(T1230-01-04) Evaluation of Critical Quality Attributes (CQA’s) of Carbomer Based Topical Hydro Gels with Process Analytical Technique (PAT)

Purpose: Evaluation of CQAs such as mixing duration, homogenization duration, order of addition of excipients like surfactant, electrolytes and Neutralizing agent and the API on the microstructure of gel suspensions was performed to help achieve a formulation with desirable characteristics (suspendability, viscosity etc) to treat open wound pressure sensitive indications.

Methods: In this study four different gel suspensions, Bench scale, A1 (Scaleup), A2 (Scaleup) and A3 (Scaleup) of similar compositions and different processing/manufacturing methods were investigated for their flow behavior, using rheological behavior analysis -three test methods. Equilibrium Flow curve method was used to understand the Viscosity vs shear rate profile of the gels. Test method: Equilibrium Flow Curve in rSpace software. Temperature: 25.0°C; Gap Value: 1.00 mm; Start Shear rate (s^-1): 0.01; End Shear rate (s^-1): 100; Samples per decade: 10. Yield stress- Shear stress ramp was used to investigate the peak Shear stress (Pa) and the shear viscosity (cP). Test method: Yield stress; Start shear stress: 0.00 Pa; End Shear stress:200.0 Pa; Ramp Time: 1:40 Sec; Gap value: 1:00mm. Linear Viscoelastic response helped study storage and loss modulus vs frequency. Test method: Frequency sweep + Shear stress; Start frequency: 0.01 Hz; End frequency: 100.0 Hz.

Results: The results show that the gels exhibited shear thinning behavior. The identified Critical Quality Attributes were- Order of addition of excipients, duration of mixing times, in the Bench Scale and A1 batches electrolyte was added at the end of preparation of the gel with the API and was neutralized at the end. Whereas the A2 and A3 batches the number of steps increased as the gel was pre-wetted with electrolyte solution and then partially neutralized, followed by addition of the surfactant and API, and in the end the gel was completely neutralized as a second stage neutralization to bring the pH to 6.5. Increasing the number of additions impacted other CQAs, i.e, increase the mixing times and increased the homogenization time for the API to be suspended homogenously uniform across the microstructure of the drug product. All these identified parameters are critical in the manufacturing of a hydrogel and these parameters were analyzed for their rheological behavior analysis to quantify them in failure mode effective analysis (FMEA) to risk mitigate during scale ups.

Conclusion: The CQAs of Carbomer based hydro gel was studied by establishing critical process parameters (CPP’s) in the unit operations such as mixing (speed & time), homogenization (speed & time) and number of addition steps impacting the microstructure of the drug product and shall result in instabilities over time. These key parameters were quantified using rheological characterization as process analytical technique in establishing the right parameter attributes and helped in finalizing the manufacturing process in establishing the robust drug product.

FIGURE 1: Shear rate Vs Equilibrium Flow Curve, Yield stress- Shear Stress ramp and Storage and loss modulus vs Frequency.

FIGURE 2: Shear rate Vs Equilibrium Flow Curve, Yield stress- Shear Stress ramp

FIGURE 3: Storage and loss modulus vs Frequency