of critical quality attributes (CQAs) from the QTPP depends on the extent of their

influence on the patient’s health. Such CQAs are the biological, physicochemical or

microbiological attributes that need to be monitored and maintained in a specific

range to attain the desired product quality (Singh et al. 2005b; Yu et al. 2014). These

CQAs are the key functional characteristics that must be determined at the initial

development phases (Singh et al. 2005b, 2013; Aksu et al. 2015; Singh et al.

2017a, b).

18.4.2 Step II: Prioritization of Key Input Variables for Optimization

Before executing optimization studies, it is imperative to prioritize the significant

input variables, i.e. factors and their appropriate levels during the initial stages, using

QRM and/or factor screening studies (Singh 2014; Aksu et al. 2015). In a federally

recommended approach, QRM aids in enhanced product/process understanding and

mitigation of associated risk (ICH Harmonised Tripartite Guideline 2005; Singh

et al. 2005b).

Material attributes (MAs) and process parameters (PPs) are the input product

and process parameters, varying independently and impacting various CQAs, nota-

bly or mildly. An Ishikawa fishbone diagram is employed, which establishes the

“cause-and-effect” relationships among multiple input factors and drug product

CQAs (Singh et al. 2005b; Beg et al. 2015a). Figure 18.4 represents an Ishikawa

diagram highlighting the cause-effect relationship for CQAs.

Prioritization exercise aims to identify statistically significant variables among

MAs and PPs, viz. critical material attributes (CMAs) and critical process parameters

(CPPs), which exert a profound impact on various CQAs. Risk estimation matrix

(REM) is one of the most prevalent risk assessment tools. In these studies, MAs and

PPs are assigned varied degrees of risk, viz. high, medium and low, based on risk

severity, frequency of incidence and, at times, its detectability too. The medium- to

high-risk factors from the patient’s point of view, based on prior literature reports

and discussions among teammates, are selected as CMAs and CPPs (Singh et al.

2005b; Aksu et al. 2015; Singh et al. 2017a, b). Figure 18.5 shows the flow layout of

a QRM plan using a REM model for looking out for high-risk CMAs. Another

Establishment

of QTPP

Requirements

Step I

Step II

Step III

Step IV

Step V

Identification

of CMAs, CPPs

& CQAs

DoE-Guided

Experimentation

Modelization

&

Validation

Scale-up

&

Control Strategy

Fig. 18.3 Five-step QbD methodology for developing drug products

18

QbD-Steered Systematic Development of Drug Delivery Nanoconstructs:. . .

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