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To find out the influence of CMAs and/or CPPs (independent variables) on CQAs (dependent variables) of topical ophthalmic emulsions, the initial risk assessment studies were performed. By employing the Minitab 18 software (M/s Minitab Inc., Philadelphia, PA, USA), an Ishikawa fish‐bone diagram was constructed to ascertain the potential cause–effect relationship among the product and process variables. Prioritization studies were carried out to select the CMAs/CPPs with high risk by constructing the Risk Estimation Matrix (REM) for qualitative analysis of risk by assigning low‐, medium‐, and high risk(s) levels to each MA and/or PP of topical ophthalmic emulsions (Table 2.2). Furthermore, the quantitative estimation of risk(s) and detection of the plausibility of failure modes associated with the emulsions were assessed with the help of the FMEA (Table 2.3). The rank order scores, ranging between 1 and 10 each, were allotted to the CMAs/CPPs (independent variables) for indicating severity, detectability, and occurrence of risks. The FMEA defines the RPN according to the formula already shown in Eq. (2.1) (Fahmy et al. 2012).

Flowchart 2.2. Evolution of QbD and multidimensional combination and interactions of critical input variables (CMAs and CPPs) on critical response variables (CQAs) for the preparation of o/w nanosized emulsions.

[Adapted from Montgomery (2013) and Yu et al. (2014).]

The parameter D is the ease that a failure mode can be detected because the more detectible a failure mode is, the less risk it presents to product quality. For D, the rank 1 is considered as easily detectable, 5 as moderately detectable, and 10 as hard to detect. The parameter O is the occurrence probability or the likelihood of an event occurring. For O, the rank 1 is considered as unlikely to occur, 5 as 50 : 50 chance of occurring, and 10 as likely to occur. The parameter S is a measure of how severe of an effect a given failure mode would cause. For S, the rank 1 is considered as no effect, 5 as moderate effect, and 10 as severe effect. Using this procedure, the REM carried out for qualitative analysis of risk associated with each MA and/or PP.

The Ishikawa fish‐bone diagram constructed for topical ophthalmic emulsions is simply portraying the cause–effect relationship among the factors that potentially affect the final product CQAs (shown in Fig. 2.4). The parameters outlined in the Ishikawa fish‐bone diagram assisted in the identification of the failure modes, i.e., the modes through which a system, process step, or piece of equipment might fail. Table 2.2 illustrates the REM carried out for qualitative analysis of risk associated with each MA and/or PP. The REM suggested that factors such as amount of chitosan, speed and time of homogenization, and volume of castor oil were found to be high risk, while the factors like the amount of poloxamer, times for premixing, and probe sonication were associated with medium risk. An in‐house exercise employing extensive brain storming among the diverse research group members as well as the existing literature reports were used for prioritizing the factors or parameters and allotting the scores for RPN computation. Using FMEA, the modes of failure can be prioritized for risk management purposes according to their seriousness of their consequences (effects), how rottenly they occur, and how easily they can be detected. Through this information, the variables that are needed to be further studied and controlled were found out or short‐listed. In addition, the process of doing the FMEA analysis within a larger organization facilitates systematic gathering of current knowledge inside the organization. Furthermore, with the help of knowledge management system, the FMEA analysis allows the information on risk to be stored for future use. In this manner, it is important for the larger organization in which the turnover results in the loss of institutional memory. The outcomes of FMEA analysis are to define the RPN and further computation of RPN.

TABLE 2.2. Risk Estimation Matrix (REM) for Qualitative Analysis of Risk Constructed After Assigning Low, Medium, and High Risk(s) Levels to Each Material Attributes and Process Parameters of Topical Ophthalmic Emulsions

Critical Quality Attributes (CQAs)	REM for Qualitative Analysis of Risk Assigned to
Volume of Castor Oil	Amount of Chitosan	Amount of Poloxamer 407	Premixing Time	Homogenization Time	Homogenization Speed	Probe Sonication Time
Mean particle size	High	Medium	Medium	Medium	High	High	Medium
Polydispersity index	Low	Low	Medium	Medium	Medium	High	Medium
Zeta potential	Low	High	Low	Low	Low	Low	Low

TABLE 2.3. Summary of Failure Mode and Effect Analysis (FMEA) Demonstrating Risk Priority Number (RPN) Scores for Various Materials and Process Variables Affecting the Critical Quality Attributes (CQAs) Such As Mean Particle Size (MPS), Polydispersity Index (PDI), and Zeta Potential (ZP)

Failure Modes	Detection (D)	Occurrence (O)	Severity (S)	RPN (=DOS)	Consequences on CQAs
Volume of castor oil (ml)	5	5	8	200	MPS
Amount of chitosan (mg)	6	5	7	210	MPS and ZP
Amount of poloxamer (mg)	5	5	5	125	MPS and PDI
Premixing time (min)	5	7	7	245	MPS and PDI
Homogenization time (min)	5	4	6	120	MPS and PDI
Homogenization speed (rpm)	5	6	7	210	MPS and PDI
Probe sonication time (min)	2	3	3	18	MPS and PDI

Figure 2.4. Ishikawa fish‐bone diagram made with the help of Minitab 18 software showcasing the potential cause–effect relationship among the product and process variables for topical ocular emulsions.

Based on the REM analysis, an elaborative risk assessment was carried out by assigning ordinal scores to each MA and PP. Table 2.3 displays the details of MAs and PPs employed during FMEA analysis together with their computed RPN scores, which collectively explain their effect and plausible/possible consequences on CQAs of topical ocular emulsions. To discriminate the high‐risk factors against the low‐risk factors, a critical cutoff value of RPN that was fixed for ocular emulsions is 100 or above. With lone exception of probe sonication time (which shows the RPN scores of 18 only), the factors such as amount of chitosan, amount of poloxamer, homogenization time, homogenization speed, premixing time, and volume of castor oil possessed the high RPN scores. The factors associated with high RPN scores were finally subjected to factor screening study by employing the Taguchi design.

Table 2.4 shows the selective list of various designs used for optimization and screening of CPPs of o/w nanosized emulsions.