Metering Valve Design and Material Selection; How can this be chosen to maximize product performance?

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Johnathan Fisher
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1 Metering Valve Design and Material Selection; How can this be chosen to maximize product performance? B. Grosjean Medical Plastics 2007 Inhalation Devices for Medicine Delivery 2007, 1-2 October 2007, Copenhagen

2 Background Following the phase out of CFCs, HFA propellants were introduced: New formulations with HFA more challenging, not as stable Valve performance affected by new formulations At the same time, new regulatory demands were introduced => As material selection and valve design are critical to valve performance, they needed to be re-evaluated

3 Examples of poor performance New propellants or addition of ethanol in formulations led to more extractables from materials drug degradation, toxic products

4 Examples of poor performance Dose of drug decreased after ageing due to adsorption onto components or absorption by elastomers

5 Examples of poor performance More friction between components: Valve blocked, low dose of drug Etc

6 Metering Valve Technology The role of a metering valve is to: Accurately meter and dispense a dose of propellant based formulation when actuated Provide a suitable closure: minimize propellant evaporation & moisture ingress

7 Metering Valve Technology Metering valves are typically made out of plastic, rubber and/or metal Ring Ferrule Spring Component Plastic or metal components Functional gaskets Sealing gasket Stainless steel, Acetal resin (POM), Polybutylene terephtalate (PBT) Polyethylene, Polyamide (Nylon) Nitrile, Butyl, EPDM*, Polychloroprene Aluminum Stainless steel Material Nitrile, Butyl, EPDM, Polychloroprene, Thermoplastic elastomer (TPE) * Ethylene propylene diene monomer

8 What impacts do materials have on valve performance?

9 Typical Interactions between formulations and components Sticking / adsorption of formulation onto components Absorption of formulation by elastomers => swelling of gaskets Release of material additives into formulation: Potential degradation of active molecule Potential toxic molecules Degradation of active molecule by direct contact with materials Degradation of components: shorter shelf life or decresased resistance

10 Basic Requirements Chemical / physical compatibility with drug formulation Mechanical properties => valve performance (shot weight, prime retention, ageing, robustness, actuation force ) Sealing properties & moisture permeability Regulatory status (including food contact) & extractable profile

11 Material selection for valve mechanism: Plastics High level of constraints in term of physicochemical properties: compatibility with propellant and mechanical resistance (modulus, heat deflection T, hardness) Compliance with relevant 21 CFR & pharmacopoeia + acceptable extractables profile Low surface energy to avoid adsorption => can be optimized with the use of surface treatments (e.g. fluorination) Only two materials used currently: PBT and POM

12 Formaldehyde from acetal resins POMs do release formaldehyde but not all POMs are alike! Formaldehyde / can (µg) Leachable formaldehyde from acetal valve in HFA 134a upon storage at 40 C/75 % RH (n=3) 1 month 3 months 6 months 12 months Copolymer 1 Copolymer 2 Homopolymer 1 Homopolymer 2 Formaldehyde /can (µg) Leachable formaldehyde from acetal valve in HFA 134a + EtOh 15% upon storage at 40 C/75% (n=3) 1 month 3 months 6 months 12 months Copolymer 1 Copolymer 2 Homopolymer 1 Homopolymer 2

13 Material selection for valve mechanism: Metal No extractives Inert surfaces Strong & robust Need to eliminate residues from manufacturing process Limitation in component design (shapes)

Material selection: Gathering ring Guides formulation towards the metering chamber and slows down moisture ingress (if made out of Nylon) 600 EPDM valve moisture uptake / Nylon Ring 134a, storage at

14 Material selection: Gathering ring Guides formulation towards the metering chamber and slows down moisture ingress (if made out of Nylon) 600 EPDM valve moisture uptake / Nylon Ring 134a, storage at 40 C/75% RH 600 EPDM valve moisture uptake / No Ring 134a, storage at 40 C/75% RH Water content (ppm) Water content (ppm) Time (months) Time (months)

Material selection: Rubbers SEALING PROPERTIES REINFORCEMENT OR DILUTION PROCESSING AID, COLD RESISTANCE PROCESSING AID, COLD RESISTANCE CROSSLINK DENSITY PROTECTION AGAINST O2, UV POLYMER

15 Material selection: Rubbers SEALING PROPERTIES REINFORCEMENT OR DILUTION PROCESSING AID, COLD RESISTANCE PROCESSING AID, COLD RESISTANCE CROSSLINK DENSITY PROTECTION AGAINST O2, UV POLYMER FILLERS PLASTICIZER PROCESSING AIDS CURING AGENTS ANTIOXYDANTS - CARBON BLACK - SILICA - CALCINATED CLAY - PETROLEUM OILS - WAX, FATTY ACIDS - SULPHUR - PEROXIDES - ACTIVATORS -PHENOLIC PRODUCT

16 Material selection: elastomers - Extractives: elimination of toxic extracts (e.g. PNAs, Nitrosamines) - Swelling (potential for swelling if strong affinity with propellant mixture) - Mechanical properties + retention of mechanical properties throughout product shelf life - Materials in compliance with relevant regulations (21 CFR chapters, food contact, etc )

17 New alloy gaskets Opportunity for the development of new gaskets: - Mix different base polymers to optimize desired properties (mechanical, barrier, etc ) - Combine advantages of the different polymers -Examples: -BIIR: bromobutyl: good sealing properties, good ageing -HNBR: hydrogenated nitrile: good mechanical properties, suitable swelling in HFA, good ageing -POE: polyolefin elastomer => low extractables level, good ageing

18 Example of material impact #1: evaluation of performance with an alloy

19 Alloy gasket evaluation Selected configuration: Valois DF316 RCU valve with: - Internal gaskets: HNBR/Butyl (mechanical properties, swelling) - Seal gasket: POE/Butyl (extractives profile, water and propellant permeability) Valve mechanical performance evaluation (with propellant & propellant/ethanol mixtures): - Shot weight, force to actuate, prime retention, continuous spray/side streaming (using specific test jigs)

20 Alloy gasket evaluation Shot weight through life of 134a/Ethanol blend (15% EtOH) with Valois DF316 RCU HNBR/Butyl POE/Butyl POM valve Shot weight (mg) Testing at Initial Dose number Shot weight (mg) Testing after 1 40 C/75% RH Unit #1 Unit #2 Unit #3 Unit #4 Unit #5 Target +/- 15% Dose number Unit 1 Unit 2 Unit 3 Unit 4 Unit 5 Target +/- 15% 161

21 Alloy gasket evaluation Valve mechanical performance tests with Valois DF316 RCU HNBR/Butyl POE/Butyl POM valve (134a/Ethanol blend) - Actuation force (after 2.7 mm travel): Newton Force (N) - Prime retention: shot weight retained for up to 48 hours Travel (mm) - No continuous spray / side streaming when evaluated with specific test jigs

22 Example of material impact #2: Compatibility studies

23 Drug compatibility study Immersion testing of components in: - Fluticasone Propionate in 134a / Ethanol / Glycerol - Formoterol Fumarate in 134a / Ethanol / IPM / HCl Monitoring of total can assay: % drug recovered vs. initial theoretical drug content Testing conditions maximize contact between components & formulation (Not an inhaler simulation)

24 Component compatibility study: Fluticasone solution % Fluticasone Recovery 0 Control Chloroprene nitrile EPDM HNBR/Butyl POE/Butyl APE POM, homopolymer POM, copolymer PBT Nylon 66 Spring (stainless steel) Initial 3 C/75%RH

25 Spring Component compatibility study: Formoterol solution Formotero recovery (%) 20 0 Control Chloroprene Nitrile EPDM HNBR/Butyl POE/Butyl APE POM homopolymer POM copolymer PBT PolyAmide 0 2 C/75%RH 5 C/75%RH

26 Drug compatibility study Drug disappearance is highest when nitrile base polymer is used (alone or as an alloy) No significant contribution of thermoplastics or thermoplastic elastomers No degradation product observed in this study when running the drug assay: where is the drug? Nitrile is the elastomer of highest polarity and is the material that swells the most in HFA/Ethanol amongst those tested

27 How to select a valve design?

28 Standard Valve Design: retention chamber No major design change introduced in valves used on marketed inhalers Valves used on marketed inhalers are typically based on retention chambers

29 Rest position

30 Chamber filled and isolated

31 Emission of a dose

32 Chamber is empty and isolated

33 Filling of the chamber

34 Rest position

35 New trends: fast fill / fast drain valves Disadvantages of retention valves: Drain back from chamber to can => loss of prime Contact between chamber components and formulation => loss of drug, interactions

36 New trends: fast fill / fast drain valves Rapid fill/rapid drain of the metered dose (gravity)

37 New trends: fast fill / fast drain valves Advantages: No prolonged contact between the formulation and the walls of the metering chamber No loss of prime by design No need to prime the valve Dose prepared immediately after shaking => better regularity for unstable formulations

38 Performance with Salbutamol formulations 250 Retention - Salbutamol 0% ethanol (unstable / sedimentation) Retention valve - Salbutamol 15% (more stable) % 25% can 1 can 2 can 3 can 4 can % 25% can 1 can 2 can 3 can 4 can # dose # dose Fast fill / fast drain - Salbutamol 0% ethanol (unstable, sedimentation) Fast fill / fast drain - Salbutamol 15% ethanol (more stable) % 25% can 1 can 2 can 3 can 4 can 5 can % 25% can 1 can 2 can 3 can 4 can # dose # dose

39 Performance with Salbutamol formulations Better regularity with more stable formulation (with ethanol) and better regularity with fast fill / fast drain Different evolution of dose from beginning to end of life: effect of sedimentation (higher concentrations of drug at the beginning), loss of drug by sticking on components (evolving sticking with number of doses), concentration of formulation via propellant evaporation

40 Conclusion Many options are available when selecting materials or surface finishes in MDI container/closure system components New options exist and need to be developed with in depth understanding of MDI technology requirements / constraints / interactions with drugs Initial screening with model formulations should help identify suitable components and valve design

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