Table 4.

Representative critical quality attributes (CQA) for the polymeric micellar injectable dosage form.

S.No.	Quality Attribute	Target Terms	Criticality	Justification
1	Description	Examples: A sterile, translucent red/green/yellow micellar dispersion	Yes	✓Critical for safety and efficacy. ✓Controlled by the quality management system.
2	pH	Target pH	Yes	✓Critical for safety and efficacy. ✓The limits were fixed based on the available information.
3	Osmolality (mOsm/kg)	Specific mOsm/kg of water	Yes	✓Osmolality is having a direct effect on the safety and efficacy of the product. ✓The range for osmolality is fixed based on the analysis. ✓An infusion after dilution may affect this parameter.
4	Average particle size	Particle size in nanometers (nm)	Yes	✓Particle size has a direct impact on the safety and efficacy of the formulation. ✓Micelles larger in size than the gaps between endothelial cells lining the tumor blood vessels will not be able to extravasate into the tumor tissue which determines product efficacy. ✓Conversely, if micelles are too small, then they are not stable, which may affect patient safety. ✓The average particle size is dependent on the synthetic step.
5	Particle size distribution	Particle size in nanometers (nm) Population distribution (D,10), (D,50), (D,90)	Yes	✓Particle size distribution may have an impact on the safety and efficacy of the formulation. ✓The limits of D10, D50, and D90 will be defined.
6	Identification (API)	Positive for specific drug substance	Yes	✓Critical for safety and efficacy, this CQA can be effectively controlled by the quality management system.
7	Identification of polymers	Positive for specific polymers (PLGA, PLA, etc.)	Yes	✓Critical for safety and efficacy, this CQA can be effectively controlled by the quality management system.
8	Assay (Dug substance)	Each mL contains a specific amount of labeled drug	Yes	✓Variability in the assay will affect safety and efficacy. Therefore, it is critical.
9	Polymer content	Each mL contains the amount of polymer	Yes	✓Polymer content directly affects the safety and efficacy of the formulation. ✓Content of individual polymers determines the in vivo stability, prolonged blood circulation, drug retention, and its release, which affects the efficacy of the product and patient safety.
10	Percentage of the entrapped drug	Should comply with the qualified limits. Example: Not less than 95.0% of the assay amount.	Yes	✓Percentage entrapped and unentrapped may have an impact on the safety and efficacy of the formulation. ✓The rationale behind encapsulation of drug into micelles is for site-specific tumor targeting. ✓In addition, the presence of more of the free drug would lead to an increase in the probability of toxicity. Hence, it is considered critical.
11	Percentage of Unentrapped drug	Should comply with the qualified limits Example: Not more than 5.0%.	Yes
12	Ion content (ppm)	Total Ion content (ppm) (Ammonium, Iron, etc.).	Yes	✓Any unwanted ions will affect patient safety.
14	Related substances (API)	Should comply with the qualified limits.	Yes	✓Related substances of the API and the polymers added in the formulation may affect the safety and efficacy of the product. Hence, it is critical.
15	Related substances (polymers)	Should comply with the qualified limits.	Yes
16	Drug release	Drug release profile.	Yes	✓The drug release profile is important for bioavailability (BA); therefore, it is critical.
17	Visible Particulate Matter Particulate Matter (sub visible)–Microscopic method	Free from visible particles. Not more than 3000 average number of particles should be greater than or equal to 10 µm. Not more than 300 average number of particles should be greater than or equal to 25 µm.	Yes	✓Important for IV infusions. ✓The absence of particulate matter is of paramount importance to ensure patient safety. Hence, it is considered critical. However, it is controlled by the quality management system.
18	Uniformity of dosage units	Content uniformity method.	Yes	✓Variability in uniformity of dosage units will affect safety and efficacy. Hence, it is considered critical.
20	Zeta Potential (by Zeta Sizer)	Defined by innovator.	Yes	✓Extremes in zeta potential values would lead to repulsion or aggregation and hence will affect the stability. Hence, it is considered critical.
21	Sterility	The product should be sterile.	Yes	✓To ensure the safety of patients, the product should be sterile. Hence, it is considered critical.
22	Bacterial Endotoxin Test	Specific limits.	Yes	✓To ensure the safety of patients, bacterial endotoxin in the product should be low. Hence, it is considered critical.
23	Residual solvents	Based on process optimization.	Yes	✓Excess amounts of solvents in the product may affect the quality.