The working group’s approach involved the use of Ishikawa (fishbone) diagrams as the tool to help identify factors, causes, or sources of variation that might lead to a specific result in a product or process. More specifically, as noted in ICH Q8(R2), Ishikawa diagrams identify “potential variables that can have an impact on the desired quality attribute” of a drug product. Ishikawa diagrams are a useful tool for providing an inventory of significant factors in a process and for identifying relationships among these factors (13
For the risk assessment strategy involving pharmaceuticals containing nanomaterials, the working group has developed Ishikawa diagrams that identify potential risks to quality, safety, and efficacy that should be addressed in the regulatory review process. For example, for the oral route of administration, five phases of the drug product were selected for specific analysis: (1) product manufacture, (2) ingestion and dissolution, (3) absorption and distribution for particles not intended for absorption or (4) absorption and distribution of particles intended for absorption, and (5) elimination. Figure shows the five phases for the oral route of administration used to organize the Ishikawa diagrams.
Summary of the five Ishikawa diagrams for the oral route of administration
Figure provides an example of a representative Ishikawa diagram for orally administered drugs, in order to highlight CDER’s approach to the risk assessment exercise. The diagram represents risks to quality, safety, and efficacy at the ingestion and dissolution phase for orally administered drugs that have a change in API particle size.
Fig. 3 Representative Ishikawa diagram for orally administered drugs. This diagram represents potential risks to safety, quality, and efficacy at the ingestion and dissolution phase for orally administered drugs that have a change in API particle size. Please (more ...)
For the absorption and distribution Ishikawa diagrams (phases 3 and 4), there were two main scenarios considered: one in which the API is intended for absorption (phase 3 or systemic delivery) and one when it is not intended for absorption (phase 4 or locally acting). Because these two scenarios were considered to have different risk profiles, they were treated independently. The risk assessment approach for particles meant for absorption (i.e., systemic delivery) focused on potential risk factors related to pharmacokinetic changes, such as differences in the rate and extent of absorption, caused by a change in particle size. On the other hand, for changes to nano-sized particles not intended for absorption (i.e., locally acting), potential risk factors resulting from a locally acting API were considered, such as a change in absorption.
The example selected in this paper is not meant to be a comprehensive depiction of the risk assessment process. Rather, it is intended to provide a framework for how CDER approached this risk assessment exercise. To illustrate the approach, the following section describes how to read the Ishikawa diagram shown in Fig. . The head of the Ishikawa diagram typically represents the desired attribute, which, in the case of the selected example, corresponds to quality, safety, and efficacy, when considering ingestion and dissolution of an orally administered drug that is not locally acting. The caption boxes at the top and bottom of the diagrams represent related categories or factors that impact the quality, safety, and efficacy of the product. The arrows pointing directly to these categories are primary causes or factors, and the branching arrows depict secondary causes or factors. For example, in Fig. , the box “Analytical methods,” corresponds to a potential risk category. The possibility of inadequate “dissolution/release rate” and “particle sizing” methods are identified as factors that may impact the evaluation of quality, safety, and efficacy. Similarly, within the box “Particle dissolution rate,” particle aggregation is a factor that could ultimately impact the quality, safety, and efficacy of the drug product containing nano-sized APIs (during ingestion and dissolution).
Ishikawa diagrams serve as visual shorthand for representing potential harms to quality, safety, and efficacy and the relationship of these possible harms to each other. It is important to note that the identification of potential risks in an Ishikawa diagram is meant to be qualitative, and that no quantification of severity or probability has been given to these potential risk factors. Such an analysis would be product specific. Note that some of the potential risk factors identified on the diagrams appear not to be unique to products containing nanomaterials, as some potential risks identified may be generally applicable to any change in physical properties of a drug substance. However, these potential risks were identified and analyzed because they were considered to be relevant to materials that undergo a change in particle size. Also, the graphical representation does not always capture the complex relationships between the factors and the implications on their review practices. Therefore, a second tool was applied to analyze the potential risk factors and to capture the adequacy of current review practices as applied to drugs that involve the application of nanotechnology