QbD In Extended Topicals Perrigo Israel Pharmaceuticals

Transcription

1 QbD In Extended Topicals Perrigo Israel Pharmaceuticals May 21, 2014 Michal Arnon Formulation R&D Manager B. Pharm, MBA

2 QbD Systematic Approach Predefined Objectives Product and Process Understanding Control Based on Quality Risk Management

3 QbD Development Be systemic See the big picture Work Systematically Based on continuous updated risk assessments

4 Ointment Drug Product

5 Ointment Drug Product The API is homogeneously dispersed in the ointment Contains 2 inactive ingredients: Liquid ingredient (15-20% of the ointment) Semisolid ingredient

6 Risk Assessment of Manufacturing Process Effect on CQA's Weighing the Ointment Base Method of Suspending the API Manufacturing Temperature Bulk Cooling Process Bulk Discharge Temperature Appearance High Low High Low Low Assay Low High High Low Low Homogeneity High High High Low High Degradation products Low High High Low Low Viscosity High Low Low High High Microscopic view Low High High Low Low

7 Ointment that contains a large amount of API Objectives: To find the best optional vehicle for the API suspending process, Liquid component of the ointment base or the entire ointment base. To understand the effect of mixing and homogenizing on the API dispersion.

8 DOE Study Design Factors: 1) Dispersion base: Liquid Component or the entire ointment base 2) Mixing Duration: 15 or 120 minutes 3) High Shear Mixing Duration: 0 or 5 or 15 minutes at 23m/s (at 75 C)

9 Batch # Vehicle for API Dispersion Process Mixing Duration (min) High Shear Mixing Duration (min) Ointment base Ointment base Ointment base Liquid Component Liquid Component Liquid Component Liquid Component 15 0 Liquid Component 15 5 Liquid Component Ointment base 15 0 Ointment base 15 5 Ointment base 15 15

10 1 Ointment base Mixing: 120 min. 2 Liquid Component Mixing: 120 min. Microscopic View - Results High Shear Mixing Duration 0 min 5 min 15 min 3 Liquid Component Mixing: 15 min. 4 Ointment base Mixing: 15 min.

11 Conclusions API should be dispersed in the liquid component, first. High shear mixing of the API up to 15 minutes in lab batches, does not affect the microscopic view of the drug product.

12 Foam Drug Product

13 Foam NDA Drug Product Foam products contains: Bulk Product and valve Gas Dip tube yes/no Applicator

14 Selecting Gas Type Packaging Process Effect on CQA's Bulk Heating Temperature Propellant Type Propellant Concentration Bath Temp. and duration Appearance Low High High Low Assay High Low Low Low Imp. High Low Low Low Homogeneity Low Low Low Low Delivery Amount High High High Low Shelf Life High High High Low

15 DOE Study Design Objectives: 1.To find the effect of different gas types on appearance and delivery amount. 2.To find the effect of packaging temperature on delivery amount. 3.To find out if there are any interactions between gas type and packaging temperature on delivery amount. Factors: 1. Filling Temperature: 55 or 80 C 2. Gas Type: 1 or 2 or 3

16 Results Delivery Amount Type 1 Type 2 Type 3

17 Appearance 3.0 Interval Plot of appearance 95% CI for the Mean 1. Liquid foam 2. Tends to liquefy 3. Stable soft foam 4. Dry foam appearance gas testing time (days) Pck temp IB-95 IP-27 PIB IB-95 IP-27 PIB IB-95 IP-27 PIB IB-95 IP-27 PIB

18 Conclusions Gas types 2 and 3 suit the product appearance and deliverable amount. Studies should continue to test the effect on other product attributes; Chemical, and microbial attributes.

19 Vaginal Cream

20 Tech Transfer of Vaginal Cream The cream product is manufactured inside a mixer. Then, it is discharged from the mixer through a high shear mixer. Discharging speed is controlled by pump speed. IPC of viscosity for the bulk product. Wide range of operating parameters for pump and high shear mixer speeds. Viscosity range of the bulk product: 600,000-1,200,000 cp Low Yield

21 Study Design Objective: Setting parameters for pump and high shear mixer speeds that would result in the desired viscosity. Viscosity Specifications: 600,000-1,200,000cp Factors: Pump: 20 or 40 Hz. Homogenizer: 1450 or 1550 or 1650 rpm

22 Results Interval Plot of Viscosity (cp) 95% CI for the Mean Viscosity (cp) Pump (Hz) PC (RPM)

23 Focused Study Design Study 2, Factors: Pump: 10 or 20 Hz. Homogenizer: 1600 or 1650 or 1700 rpm

24 Results Interval Plot of Viscosity 95% CI for the Mean Viscosity (Cp) Pump (Hz) PC (RPM)

25 Recommended Parameters Suggested factors to start with: Pump: 10hz High Shear mixing: 1600 rpm

26 Take Home Messages Plan short DOE studies 2-3 factors. Make sure to have repeated samples to increase the power of the results. When repetitions are hard to get, pay attention to reduce variability. Involve cross functional departments in risk assessment process from early stages.

27 One thing you can count on

28 Thanks to the Team Tatiana Kamenetsky Liat Barad Lena Kojukarov