and process controls, that the change will not have a negative impact on product quality or patient safety. For a product that is globally marketed, the manufacturer may have to contact dozens of regulators before making a change. This paper suggests that industry work together to identify ways to demonstrate to regulators that product and process knowledge as well as pharmaceutical quality systems are strong enough that the manufacturers should be allowed to manage some post-approval changes themselves.

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OBJECTIVE: To analyze the key problems in the management of drug production process changes during the drug life cycle, thus to improve the management of pharmaceutical production process changes. METHODS: Taking the change of injection sterilization process as an example, the issues in the study and management of process change were analyzed by employing empirical a-nalysis methods and introducing the concept of equilibrium analysis of the pharmaceutical quality system. RESULTS AND CONCLUSION: The pharmaceutical quality system is the equilibrium system of five aspects, including prescription composition, raw material control, production process, packaging and quality control. Process change research should follow the concept that quality comes from design, use process analytical technologies, and give full consideration to the quality system equilibrium. Process change management needs a systematic management of drugs.

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This article is the first in a series of articles that will focus on understanding the implementation essentials necessary to deliver operational excellence through a International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) Q10-based pharmaceutical quality system (PQS). The authors examine why, despite the fact that the ICH Q10 guideline has been with us since 2008, the transformation of the traditional Quality Management Systems QMS in use within the pharmaceutical industry is a work in progress for only a few forward-thinking organisations. Unfortunately, this transformation remains a mere aspiration for the majority of organisations. We explore the apparent lack of progress by the pharmaceutical sector in adopting six sigma and related quality management techniques to ensure the availability of high-quality medicines worldwide. The authors propose that the desired progress can be delivered through two key shifts in our current practices; by embodying the principles of operational excellence in every aspect of our business and by learning how to unlock the scientific and tacit knowledge within our organisations. LAY ABSTRACT: It has been ten years since The Wall Street Journal revealed the pharmaceutical industry's "little secret" comparing the perceived level of manufacturing expertise in the industry as lagging far behind those of potato-chip and laundry-soap makers. Would you consider the quality and manufacturing strategies in place today in your organisation to be more efficient and scientifically based than those of 2003? If so, what evidence exists for you to draw any conclusion regarding enhanced performance? Do your current practices drive innovation and facilitate continual improvement and if so, how? Ultimately, can you confidently affirm that patient-related risks associated with the product(s) manufactured by your organisation have been reduced due to the quality assurance program now applied within your organisation? This article asks you to question if you have truly embraced Q8(R2), Q9, and Q10, and in doing so can you demonstrate that you have made the necessary changes that would warrant reduced regulatory oversight?

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