Metered Dose Inhaler Manufacture

User Requirement
1. General Requirements
No. 1. 2. Description Product contact surfaces - metallic materials of construction. Product contact surfaces - polymeric materials Acceptance Criteria Stainless steel type EN 1.4435 PTFE or PVDF compliant with ASME BPE 2012 Part PM Perfluorelastomer, silicone, or PTFE encapsulated EPDM compliant with ASME BPE 2012 Part PM Compliant with ASME BPE 2012 Table SF2.2-1 Electro-polished to 0.38 micron. Compliant with ASME BPE Table SF-2.4-1 Compliant with ASME BPE 2012 Table SF3.3-1 EN 10204 Type 3.1 OD hygienic tubing - True imperial dimensions Hygienic union couplings compliant with EN 11864 Weir type diaphragm compliant with ASME BPE SG-2.3.1.2

3.

Product contact surfaces - elastomeric materials Product contact surfaces - metallic materials surface condition. Product contact surfaces - metallic materials surface finish. Product contact surfaces - non-metallic materials surface condition. Material certificate of compliance. Product contact piping. Product piping couplings Product contact liquids and clean steam - valves

4. 5. 6. 7. 8. 9. 10.

Note: Product contact surfaces include all clean utilities downstream of the final sterilising grade filter, propellant downstream of the final sterilising grade filter and clean in place systems.

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2. Dispensary Operations
No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. 12. 13. 14. Description Active Ingredient maximum water content Active Ingredient maximum ethanol content Active ingredient drying time. Active Ingredient dryer end point Active Ingredient dryer yield Active ingredient median particle size Active ingredient milling yield Active ingredient CIP fluid Active ingredient CIP fluid flow Active ingredient CIP final rinse liquid. Active ingredient dispensing accuracy Excipient dispensing accuracy Lubricant maximum water content Sweetener maximum water content Flavour maximum water content Acceptance Criteria 2% w/w 1% w/w 15 hours maximum 80oC at 20 mbar abs >98% mass basis 2 micron mass basis >98% mass basis Purified water BP 35 litres/min/m of vessel circumference with a static spray device Purified water BP +/- 0.1% mass basis +/- 0.5% mass basis 1% w/w 0.5% w/w 0.5% w/w

3. Propellant Storage and Distribution

No. 1. 2. 3. 4. 5. 6. 7. 8. 9. Description Design pressure - maximum Design pressure - minimum Design temperature - maximum Design temperature - minimum Tank capacity Temperature of propellant transferred to manufacturing Transfer rate to manufacturing Level indication accuracy Pressure relief requirements Page 2 of 5 Acceptance Criteria Vapour pressure at maximum design temperature plus 1 bar g Full vacuum 50o C -20o C Tanker load plus 5000 litres 20 +/- 1o C To take no more than 20 minutes +/- 1% Duplex pressure relief valve.

No.

Description

Acceptance Criteria Static head 10 m Piping equivalent length 300 m Heat exchanger pressure drop max 0.5 bar To avoid cavitation at all times. Stainless steel type EN 1.4404 Sealess magnetic seal PTFE or EPDM Flanged to BS 4504 Flanged Ball Valves Pre- filter 5 microns Final filter 0.2 micron sterilising grade filter

10.

Pump head

11. 12. 13. 14. 15. 16. 17.

Pump NPSH Piping upstream of sterilising filter - metallic material Pump mechanical seal Piping upstream of sterilising filter - non-metallic material Piping upstream of sterilising filter - piping standard Piping upstream of sterilising filter - valves Propellant filtration

4. Formulation
No. 1. 2. 3. 4. 5. 6. 7. 8. 9. 10. 11. Description Design pressure maximum Design pressure minimum Design temperature maximum Design temperature minimum Maximum batch size Minimum batch size Vessel nominal volume Vessel minimum stirred volume Formulation temperature Dispersion time Mixing requirement Acceptance Criteria Vapour pressure at maximum design temperature plus 1 bar g Full vacuum 100oC -20o C 1000 litres 500 litres To the top of the heat transfer surface 50 litres maximum. Batch shall remain homogeneous at minimum stirred volume. 20 +/- 1oC 10 mins at 400 rpm To achieve full suspension To achieve efficient heat transfer

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No. 12. 13. 14. 15. 16. 17. 18. 19. 20. 21. 22. 23. 24. 25.

Description Heating requirement Cooling requirement In-place cleaning fluid In-place cleaning final rinse In-place cleaning temperature In-place cleaning fluid flow Heat transfer method Maximum pressure drop through heat transfer jacket Maximum variation of propellant concentration during can filling Maximum water concentration in final formulation. Maximum oxygen concentration in final formulation. Maximum nitrogen concentration in final formulation. Vessel drainability Mixing dead spots

Acceptance Criteria Hold at 20oC during formulation and can filling. Hold at 80oC during CIP and drying Cool to 20oC after drying in 30 minutes 2% w/w NaOH in purified water BP Purified water BP 80 +/- 1oC 35 litres/min/m of vessel circumference with a static spray device External dimpled jacket covering shell and bottom head. 0.5 bar g +/- 1% of propellant concentration 0.5% w/w 0.1% w/w 0.1% w/w Fully drainable with no pools greater than 5 mm diameter after draining. No mixing dead spots, vessel surface shall be flush below the liquid level including the bottom outlet.

5. Can Filling
No. 1. 2. 3. 4. 5. 6. Description Can purge Filling temperature Filling rate Rejects Samples Function testing Acceptance Criteria 2 can volumes minimum 20 +/- 1oC 30 cans per minute 2% maximum 1 per 1000 cans 3 valve actuations

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No. 7. 8.

Description Maximum air concentration Maximum water content

Acceptance Criteria 1% w/w 1% w/w

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