How does CDER assess the potential risks of using nanomaterials in drugs?

1、 Nanotechnology is being applied in pharmaceutical industry as a means of developing innovative products, including new dosage forms, complex delivery systems and targeted therapy The application of nanotechnology in the pharmaceutical industry can improve drug performance, stability, efficacy and patient compliance FDA supports improvements to development products, including performance, safety, and quality, while ensuring that possible risks are minimized In June 2011, FDA issued draft guidance: considering which an FDA regulated product involves the application of nanotechnology, clarifying the principle of considering whether the product contains nanomaterials Although the considerations listed in the draft guide are not formal provisions, they are related to the characteristics that the product may show that will eventually cause safety, effectiveness, quality or public health impact problems, which in turn requires FDA to review its review practices In order to better understand the consequences or risks of using nanomaterials, FDA has taken several methods to better understand how to use nanomaterials in receiving drugs In the first step, an internal database of submitted and approved drugs containing nanomaterials was created to better understand the product profile being reviewed by the center for drug evaluation and Research (CDER) The next step is to assess the potential impact of nanomaterials on drug product development and use in the future To this end, CDER initiated the risk assessment described in this paper In 2010, CDER released MAPP 5015.9, the report format for nanotechnology related information in CMC review In this MAPP, CMC reviewers of CDER are provided with information on how to continuously capture relevant information from submitted products containing nanomaterials, which is also the purpose of building the database For this purpose, CMC reviewers in the CDER are directed to MAPP to collect information on all products smaller than 1000 nm in size (excluding dissolved molecular entities and biological agents) Although there is no FDA official definition of nanotechnology, the purpose of MAPP is for CDER to use 1000nm size products to widely establish methods to help reviewers identify the data related to nanotechnology that should be collected In order to understand the quality and safety characteristics of drugs containing nanomaterials, the collected information (such as particle size, particle size distribution, etc.) is collated and analyzed in the database The goal of database analysis is to finalize possible trends and generalizations that may contribute to the review methodology for nanomaterials applications At the meeting on August 9, 2012, the Advisory Committee of the Research Office of pharmaceutical science and clinical pharmacology introduced the preliminary analysis of the information collected by CDER in the CMC review of therapeutic drugs In order to ensure that CDER can better understand the possible impact of using nanomaterials in drugs from the perspective of development and manufacturing, a nanotechnology risk assessment working group was established in 2011 The team consists of a multidisciplinary team that evaluates the potential risks associated with nanotechnology applications in drug development and manufacturing The risk assessment working group is identifying areas related to the assessment of product safety and quality that can be further optimized in the current assessment process of CDER to specifically address considerations related to nanotechnology product characteristics The working group has two main objectives: 1 To identify potential risks in safety, quality and effectiveness of nanomaterials used in pharmaceutical products 2 According to the results of risk management, determine the areas to be improved At present, the regulatory requirements of CDER are very firm, and it has been successfully applied to the evaluation of new therapies containing nano materials The purpose of this risk assessment is to comprehensively assess how to optimize the review practice of products containing nano materials The recently adopted food and drug administration safety and innovation act reaffirmed the importance of a better understanding of the potential impact of nanotechnology on pharmaceutical products (signed 10 July 2012) In the current risk assessment work, although the non clinical safety assessment has been solved, the focus will be on the review of product quality The information generated by the risk assessment will help CDER to continue to ensure the safety, effectiveness and quality of drugs, including those containing nanomaterials, while keeping in mind the benefits of scientific progress in drug development 2、 Risk assessment strategy overview when developing and manufacturing drugs using nanomaterials, the following section describes the strategies used by the nanotechnology risk assessment team to identify potential risk factors that could lead to quality, effectiveness and safety According to ICH Q9, risk management includes risk assessment (identification, analysis and evaluation), risk control (reduction and acceptance) and risk assessment (continuous assessment and adjustment) Some applications that contain design elements include the risk management tools described in ICH Q9 (10) In addition, risk-based strategies are increasingly used in product development with nanotechnology The first step in the risk assessment process is to organize the regulatory, policy and research departments to form a multidisciplinary CDER expert group Using traditional risk assessment tools, the nanotechnology risk assessment working group has developed a strategy, namely, the combination management table of Ishikawa chart (also known as Ishikawa chart) (potential risk identification and classification) and risk, which is used to describe and analyze the current risk management methods used in CDER In this risk assessment, as a result of API granularity change, hazard or potential risk factors are defined as factors that may affect product quality, safety and / or effectiveness In addition, the working group invited CDER experts to discuss as needed Common routes of administration are used to organize risk assessment The following routes of administration were chosen: oral administration, skin (local and transdermal), inhalation and parenteral administration API and accessories need to be evaluated Once potential risks are identified, the risk management form is completed The results were analyzed to determine the priority of recommendations III The practice of the risk identification and characterization working group involves the use of Ishikawa diagrams as a tool to help identify factors, causes or sources of change that may lead to specific results of a product or process More specifically, as described in ICH Q8 (R2), the Ishikawa map identifies "potential variables that may have an impact on the quality attributes of drug products." Therefore, Ishikawa diagram is a useful tool to provide a list of important factors in the process and identify the relationship between these factors For risk assessment strategies involving drugs containing nanomaterials, the working group developed the Ishikawa chart, identifying potential risks of quality, safety and effectiveness that should be addressed in the regulatory review process For example, for the oral administration route, five stages of the drug product are selected for specific analysis: (1) product production (2) digestion and dissolution (3) absorption and distribution of non absorption particles or (4) absorption and distribution of absorption particles (5) elimination Figure 3 provides an example of a representative Ishikawa map of oral drugs to highlight the working methods of CDER risk assessment This graph represents the risks to quality, safety, and effectiveness during the oral drug intake and dissolution phase of API particle size changes This graph shows the potential risks of API particle size changes for the safety, quality, and effectiveness of oral drugs at the ingestion and dissolution stages For the Ishikawa diagram of absorption and distribution (stages 3 and 4), two main scenarios are considered: the API for absorption (stage 3 or whole body delivery) and the API for absorption (stage 4 or local action) Because these two situations are considered to have different risk characteristics, they are treated independently The risk assessment methods for particles used for absorption (i.e system transfer) focus on potential risk factors related to pharmacokinetic changes, such as differences in absorption rate and degree caused by particle size changes On the other hand, for nano particle changes that are not suitable for absorption (i.e local action), the potential risk factors caused by the API of local action, such as absorption changes, are mainly considered The example chosen in this article is not a comprehensive description of the risk assessment process Instead, it aims to provide a framework for how cders conduct risk assessment To illustrate the method, the following section describes how to read Ishikawa Figure 3 1 The head of Ishikawa graph usually represents the required attributes In the case of the selected example, when considering the uptake and dissolution of nonlocal oral drugs, it corresponds to the quality, safety and effectiveness 2 The title boxes at the top and bottom of the chart indicate the relevant categories or factors affecting product quality, safety and effectiveness Arrows pointing directly to these categories are the primary cause or factor, while branch arrows depict the secondary cause or factor For example, the "analysis method" box in Figure 3 corresponds to the potential risk category Insufficient research on "dissolution / release rate" and "particle size" methods is considered to be factors that may affect quality, safety and effectiveness evaluation Similarly, in the "particle dissolution rate" box, particle aggregation is a factor that may ultimately affect the quality, safety and effectiveness of API drugs (ingestion and dissolution) containing nanoscale particles Ishikawa diagram is a visual sketch of the potential hazards to quality, safety and effectiveness, and their relationship with each other It is important that the potential risks identified in the Ishikawa chart are qualitative and that the severity or probability of these potential risk factors are not quantified Note that some of the potential risk factors identified in the figure do not appear to include the uniqueness of nanomaterial products, as some of the potential risks identified may generally apply to any change in the physical properties of the drug However, these potential risks are identified and analyzed because they are believed to be related to changes in the size of the material In addition, graphical representations do not always capture the complex relationship between these factors and the impact of their review practices 4、 Development of the risk management table as each Ishikawa diagram is developed, a risk management table is created to describe and analyze the review practices currently used to address potential risks An example of a risk management table is shown in Table 1 For each risk category, the working group addressed the following issues and reported them in different columns of the risk management table: 1 What information does the reviewer currently assess to address each potential risk? In this column of the risk management table, the group lists any guidance, policies, submitted data or studies that currently address potential risks 2 Are the potential risks identified by the CDER nanotechnology risk assessment team addressed by current review methods? 3 What are the initial recommendations on drug review methods for nanotechnology applications so that potential risks can be appropriately managed? As the current review practice may vary for different types of drugs submitted, the working group considered different types of submissions, such as 501 (b) (1), 505 (b) (2) and 505 (J), when dealing with potential risk factors in the risk management table In addition, the team considered possible changes after the completion of the primary safety and efficacy clinical study In this case, the team considered possible changes to the API after phase III clinical testing, before approval and after market application for approval of approved products Table 1 The representative summary of API particle size change oral drugs in "analysis method" risk factor analysis during the ingestion and dissolution stage 5 The CDER risk assessment described in the risk assessment and recommendations shows that in most cases, if the applicant is early in the development process