Understanding and Addressing Variability in Pharmaceutical Manufacture

1. Understanding and Addressing Variability in Pharmaceutical Manufacture Ross Errington - 3M Health Care Ltd 10 years working in Scale Up, Optimisation and technical support of metered dose inhalers

2. What is the approach • A Systematic methodology focusing on problem solving & continuous improvement of existing processes • This methodology is used to: • Promote continuous improvement • Correct and prevent defects • Improve business processes and performance • A data- and fact-driven approach versus a traditionally intuitive approach

3. Application Metered Dose Inhaler Waste Reduction Valve Performance Improvement

4. Metered Dose Inhalers • Used widely in the treatment of Asthma • Valve on aerosol delivers a metered dose of formulation from the can • Can has both excipients and propellant • Devices vary as to requirements of patient & drug

5. Aerosol Filling • 2 types: Pressure & Cold • Example based on Cold Filling • Formulation chilled to approximately -60ºC • Poured into can as liquid • Sealed with valve (container closure system) • Allowed to equilibrate to room temperature

6. Historical Performance

7. INPUT INPUT INPUT INPUT INPUT OUTPUT OUTPUT OUTPUT OUTPUT OUTPUT How do we get the right information ? • Map the Process

8. How do we get the right information ? • Identify critical inputs and outputs • Rank these critical parameters

9. Fault Identification Detailed log of reason why production line stopped

10. Impact of Water Bath The water bath stresses the units filled at –55 °C by putting them in water at +55 °C for 2.5 minutes – not all products require this

11. Impact of Bottle Size 3 main bottle types – main difference is the centre of gravity

12. Crew Impact Crew on shift in the Aerosol Module does not impact the number of stoppages

13. Process Improvements • As a result of the Fault Identification process a combination of changes were completed • Transactional Changes • Focused on ‘how’ we operate the line • Improved work instructions • Clear definition of roles and responsibilities • Engineering Changes • Focused on improving ‘design’ of handling equipment • Redesign & replacement of key line components • Improved planned maintenance procedures

14. Final Performance – Stops/1000 Aerosols

15. Stem Stainless Steel Diaphragm Nitrile Ferrule Aluminum Tank Stainless Steel Gasket Copolymer or Nitrile Spring Stainless Steel Seal Nitrile Bottle Emptier Stainless Steel MDI Valve Manufacture

16. Historical Performance Individual value = measurement of gap between components

17. Key Performance Inputs Key Performance Measure Gage R&R Study Sample Difference 1 2 3 4 Operator Difference 1 2 3 4

18. Designed Experiment Data Analysis Aim: Maximise Performance Characteristic Performance Component Shape Seal Change

19. 0 . 0 4 U C L = 0 . 0 3 8 2 4 e u 0 . 0 3 l _ a V X = 0 . 0 2 4 2 8 l a 0 . 0 2 u d i v i 0 . 0 1 L C L = 0 . 0 1 0 3 1 d n I 0 . 0 0 1 7 1 4 2 1 2 8 3 5 4 2 4 9 5 6 6 3 O b s e r v a t i o n 0 . 0 2 4 e g 0 . 0 1 8 n U C L = 0 . 0 1 7 1 5 a R g 0 . 0 1 2 n i v o _ _ M 0 . 0 0 6 M R = 0 . 0 0 5 2 5 0 . 0 0 0 L C L = 0 1 7 1 4 2 1 2 8 3 5 4 2 4 9 5 6 6 3 O b s e r v a t i o n Final Process Performance M i n G A P C a p a b i l i t y : P p k = 0 . 6 0 P p k = 1 . 5 5 1

20. Framework for a Project